A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Comparing the Efficacy and Safety of Tirzepatide Versus Placebo in Patients With Heart Failure With Preserved Ejection Fraction and Obesity (SUMMIT)
Phase: PHASE3
Conditions: Obesity, Heart Failure With Preserved Ejection Fraction (HFpEF)
Sponsor: Eli Lilly and Company

Protocol: I8F-MC-GPID 
 
 
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Comparing the Efficacy and 
Safety of Tirzepatide versus Placebo in Patients with Heart Failure with Preserved Ejection 
Fraction and Obesity (SUMMIT) 
 
 
NCT04847557 
 
 
Approval Date: 14-Feb-2024 

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I8F-MC-GPID(c) 
 
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Title Page  
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of tirzepatide (LY3298176), unless such persons are bound by a confidentiality agreement with Eli Lilly and Company 
or its subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Comparing 
the Efficacy and Safety of Tirzepatide versus Placebo in Patients with Heart Failure with 
Preserved Ejection Fraction and Obesity (SUMMIT) 
Protocol Number: I8F-MC-GPID 
Amendment Number: c 
Compound: LY3298176 
Study Phase: 3 
Short Title: Tirzepatide vs Placebo in Obesity-related HFpEF  
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Manufacturer: Eli Lilly and Company 
Regulatory Agency Identifier Number 
IND: 147352 
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-120976  
 
 
 
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Medical Monitor Name and Contact Information will be provided separately.  
 
 
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Amendment (b) 
21-Jan-2022 
Amendment (a)  
15-Dec-2021 
Original Protocol 
13-Jan-2021 
Amendment c 
This amendment is considered to be substantial. 
The amendment is considered to be substantial because of the change in design and 
methodology, and revision to the primary endpoints, which impacts the scientific value of the 
study. 
 
Overall Rationale for the Amendment: 
The purpose of this protocol amendment is to revise the dual primary endpoints.  
Given the significant weight loss, and associated cardiometabolic improvements, achieved with 
tirzepatide, assessment of CV death and HF events, in addition to KCCQ score as a primary 
endpoint, offers the unique opportunity to evaluate tirzepatide for the benefit of patients with 
HFpEF and obesity. The dual primary endpoints described in GPID Protocol Amendment (b) 
may not be able to capture the full potential benefit offered by tirzepatide in this patient 
population. 
Additionally, this amendment broadens the heart failure endpoint definition based on growing 
evidence that supports outpatient intensification of oral diuretics indicating worsening of HF. 
This change results in a new definition of HF event, defined as worsening symptoms or signs of 
HF, which are treated either as an inpatient (by hospitalization, treated by oral or IV diuretic 
intensification) or as an outpatient (by IV or oral diuretic intensification). 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
3. Objectives and Endpoints 
Revised primary endpoints to 
 Change from baseline 
to Week 52 in the 
KCCQ-CSS 
 Occurrence of the 
composite endpoint of 
CV death and/or HF 
events over time 
Assessment of CV death and 
HF events, in addition to 
change from baseline to Week 
52 in the KCCQ-CSS score as a 
primary endpoint, offers the 
unique opportunity to evaluate 
tirzepatide for the benefit of 
patients with HFpEF and 
obesity. 
The hierarchical components 
using the win ratio were 
removed from alpha-adjusted 
endpoints as they present 
significant complexity in 
analytics and interpretation 
 
Key secondary endpoints 
revised to  
 change from baseline 
to Week 2452 in 
6MWD 
 percent change from 
baseline to week 52 in 
body weight 
 Change from baseline 
to Week 52 in hsCRP 
 NYHA class change 
at week 52 
 Change from baseline 
to week 52 in the 
KCCQ-CSS 
Revisions aligned with change 
in primary endpoint. hsCRP 
added as key secondary as it is 
considered a clinically 
significant biomarker in HF 
population 
Removed “The maximum 
duration of participation 
depends on when the last 
participant completes 52 
weeks of treatment” from 
Overall Design 
This was duplicated text in 
same section 
EVa, EVb, EVc weeks from 
randomization updated to 
Provides clarity of when the 
extended visits occur based 
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1.3. Schedule of Activities 
(SoA) 
“(+3, 6, 9, 15, 18, 21 months 
from Visit 12)” 
from Visit 12 and not from 
randomization 
EVd weeks from 
randomization updated to 
“(+12, 24 months from Visit 
12)” 
Provides clarity of when the 
extended visits occur based 
from Visit 12 and not from 
randomization 
“Including product 
complaints” removed from 
adverse events (AEs) row 
Clarification; product 
complaints are not AEs 
Footnote “c” added sentence 
noting that if a participant 
requires a telephone visit, 
they must still pick up study 
drug from the site  
Clarification 
Footnotes “d,” “e,” “f,” “h,” 
“j,” “k,” and “l” text in 
comment column of table 
moved to footnote section 
below SoA 
Editorial 
2.1. Study Rationale 
Revised study objectives 
summary statement relative 
to updated endpoints 
Alignment with updated 
endpoints 
2.2. Background 
Section revised and updated 
to provide additional 
background information and 
references 
Alignment with updated 
endpoints 
3. Objectives and Endpoints Hierarchical composite 
assessed by win ratio moved 
to other secondary endpoint 
Alignment with updated 
endpoints 
NYHA class, exercise 
capacity (6MWD at Week 
24) moved from Key 
Secondary endpoints to Other 
Secondary endpoints 
Exercise capacity analyzed as 
other secondary and NYHA 
class moved as part of the 
revised endpoint strategy 
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Change from baseline to 
Week 24 in KCCQ-CSS 
added to other secondary 
endpoints 
Proportion of participants 
attaining KCCQ-CSS 
meaningful within-patient 
change (MWPC) threshold at 
Week 52 added to other 
secondary endpoints 
MWPC analysis added to 
support KCCQ-CSS  
Exploratory endpoint “HF 
medication use” integrated 
into primary endpoint CV 
death and/or HF event 
Heart failure event definition 
expanded to include oral 
diuretic augmentation; 
therefore, a separate HF 
medication use is no longer 
needed  
Exploratory endpoint 
“Evaluation of prespecified 
biomarkers” hsCRP; moved 
to key secondary endpoint 
Alignment with updated 
endpoints 
 
Added exploratory endpoints: 
 Change from baseline 
to week 52 in waist to 
height ratio 
 eGFR slope 
Alignment with updated 
endpoints 
 
4.1. Overall Design 
Study Closeout and Final 
Visit: study duration revised 
as the duration of the trial 
depends on the last patient 
visit 
Provides guidance to sites 
regarding final visit scheduling 
and expectations 
Study Closeout and Final 
Visit: indicated sponsor will 
notify sites of the study 
closeout based on the visit 
date of the last patient 
randomized 
Provides guidance to sites 
regarding final visit scheduling 
and expectations 
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Study Closeout and Final 
Visit: added statement that 
participants who have 
completed 52 weeks of the 
study are expected to 
complete V99 during the 3-
month period prior to study 
close; no investigational 
product will be dispensed at 
the final visit 
Provides guidance to sites 
regarding final visit scheduling 
and expectations 
Study Closeout and Final 
Visit: added “Any participant 
who has discontinued the 
study prior to completing 52 
weeks of study duration is 
expected to complete an early 
termination visit per the 
SoA.” 
Provides guidance to sites of 
when to schedule final visit for 
participants 
4.2. Scientific Rationale for 
Study Design 
Revised section to provide 
rationale regarding updated 
primary endpoints 
Alignment with revised 
endpoints 
4.4. End of Study 
Definition 
Clarified to indicate that the 
end of the study will occur 
approximately 52 weeks after 
the last participant has been 
randomized 
Clarification 
6.4. Study Intervention 
Compliance 
Compliance revised as 
follows: 
Treatment compliance for 
each visit interval is defined 
as taking at least 75% of the 
required doses of study drug 
Clarification 
6.5. Concomitant Therapy 
Dosage information for 
concomitant therapy of 
special interest updated to 
include drugs for diabetes, 
obesity diuretics, and 
cardiovascular drugs 
Clarification 
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6.6.1. Temporary 
Interruption 
Indicated that for cases where 
increased ALT, AST, or ALP 
occur, close hepatic 
monitoring must be initiated 
Language regarding hepatic 
safety streamlined for clarity 
and consistency 
6.6.2. Restarting Study 
Drug after Interruption 
Added “During re-escalation 
after a temporary dose 
interruption, participants 
should be followed every 4 
weeks until either a new 
lower maintenance dose level 
or prior maintenance dose 
level is reached.” 
Clarification 
Clarified that if an 
unscheduled visit occurs in 
the same week or date of a 
regular scheduled visit per the 
SoA, the site should complete 
all procedures included for 
the regular scheduled visit 
Clarification 
7.1.1. Permanent 
Discontinuation from Study 
Drug 
Revised permanent 
discontinuation to indicate 
that participants who 
permanently discontinue the 
study drug will remain in the 
trial 
Clarification 
Revised discontinuation due 
to hepatic event to reference 
appropriate section 
Clarification 
Added bariatric surgery to 
permanent discontinuation 
circumstances 
Bariatric surgery may pose a 
safety risk to subject taking IP 
Added GLP-1RA to 
permanent discontinuation 
circumstances 
Added as co-administration of 
GLP-1RA and study drug may 
have safety implications to the 
participant 
7.2. Participant 
Discontinuation/Withdrawal 
from the Study 
Added instruction for sites 
regarding participants 
unwilling/unable to return for 
follow-up visits 
Clarification  
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7.3. Lost to Follow up 
Revised section to include 
updated instructions to sites 
regarding determination of 
participant vital status 
Clarification to guide sites to 
continue attempts to reach 
participants until end of study 
8.1.1. Primary Efficacy 
Assessment 
Updated primary efficacy 
assessment to KCCQ-CSS 
and CV death and/or HF 
event 
Alignment with revised 
primary endpoints 
Hierarchical composite 
assessed by win ratio moved 
to other secondary endpoint 
Alignment with updated 
endpoints 
6MWT moved to Section 
8.1.2 
Alignment with revised 
primary endpoints 
Removed Time to All-Cause 
Mortality 
Alignment with revised 
primary endpoints 
8.1.1.2. Kansas City 
Cardiomyopathy 
Questionnaire 
Addition of information 
regarding KCCQ collection at 
V8, V12, and ET 
Clarification  
8.1.1.2. Definition of Heart 
Failure Events 
Revised definition of HF 
events to include outpatient 
intensification of oral 
diuretics due to HF events 
Alignment with revised 
primary endpoints 
8.1.2. Secondary Efficacy 
Assessments 
Revised section header to 
“Additional Secondary 
Efficacy Assessments” 
Clarification 
Addition of information 
regarding 6MWT collection 
at V8, V12, and ET 
Clarification 
Revised secondary endpoint 
“Body Weight” to include 
hsCRP; revised section 
subheader: “Body Weight 
and hsCRP”  
hsCRP assessment added to 
align with change to key 
secondary endpoints 
8.1.3. Exploratory Efficacy 
Assessments 
Moved NYHA Classification 
from Secondary Efficacy 
Alignment with revised 
primary and secondary 
endpoints 
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Assessments to Exploratory 
Efficacy Assessments 
8.2.5.1. Hepatic Safety 
Monitoring, Evaluation, and 
Criteria for Study Drug 
Interruption or 
Discontinuation 
Section header updated, 
addition of tables for hepatic 
safety monitoring which 
indicate when to initiate close 
hepatic monitoring, 
comprehensive evaluation, or 
interrupt or discontinue study 
drug 
Updated to current Lilly 
procedures. No major changes  
8.2.5.2. Close Hepatic 
Monitoring 
Separate section header 
created, removed table, 
addition of CBC with 
differential to laboratory tests 
Clarification 
8.2.5.3. Comprehensive 
Hepatic Evaluation 
Separate section header 
created, removed table 
Clarification 
8.2.5.4. Study Drug 
Interruption or 
Discontinuation due to a 
Hepatic Event 
Section added; additional 
instruction provided 
regarding study drug 
interruption or 
discontinuation 
Clarification 
8.3.1. Timing and 
Mechanism for Collecting 
Events 
Pregnancy reporting 
mechanism and back-up 
mechanism updated to 
pregnancy paper form eCRF 
and pregnancy paper form 
respectively 
Correction 
8.3.2. Primary, Secondary, 
and Additional Study 
Endpoint Reporting 
Revised “hospitalization for 
HF or an urgent HF visit” to 
“HF events” 
Alignment with revised 
primary and secondary 
endpoints 
8.4. Treatment of Overdose 
Removed reference to IB 
Template update 
Definition of overdose 
updated to injection of study 
drug more than 1 time in 72 
hours 
Correction and clarification 
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Revised required investigator 
action in the event of an 
overdose 
Correction and clarification 
9.1. Statistical Hypotheses 
Revised primary hypotheses 
to 
 tirzepatide MTD is 
superior to placebo 
for the change from 
baseline in KCCQ-
CSS at Week 52 
 tirzepatide MTD is 
superior to placebo 
for the occurrence of 
the composite 
endpoint of CV death 
and/or HF events over 
time 
Alignment with revised 
primary endpoints 
Revised key secondary 
hypotheses to that tirzepatide 
MTD is superior to placebo 
with regards to: 
 change from baseline 
in 6MWD at Week 
2452 
 percent change from 
baseline in body 
weight at Week 52 
 change from baseline 
in hsCRP at Week 52 
Alignment with revised 
endpoints 
Revised statistical methods 
related to updated primary 
and key secondary endpoints 
Alignment with revised 
primary and key secondary  
endpoints 
9.2. Sample Size 
Determination 
Updated sample size 
justification description as 
related to revised primary 
endpoints 
Alignment with revised 
primary endpoints 
9.4.2. Primary Endpoint(s) 
Revised statistical methods 
related to primary endpoints; 
removed hierarchical 
Alignment with revised 
primary endpoints 
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composite endpoint and 
change in 6MWD, added 
KCCQ-CSS (9.4.2.1) and HF 
outcomes (9.4.2.2) 
9.4.3. Key Secondary 
Endpoint(s) 
Revised statistical methods 
related to key secondary 
endpoints:  
 KCCQ-CSS endpoint 
moved to primary 
endpoint 
 6MWD revised from 24 
weeks to 52 weeks 
 Analysis method of 
percent change in body 
weight revised from 
MMRM to ANCOVA 
 NYHA class removed 
 hsCRP endpoint added 
(ANCOVA analysis) 
Alignment with revised key 
secondary endpoints and 
correct analysis method 
appropriate for the estimand 
9.4.4. Tertiary/Exploratory 
Endpoint(s) 
“Other secondary” removed 
from section 
Alignment with revised 
secondary endpoints 
10.4.2. Female participants 
Revised contraception 
requirement from 2 months 
after the last administration of 
study drug to 4 weeks 
Update to align with 
Investigator’s Brochure 
Throughout the protocol 
Minor editorial corrections, 
minor clarifying changes 
Minor editorial changes, 
therefore not described; 
clarification 
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Table of Contents  
1. 
Protocol Summary ........................................................................................................16 
1.1. 
Synopsis ..........................................................................................................................16 
1.2. 
Schema ............................................................................................................................18 
1.3. 
Schedule of Activities (SoA) ..........................................................................................19 
2. 
Introduction ...................................................................................................................42 
2.1. 
Study Rationale ...............................................................................................................42 
2.2. 
Background .....................................................................................................................42 
2.3. 
Benefit/Risk Assessment ................................................................................................43 
3. 
Objectives and Endpoints ............................................................................................44 
4. 
Study Design ..................................................................................................................47 
4.1. 
Overall Design ................................................................................................................47 
4.2. 
Scientific Rationale for Study Design ............................................................................49 
4.2.1. 
Patient Input into Design ................................................................................................50 
4.3. 
Justification for Dose ......................................................................................................50 
4.4. 
End of Study Definition ..................................................................................................50 
5. 
Study Population ...........................................................................................................51 
5.1. 
Inclusion Criteria ............................................................................................................51 
5.2. 
Exclusion Criteria ...........................................................................................................53 
5.3. 
Lifestyle Considerations .................................................................................................55 
5.4. 
Screen Failures ................................................................................................................55 
6. 
Study Intervention ........................................................................................................57 
6.1. 
Study Interventions Administered ..................................................................................57 
6.1.1. 
Medical Devices..............................................................................................................58 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................58 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................59 
6.4. 
Study Intervention Compliance ......................................................................................59 
6.5. 
Concomitant Therapy .....................................................................................................60 
6.6. 
Dose Modification ..........................................................................................................63 
6.6.1. 
Temporary Interruption ...................................................................................................63 
6.6.2. 
Restarting Study Drug after Interruption ........................................................................64 
6.7. 
Intervention after the End of the Study ...........................................................................65 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................66 
7.1. 
Discontinuation of Study Intervention ............................................................................66 
7.1.1. 
Permanent Discontinuation from Study Drug.................................................................66 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................67 
7.2.1. 
Inadvertently Enrolled Participants.................................................................................68 
7.3. 
Lost to Follow up ............................................................................................................68 
8. 
Study Assessments and Procedures.............................................................................70 
8.1. 
Efficacy Assessments .....................................................................................................70 
8.1.1. 
Primary Efficacy Assessment .........................................................................................70 
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8.1.2. 
Secondary Efficacy Assessments ....................................................................................71 
8.1.3. 
Exploratory Efficacy Assessments .................................................................................72 
8.2. 
Safety Assessments .........................................................................................................73 
8.2.1. 
Physical Examinations ....................................................................................................73 
8.2.2. 
Vital Signs .......................................................................................................................73 
8.2.3. 
Electrocardiograms .........................................................................................................74 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................74 
8.2.5. 
Safety Monitoring ...........................................................................................................75 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................78 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................79 
8.3.2. 
Primary, Secondary, and Additional Study Endpoint Reporting ....................................81 
8.3.3. 
Adverse Events of Special Interest .................................................................................82 
8.4. 
Treatment of Overdose ...................................................................................................82 
8.5. 
Pharmacokinetics ............................................................................................................82 
8.6. 
Pharmacodynamics .........................................................................................................83 
8.7. 
Genetics ..........................................................................................................................83 
8.8. 
Biomarkers ......................................................................................................................83 
8.9. 
Immunogenicity Assessments.........................................................................................84 
8.10. 
Medical Resource Utilization and Health Economics ....................................................84 
9. 
Statistical Considerations .............................................................................................85 
9.1. 
Statistical Hypotheses .....................................................................................................85 
9.2. 
Sample Size Determination ............................................................................................85 
9.3. 
Populations for Analyses ................................................................................................86 
9.4. 
Statistical Analyses .........................................................................................................86 
9.4.1. 
General Considerations ...................................................................................................86 
9.4.2. 
Primary Endpoint(s) ........................................................................................................86 
9.4.3. 
Key Secondary Endpoint(s) ............................................................................................87 
9.4.4. 
Tertiary/Exploratory Endpoint(s)....................................................................................88 
9.4.5. 
Other Safety Analyses.....................................................................................................88 
9.4.6. 
Subgroup Analyses .........................................................................................................88 
9.5. 
Interim Analyses .............................................................................................................88 
9.6. 
Data Monitoring Committee ...........................................................................................89 
10. 
Supporting Documentation and Operational Considerations ..................................90 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................90 
10.1.1. Regulatory and Ethical Considerations ...........................................................................90 
10.1.2. Financial Disclosure........................................................................................................90 
10.1.3. Informed Consent Process ..............................................................................................91 
10.1.4. Data Protection................................................................................................................91 
10.1.5. Dissemination of Clinical Study Data.............................................................................91 
10.1.6. Data Quality Assurance ..................................................................................................92 
10.1.7. Source Documents ..........................................................................................................93 
10.1.8. Study and Site Start and Closure ....................................................................................94 
10.1.9. Publication Policy ...........................................................................................................94 
10.1.10. Long-Term Sample Retention.........................................................................................94 
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10.1.11. Investigator Information .................................................................................................95 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................95 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................98 
10.3.1. Definition of AE .............................................................................................................98 
10.3.2. Definition of SAE ...........................................................................................................99 
10.3.3. Definition of Product Complaints .................................................................................101 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ....................................................................................................................101 
10.3.5. Reporting of SAEs ........................................................................................................103 
10.3.6. Regulatory Reporting Requirements .............................................................................103 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information .................................................................................................104 
10.4.1. Male participants:..........................................................................................................104 
10.4.2. Female participants: ......................................................................................................104 
10.5. 
Appendix 5: Adverse Events of Special Interest: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and 
Reporting. .....................................................................................................................108 
10.5.1. Special Safety Topics ....................................................................................................108 
10.6. 
Appendix 6: Genetics....................................................................................................113 
10.7. 
Appendix 7: Recommended Laboratory Testing for 
Hypersensitivity Events ................................................................................................114 
10.8. 
Appendix 8: Liver Safety: Suggested Actions and Follow-Up 
Assessments ..................................................................................................................116 
10.9. 
Appendix 9: Medical Device Adverse Events (AEs), Adverse 
Device   Effects (ADEs), Serious Adverse Events (SAEs) and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .........................................................................118 
10.10. 
Appendix 10: Six-Minute Walk Test Screening Procedures ........................................119 
10.10.1. Screening Procedures and Flow Diagram .....................................................................119 
10.11. 
Appendix 11: New York Heart Association Classification of 
Heart Failure .................................................................................................................120 
10.12. 
Appendix 12: Abbreviations .........................................................................................121 
10.13. 
Appendix 13: Protocol Amendment History ................................................................126 
11. 
References ....................................................................................................................131 
 
 
 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Comparing 
the Efficacy and Safety of Tirzepatide versus Placebo in Patients with Heart Failure with 
Preserved Ejection Fraction and Obesity (SUMMIT) 
Short Title: Tirzepatide vs Placebo in Obesity-related HFpEF 
Rationale: 
Heart failure with preserved ejection fraction is a heterogenous clinical syndrome resulting from 
various pathophysiological processes. Among the broad spectrum of HFpEF clinical 
presentation, obesity-related HFpEF displays a distinct phenotype where increased visceral and 
ectopic adiposity as well as volume expansion plays a causal role (Kitzman and Shah 2016; 
Packer 2018; Miller and Borlaug 2020). Given tirzepatide’s anti-inflammatory and antifibrotic 
effects and a reduction in circulating plasma volume as a consequence of the treatment of 
obesity, tirzepatide may provide clinical benefit to patients with HFpEF and BMI ≥30 kg/m2.  
Study I8F-MC-GPID, also known as SUMMIT, is a Phase 3, randomized, multicenter, 
international, placebo-controlled, double-blinded, parallel-arm study. This study will evaluate the 
effect of SC QW injection of tirzepatide, MTD up to 15 mg, on the health status, risk of death, 
HF events, and exercise capacity in participants with HFpEF and BMI ≥30 kg/m2. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To demonstrate that a maximally tolerated 
tirzepatide dose up to 15 mg administered 
SC QW is superior to placebo to improve 
patient-reported symptoms and physical 
limitations in participants with HFpEF and 
obesity 
Change from baseline to Week 52 in the KCCQ-
CSS 
To demonstrate that a maximally tolerated 
tirzepatide dose up to 15 mg administered 
SC QW is superior to placebo based on the 
composite HF outcome endpoint in 
participants with HFpEF and obesity 
Occurrence of the composite endpoint of CV 
death and/or HF events over time 
Key Secondary (multiplicity controlled) 
 
Exercise capacity  
Change from baseline to Week 52 in 6MWD  
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Long-term weight loss 
Percent change from baseline to Week 52 in 
body weight 
Evaluation of change in inflammation 
Change from baseline to Week 52 in hsCRP 
Abbreviations: 6MWD = 6-minute walk distance; CV = cardiovascular; HF = heart failure; HFpEF = heart failure 
with preserved ejection fraction; KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire – Clinical Summary 
Score; QW = once weekly; SC = subcutaneous. 
Overall Design 
Study GPID is a randomized, outpatient, multicenter, international, placebo-controlled, double-
blind, parallel-arm, Phase 3 study with 2 study periods. The study is designed to evaluate the 
efficacy and safety of SC QW tirzepatide, MTD up to 15 mg, compared to placebo, in 
participants with HFpEF and obesity.  
Two intervention groups will be studied:  
 Tirzepatide, MTD up to 15 mg, SC QW 
 Placebo 
The starting dose of tirzepatide is 2.5 mg QW, which is to be escalated at 4-week intervals to a 
maximum of 15 mg QW or to the highest maintenance dose tolerated by the participant (see 
Section 6).  
Disclosure Statement: This is a parallel-treatment study with 2 intervention groups that is 
double blinded. 
Number of Participants: 
Approximately 700 participants will be randomly assigned to study drug with approximately 
350 participants per intervention group. 
Intervention Groups and Duration: 
The study will compare treatment with tirzepatide and treatment with placebo. Assignment to 
tirzepatide or placebo groups will be randomly allocated in a 1:1 ratio.  
The starting dose of tirzepatide 2.5 mg QW is to be escalated to 15 mg QW or the highest 
maintenance dose tolerated by the participant (5 mg, 10 mg, QW). 
Study participation for each participant is sectioned into the following study periods: 
 Study Period 1: screening period, approximately 6 weeks and not more than 12 weeks 
 Study Period 2: treatment period, at least 52 weeks 
The study will continue until approximately 52 weeks after the last participant is randomized. 
The maximum duration of an individual’s participation is estimated to be 120 weeks and will 
depend on duration of study enrollment. 
Data Monitoring Committee: Yes 
 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
18 
1.2. 
Schema  
 
 
Abbreviations: HF = heart failure; QW = weekly.  
 
Note: Screening procedures may take longer or shorter than 6 weeks but no more than 12 weeks.  
 
 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
19 
1.3. 
 Schedule of Activities (SoA)  
Visit 1 and 2 procedures may be conducted over more than 1 day each as long as all activities are completed within the allowable visit 
interval tolerance for each visit.   
For early terminations (ET) from the study that occur before the final visit (V99) in treatment period, see the activities listed for ET in this 
table.  
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion criteria, 
review and 
confirm 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
20 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preexisting 
conditions and 
medical history, 
including relevant 
surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
21 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Prespecified 
medical history 
(indication and 
history of interest) 
X 
 
 
 
 
 
Includes HF history, 
hospitalization for HF, 
CVD, MI, atrial 
fibrillation, stroke, CV 
risk (T2DM, HTN, 
dyslipidemia, metabolic 
syndrome) 
Prior treatments 
for HFpEF 
X 
 
 
 
 
 
Substance use 
(alcohol, tobacco 
use) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
22 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Concomitant 
medications 
X 
X 
X 
X X 
X 
X 
X 
X 
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 
X 
X 
X 
X 
X 
X 
Physical Evaluation 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Waist 
circumference 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
23 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Vital Signs 
X 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Include 2 Sitting BP and 
HR. HR to be performed 
by apical auscultation. 
Vital signs should be 
collected prior to the first 
6MWT of the day and 
before ECG. 
Physical 
examination 
X 
X 
 
X 
 
 
 
X 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
24 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Symptom-directed 
physical 
examination 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
As indicated based on 
participant status and 
standard of care, 
including dyspnea, 
orthopnea, paroxysmal 
nocturnal dyspnea 
(PND), edema, jugular 
venous distension (JVD), 
rales 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
25 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
NYHA class 
assessment 
X 
X 
X 
X 
 
X 
 
 
 
X
d 
NYHA class assessment 
must be performed by an 
independent assessor.  
See footnote d. 
HF events 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Evaluation of 
injection site 
reactions 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
26 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Single-read 12-
lead ECG 
X 
X 
X 
X 
 
 
 
 
 
X
d 
Collect locally. Report 
atrial fibrillation or other 
abnormalities on the 
eCRF. Optional ECG is 
allowable if indicated. 
See footnote d 
Echocardiography 
X 
 
 
 
 
 
For those required to 
complete the ECHO 
examination 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
27 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Dilated 
fundoscopic 
examination 
X 
 
 
 
 
 
Perform for participants 
with T2DM who have 
not had an evaluable 
dilated fundoscopic 
examination in the last 
12 months. See 
exclusion criterion 25 
(Section 5.2) 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
28 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Follow-up dilated 
fundoscopic examination 
should be performed 
when clinically indicated 
by any AE suspected of 
worsening retinopathy. 
6MWT 
Xe 
X
f 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X
d 
 
Ensure that participant 
completes the associated 
Borg Questionnaire prior 
to and after the 6MWT. 
See footnotes e, f, and d 
Participant Education 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
29 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Diary instruction 
X 
 
 
 
 
 
 
 
Participant Diary 
Participant diary 
dispensed 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
 
 
 
Diary compliance 
check/Assess 
study drug 
complianceg 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
Diary return 
X 
X X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
Patient-Reported Outcomes (PROs) (Electronich) 
See footnote h 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
30 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Kansas City 
Cardiomyopathy 
Questionnaire 
(KCCQ) 
X 
X 
X 
X 
 
 
 
 
 
X 
EQ-5D-5L 
X 
X 
X 
 
 
 
 
 
X 
Patient Global 
Impression of 
Status – Overall 
(PGIS-Overall) 
X 
X 
X 
X 
 
 
 
 
 
X 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
31 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Patient Global 
Impression of 
Status – Physical 
Function (PGIS-
Physical Function) 
X 
X 
X 
X 
 
 
 
 
 
X 
Patient Global 
Impression of 
Status – Symptom 
Severity (PGIS-
Symptom 
Severity) 
X 
X 
X 
X 
 
 
 
 
 
X 
Laboratory Tests and Sample Collections 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
32 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Hematology 
 
X 
X 
X 
X 
X 
 
X 
Xi 
Xi 
 
X 
X 
See footnote i 
Hemoglobin A1c 
(HbA1c) 
X  
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
Clinical chemistry 
(with glucose) 
X 
X
j 
X 
X 
X 
 
X 
Xi 
Xi 
 
X 
X 
See footnote j 
Lipid panel 
X  
X
j 
X 
X 
X 
 
X 
Xi 
Xdi 
 
X 
X 
See footnote j 
Thyroid-
stimulating 
hormone (TSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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CONFIDENTIAL 
I8F-MC-GPID(c) 
 
33 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Serum pregnancy 
X  
X
k 
 
 
 
 
 
For women of 
childbearing potential 
only. See Appendix 
4 (Section 10.4). 
See footnote k 
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I8F-MC-GPID(c) 
 
34 
Urine pregnancy 
(local) 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
A local urine pregnancy 
test must be performed at 
Visit 2 after patient 
eligibility has been 
confirmed with the result 
available prior to 
randomization and first 
injection of study drug(s) 
for WOCBP only. 
Additional local urine 
pregnancy tests may be 
performed at the 
investigator’s discretion 
during the study. If 
required per local 
regulations and/or 
institutional guidelines, 
pregnancy testing can 
also occur at other times 
during the study 
treatment period. See 
Appendix 4 (Section 
10.4). 
Follicle-stimulatin
g hormone (FSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collect FSH only in 
women whose 
menopausal status needs 
to be determined. 
For participants known 
to be either 
premenopausal or 
postmenopausal, these 
tests do not need to be 
collected 
NT-proBNP 
X  
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X
d 
 
See footnote d 
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CONFIDENTIAL 
I8F-MC-GPID(c) 
 
35 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Cardiac troponin T 
(cTnT) 
X 
X 
X 
X 
 
 
 
 
 
X
d 
See footnote d 
Calcitonin 
X  
X 
X 
 
X 
 
 
 
X 
X 
Cystatin C 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X
d 
 
See footnote d 
C-reactive protein, 
high-sensitivity 
(hsCRP) 
X 
X 
X 
X 
 
 
 
 
 
X
d 
See footnote d 
Pancreatic 
amylase 
X  
X
j 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
X 
See footnote j 
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CONFIDENTIAL 
I8F-MC-GPID(c) 
 
36 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Lipase 
X  
X
j 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
See footnote j 
eGFR (CKD-EPI) 
X  
X
l 
X 
X 
X 
 
X 
 
 
 
X 
X 
The CKD-EPI equation 
will be used by the 
central lab to estimate 
and report eGFR. 
See footnote l 
Urinary 
albumin/creatinine 
ratio (UACR) 
X  
X 
X 
 
X 
 
 
 
X 
X 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
37 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Pharmacokinetic 
(PK) samples 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
PK samples should be 
taken prior to dose 
administration at the visit 
and at the same time as 
immunogenicity 
samples. 
Immunogenicity 
samples 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
Stored Samples 
Genetics sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory 
biomarker samples 
X 
X 
X 
X 
 
 
 
 
 
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CONFIDENTIAL 
I8F-MC-GPID(c) 
 
38 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Randomization and Dosing 
Randomization 
X 
 
 
 
 
 
Dispense study 
drug 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Injection training 
with autoinjector 
demonstration 
device 
X 
 
 
 
 
 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
39 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Observe 
participant 
administer study 
drug 
X 
X 
X X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
Participants should 
administer the first dose 
of study drug at Visit 2 
after study procedures 
and randomization have 
been completed. Review 
technique with the 
participant at each in 
clinic visit. 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
40 
Study 
I8F-MC-GPID 
Study 
Period 
I 
Screen 
ing 
Study Period II - Treatment period 
 
 
Unscheduled Visit (UV)a 
 
 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EVa, 
EVb, 
EVc 
(13, 14, 
15, 17, 
18, 19, 
etc.) 
EVd 
(16, 
20, 
etc.) 
UV 
Dosing 
UV 
Phone 
Follow-
Up 
Dosing 
UV 
E
T 
99 
Comment 
Weeks from 
randomization 
-6 
0 
4 
8 
1
2 
1
6 
2
0 
2
4 
3
2 
40 
48 
52 
(+3, 6, 9, 
15, 18, 
21 
months 
from 
Visit 12) 
(+12
, 24 
mon
ths 
from 
Visit 
12) 
 
 
 
— Fina
l 
Visit 
See footnote b 
Visit interval 
tolerance (days) 
±
3 
±
3 
±
3 
±
3 
±
3 
±
3 
±
7 
±7 
±7 
±7 
±15 
±15 
 
 
 
— 
Telephone Visit 
 
 
X 
X 
X 
 
 
 
X 
See footnote c 
Sites should coach and 
oversee if participants 
self-administer study 
drug at a scheduled visit. 
Dispense ancillary 
supplies to 
participant 
X 
X 
X X 
X 
X 
X 
X 
 
X 
 
 
 
 
Participant returns 
study drugs and 
injection supplies 
X 
X X 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
X 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
41 
Abbreviations: 6MWT = 6-minute walk test; BP = blood pressure; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CVD = cardiovascular 
disease; ECG = electrocardiogram; ECHO = echocardiography; eCRF = electronic case report form; eGFR = estimated glomerular filtration rate; EQ-5D-5L = 5-
Level European Quality of Life Questionnaire; ET = Early Termination; EV = Extended Visit; HF = heart failure; HFpEF = heart failure with preserved ejection 
fraction; HR = heart rate; HTN = hypertension; MI = myocardial infarction; NT-proBNP = N-terminal pro b-type natriuretic peptide; NYHA = New York Heart 
Association; T2DM = type 2 diabetes mellitus; WOCBP = women of childbearing potential.  
 
a   There are 3 types of Unscheduled Visits (UV): These visits can occur during the dose-escalation period and maintenance period.  
 
Unscheduled Visits (UV) – Unscheduled Visit per investigator discretion. All activities with a check mark in UV visit are required. 
 
Dosing Unscheduled Visit (UV) – these visits will include dose re-escalation. The study drug must be restarted when it is safe to do so and only while at 
the clinic visit. The subsequent unscheduled dosing visits will be scheduled every 4 weeks (±7 days) until maximum tolerated dose is achieved.  
 
Phone Follow-up Dosing Unscheduled Visit (UV) – these visits are optional phone visits.  
b At least 52 weeks (Visit 12) of treatment are planned. Additional visits after Visit 12 will occur every 3 months. The visits occurring after Visit 12 will follow 
the Extended Maintenance Visit schedule in sequence (EVa, EVb, EVc, and EVd) then repeat. If the final study visit is combined, site should only use the 
visit 12 lab kit; please refer to Study Closeout and Final Visit in Section 4.1. 
c Telephone visits can become office visits. Site documentation will serve as the source for telephone visits. Additional, optional telephone visits may be 
conducted at investigator discretion. If patient requires study drug at a telephone visit, the participant will need to come to the clinic to pick up study drug in 
addition to telephone visit.  
d Perform at ET only if participant early terminates at or prior to Week 52. 
e 
Two 6MWTs conducted at screening visit. 
f 
See Section 10.10.1 to determine if the 6MWT needs to be repeated for Visit 2. 
g    This includes glucose monitoring for participants with T2D, weekly study drug injection. 
h Perform PRO at ET only if participant early terminates at or prior to Week 52. 
i Unscheduled Visits: laboratory tests may be drawn according to investigator discretion. If only re-test labs required, site is not required to complete an 
unscheduled visit and associated procedures.  
j 
Required at Visit 2 randomization if screening labs are older than 28 days for chemistry, lipid, and pancreatic lipase/amylase.  
k Collect serum pregnancy at Visit 2 only if Visit 1 serum was ≥28 days prior. 
l 
Only collect calculated eGFR with Clinical Chemistry sample if screening labs are older than 28 days. 
 
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CONFIDENTIAL 
I8F-MC-GPID(c) 
 
42 
2. 
Introduction  
2.1. 
Study Rationale  
Heart failure with preserved ejection fraction is a heterogenous clinical syndrome resulting from 
various pathophysiological processes. Among the broad spectrum of HFpEF clinical 
presentation, obesity-related HFpEF displays a distinct phenotype where increased visceral and 
ectopic adiposity as well as volume expansion plays a causal role (Kitzman and Shah 2016; 
Packer 2018; Miller and Borlaug 2020). Given tirzepatide’s potential to decrease inflammation 
and fibrosis and a to reduce circulating plasma volume as a consequence of the treatment of 
obesity, tirzepatide may provide clinical benefit to patients with HFpEF and BMI ≥30 kg/m2. 
Study I8F-MC-GPID, also known as SUMMIT, is a Phase 3, randomized, multicenter, 
international, placebo-controlled, double-blinded, parallel-arm study. This study will evaluate the 
effect of SC QW injection of tirzepatide, MTD up to 15 mg, on the health status, risk of death, 
HF events, and exercise capacity in participants with HFpEF and BMI ≥30 kg/m2. 
2.2. 
Background  
Obesity is one of the main attributes to worsen quality of life in patients with HFpEF (Reddy et 
al. 2020). There is a significant unmet need in treatment of patients with HFpEF. Tirzepatide, a 
GIP and GLP-1 dual agonist, has the potential to provide benefit to patients with HFpEF and 
BMI ≥30 kg/m2. Tirzepatide may improve symptoms and exercise capacity and may also a 
reduce in HF events and/or increase survival. Supporting a causal association between obesity 
and HFpEF, bariatric surgery improved NYHA class, patient-reported outcomes, and echo 
parameters (LV wall thickness, LV relaxation) in patients with HFpEF and obesity (Mikhalkova 
et al. 2018). A meta-analysis of bariatric surgery also showed improvement in functional 
capacity 6 to 12 months after surgery in patients with obesity (Herring et al. 2016). In patients 
with HFpEF and obesity, diet-induced weight loss (Δ=−7 kg, 20 weeks) significantly improved 
symptoms (KCCQ) and exercise capacity (6MWD and peak oxygen uptake) (Kitzman et al. 
2016). Furthermore, weight reduction is proven to be effective in reducing HF risk and HF 
hospitalizations. A large observational study has demonstrated a 62% decrease (over 8 years) of 
HF incidence after bariatric surgery in patients with T2DM (Aminian et al. 2019). The reduction 
of HF risk after bariatric surgery has been consistently demonstrated in broader patient 
populations and considered to be mediated by weight loss with a hazard ratio for a 10-kg weight 
loss being 0.77 (Sundström et al. 2017; Jamaly et al. 2019). Moreover, a self-controlled case 
study showed a 29% (0 to 12 months) and a 43% (13 to 24 months) risk reduction of HF events 
in patients with HFpEF after bariatric surgery (Shimada et al. 2016). Finally, in a recently 
published placebo-controlled study (STEP-HFpEF), semaglutide reduced body weight by 10.7% 
and improved KCCQ-CSS by 7.8 points at 52 weeks, both with p<0.001 (Kosiborod et al. 2023; 
Borlaug et al. 2023). In addition, superiority on the hierarchical composite endpoint (death, HF 
events, differences in the change in KCCQ-CSS, and 6MWD) was achieved, including the 
proportion of patients who had improved KCCQ score by at least 15 points in the semaglutide 
group. Semaglutide also improved 6MWD, with between-group difference of 20.3 meters. Most 
intriguingly, adjudicated events of hospitalization for heart failure or an urgent visit occurred in 
Approved on 14 Feb 2024 GMT

CONFIDENTIAL 
I8F-MC-GPID(c) 
 
43 
12 patients in the placebo group, but only in 1 patient in the semaglutide group (HR 0.08; 95% 
CI 0.00 to 0.42) 
It has been demonstrated that tirzepatide can provide significant body weight loss and 
improvement of lipid and glucose metabolism in patients with and without T2DM (Frias et al. 
2018; Wilson et al. 2020; Jastreboff et al. 2022). It is known that the body weight reduction with 
GLP-1 RAs in patients without T2DM is higher than in patients with T2DM (Davies et al. 2015; 
Pi-Sunyer et al. 2015; Lingvay et al. 2018). If Study GPID is assumed to include 40% to 50% of 
patients with T2DM, the mean placebo-adjusted body weight percent reduction that tirzepatide 
can provide in 52 weeks in this study is estimated to be 15% to 16%. This is based on tirzepatide 
clinical data and the understanding of body weight loss differences between patients with and 
without T2DM treated with GLP-1 RAs. Thus, the predicted body weight loss with treatment 
with tirzepatide is close to that shown with bariatric surgery.  
Tirzepatide may provide benefit to patients with HFpEF and obesity by virtue of cardiometabolic 
improvements (Wilson et al. 2020). Given the wide distribution of GIP receptor in the adipose 
tissue, GIP is thought to be actively involved in lipid and glucose metabolism. As suggested by 
the results of emerging data (Kosiborod et al. 2023) and the significant weight loss achieved with 
tirzepatide, the effect of tirzepatide on HF events in an obesity-related HFpEF population are 
expected to be robust. Therefore, it will be meaningful to assess the impact of tirzepatide not 
only on functional and symptomatic endpoints but also on the reduction in the risk of HF events 
in SUMMIT, thereby facilitating the holistic understanding of the clinical impact of tirzepatide 
treatment in patients with HFpEF and obesity. 
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of tirzepatide may be found in the Investigator’s Brochure.
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I8F-MC-GPID(c) 
 
44 
3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To demonstrate that a maximally tolerated 
tirzepatide dose up to 15 mg administered 
SC QW is superior to placebo to improve 
patient-reported symptoms and physical 
limitations in participants with HFpEF and 
obesity 
Change from baseline to Week 52 in the 
KCCQ-CSS 
To demonstrate that a maximally tolerated 
tirzepatide dose up to 15 mg administered 
SC QW is superior to placebo based on the 
composite HF outcome endpoint in 
participants with HFpEF and obesity 
Occurrence of the composite endpoint of CV 
death and/or HF events over time 
Key Secondary (multiplicity controlled) 
 
Exercise capacity  
Change from baseline to Week 52 in 6MWD 
Long-term weight loss 
Percent change from baseline to Week 52 in 
body weight 
Evaluation of change in inflammation 
Change from baseline to Week 52 in hsCRP 
Other Secondary 
 
Hierarchical composite assessed by win ratio 
A hierarchical composite of the following: 
1. Time to all-cause mortality through the 
end of the study 
2. Occurrence of heart failure (HF) events 
through end of the study, where HF 
events are defined as worsening heart 
failure with intensification of diuretics 
(oral or IV) during a hospitalization, 
urgent care visit or outpatient visit 
(adjudicated) 
 number of HF events 
 time to first HF events 
3. Change from baseline in KCCQ-CSS 
category at Week 52 
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I8F-MC-GPID(c) 
 
45 
4. Change from baseline in the 6-minute 
walk test distance (6MWD) category at 
Week 52 
The categories for change from baseline in the 
KCCQ-CSS are: 
1. ≥10-point worsening 
2. ≥5- but <10-point worsening 
3. No change (<5-point change) 
4. ≥5- but <10-point improvement 
5. ≥10- but <15-point improvement 
6. ≥15-point improvement 
The categories for change from baseline in the 
6MWD are:  
1. ≥30% worsening 
2. ≥20% and <30% worsening 
3. ≥10% and <20% worsening 
4. No change (˂10% change) 
5. ≥10% and <20% improvement 
6. ≥20% and <30% improvement 
7. ≥30% improvement.  
Clinical outcome events of HF 
 Time to all-cause death 
 Time to first occurrence of HF events 
or all-cause death 
 Time to recurrent events of HF events 
and all-cause death 
 Time to first occurrence of HF events 
 Time to recurrent events of HF events 
New York Heart Association (NYHA) Class  Proportion of participants with NYHA Class 
change at Week 52 
Exercise capacity 
Change from baseline to Week 24 in 6MWD 
Patient-reported symptoms and physical 
limitations 
 Change from baseline to Week 24 in 
KCCQ-CSS 
 Proportion of participants attaining 
KCCQ-CSS meaningful within-patient 
change (MWPC) threshold at Week 52 
Exploratory 
 
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I8F-MC-GPID(c) 
 
46 
Atrial fibrillation  
Proportion of participants with atrial 
fibrillation 
Waist circumference  
Change from baseline (centimeters) 
Patient-reported health-related quality of life 
Change from baseline in KCCQ: 
 Total Symptom Score (TSS) 
 Overall Summary Score (OSS) 
Patient-reported health status 
Change from baseline in EQ-5D-5L: 
o Index Score 
o VAS Score 
Patient-reported global health status 
Proportion of participants with improvements 
in global health status from baseline as 
assessed by the PGIS-Overall 
Patient-reported global impression of 
physical function 
Proportion of participants with improvements 
in physical function from baseline as assessed 
by the PGIS-Physical Function 
Patient-reported global symptom severity 
Proportion of participants with improvements 
in symptom severity from baseline as assessed 
by the PGIS-Symptom Severity 
Evaluation of prespecified biomarkers 
 NT-proBNP 
 cTnT 
Waist to height ratio 
Change from baseline to Week 52 in waist to 
height ratio  
Kidney function 
eGFR slope 
Abbreviations: 6MWD = 6-minute walk distance; BMI = body mass index; CV = cardiovascular; hsCRP = high-
sensitivity C-reactive protein; HF = heart failure; HFE(s) = heart failure event(s); HFpEF = heart failure with 
preserved ejection fraction; KCCQ-CSS = Kansas City Cardiomyopathy Questionnaire – Clinical Summary 
Score; NYHA = New York Heart Association; QW = once weekly; SC = subcutaneous. 
 
 
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4. 
Study Design  
4.1. 
Overall Design  
Study GPID is a randomized, outpatient, multicenter, international, placebo-controlled, double-
blinded, parallel-arm, Phase 3 study with 2 study periods. The study is designed to evaluate the 
efficacy and safety of SC QW tirzepatide, MTD up to 15 mg, compared to placebo, in 
participants with HFpEF and obesity.  
Two intervention groups will be studied:  
 Tirzepatide MTD up to 15 mg SC QW 
 Placebo 
The study will compare treatment with tirzepatide and treatment with placebo. Assignment to 
tirzepatide or placebo groups will be randomly allocated in a 1:1 ratio.  
The starting dose of tirzepatide or placebo is 2.5 mg QW, which is to be escalated at 4-week 
intervals to a maximum of 15 mg QW or to the highest maintenance dose tolerated by the 
participant (see Section 6).  
 
The study will consist of 2 periods: 
 Study Period 1: screening period, lasting no more than 12 weeks.  
 Study Period 2: treatment period, with a 20-week escalation followed by at least a 
32-week maintenance period. 
The study will continue until approximately 52 weeks after the last participant is randomized. 
The maximum duration of an individual’s participation is estimated to be 120 weeks and will 
depend on duration of study enrollment. 
Participant Visit Scheme 
Study participants will undergo screening assessments and procedures, randomization, 
and double-blinded treatment with tirzepatide or placebo. Assessments and procedures to 
be conducted in each treatment period are described in the SoA (Section 1.3) and in Study 
Assessments and Procedures (Section 8). 
Screening 
Screening procedures will be performed at Visit 1. Visit 1 procedures may be conducted over 
more than 1 day as long as all activities are completed within the allowable visit tolerance for 
each visit. The duration of Visit 1 is anticipated to be <6 weeks but may be longer. Visit 1 should 
no more than 12 weeks from date of informed consent. 
 
At Visit 1, two 6MWTs will be conducted. The investigator must ensure that the participant is 
recovered from completion of the first 6MWT prior to conducting the second 6MWT (at least 1 
hour between each test). The screening 6MWTs may be conducted over more than 1 day.  
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Randomization 
At Visit 2, prior to randomization, the participant needs to complete the 6MWT. Visit 2 may 
need to be conducted over 2 in-clinic visits (considered Visit 2a and Visit 2b) if a repeat 6MWT 
is necessary to assess participant eligibility. If the participant is required to return to repeat the 
6MWT, the remaining procedures should be conducted at the second in-clinic visit for 
randomization (Visit 2b), more than 10 days from Visit 2a. See Section 10.10.1 for details on 
when a participant must return for a second Visit 2 6MWT.  
Participants will be randomized and receive blinded study drug at the end of Visit 2 after all 
screening procedures are completed. The participant must not receive study drug until all 
eligibility criteria, including the 6MWT, are met.  
Treatment  
Starting from randomization, the participant receives study drug and procedures are conducted as 
described in the SoA (Section 1.3). Every effort should be made by the investigator to maintain 
participants on study drug. 
Study drug dose will be escalated as illustrated in the study schema (Section 1.2). Dose 
escalation will continue until the participant reaches the maintenance dose of either 5 mg, 10 mg, 
or 15 mg. Participants who do not tolerate the first dose escalation (that is, from 2.5 mg to 5 mg 
[or placebo equivalent]) will need to discontinue from study drug. 
Participants begin treatment with either tirzepatide or placebo starting at 2.5 mg given as a 
subcutaneous (SC) injection every week (QW). The dose level is increased by 2.5 mg increments 
approximately every 4 weeks for the first 20 weeks according to the participant’s tolerability, 
reaching a MTD up to 15 mg. Once a MTD has been achieved, participants will continue at this 
MTD until study end, treatment discontinuation, or study discontinuation. Dose modifications 
will be permitted during the study under the circumstances specified in Section 6.6. 
During the study treatment period, if an unscheduled visit or telephone visit is deemed necessary 
to support participant compliance, this is allowable at the discretion of the investigator site 
personnel.  Optional telephone visits can be performed approximately 2 weeks after starting 
study drug and after each dose increase. 
Participants will continue into the extended maintenance period with the same treatment 
assignment starting with Visit 13. Extended visits (EV) continue until criteria for study 
discontinuation is met or study ends (see Study Closeout and Final Visit below).  
Study Closeout and Final Visit 
The study will continue until approximately 52 weeks after the final participant is randomized 
The final study visit (Visit 99) for the study is based from the date of when the last patient for the 
trial was randomized.  
Approximately 3 months prior to the anticipated end of study, the sponsor will notify sites of 
upcoming study closeout based on projected last patient visit date of the last patient randomized 
to the study. During the study closeout, a final visit (Visit 99) will be planned for each 
participant, with the exception of those who have died or prematurely discontinued from the 
study (Section 7.2). Any participant that has completed at least 52 weeks of study duration 
should be scheduled to complete the final visit (Visit 99) during this 3-month period prior to the 
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study final visit. No additional investigational product will be dispensed at this final visit. Study 
procedures for the final visit will be performed as outlined in the SoA (Section 1.3). Subjects 
completing 52 weeks of treatment during the last 3 months of the study will have a combined 
Visit 12 (52-week treatment visit) and Visit 99 (final visit) on the same day. During this 
combined visit, sites should only use the Visit 12 lab kit for blood draws and processing.   
All unused study drug (unused single-dose pens) must be returned for compliance and final drug 
accountability. The sharp items container should also be returned to site or disposed of per local 
regulations. 
Any participant who has discontinued the study prior to completing 52 weeks of study duration 
is expected to complete an early termination visit per the SoA. 
4.2. 
Scientific Rationale for Study Design  
Study GPID is a Phase 3 study designed to examine the efficacy and safety of SC QW tirzepatide 
MTD compared with placebo in participants with HFpEF and BMI ≥30 kg/m2. 
A placebo comparator was selected for this trial in accordance with regulatory guidance 
(FDA 2007; EMA 2016). Inclusion of a placebo comparator in Study GPID will allow for a 
direct assessment of the safety and efficacy of tirzepatide in participants with HFpEF and 
obesity.  
Additionally, there is currently no approved therapy to be used as an active comparator in this 
population. 
An endpoint assessment at 52 weeks of treatment is considered appropriate to assess the 
improvement of symptom and functional capacity. An extended maintenance treatment period 
increases the opportunity to evaluate HF events and outcomes. 
The parallel-group design for treatment comparison was chosen to avoid any interaction between 
treatments that may interfere with the interpretation of the trial outcome. To minimize potential 
confounding effect of changes to concomitant medications, participants will be permitted to use 
the stable dose of concomitant medications that they require during the study. Medications that 
may interfere with the assessment of efficacy and safety characteristics of the study drug will not 
be allowed (see Section 6.5). 
Assessment of HF events is relevant to HFpEF, which is characterized by a high frequency of 
recurrent HF hospitalizations. Moreover, hospitalization events reflect disease progression and 
high subsequent risk and predisposition, both of readmission and death (Solomon et al. 2007). 
Recent studies have shown that outpatient oral diuretic intensification in ambulatory care carries 
similar risk as an urgent HF visit and is independently associated with subsequent cardiovascular 
events, including death (Chatur et al. 2023; Ferreira et al. 2022; Madelaire et al. 2020).  
 Obesity is associated with important degrees of exercise intolerance and a markedly impaired 
quality of life and health status (Reddy et al. 2020). In patients with HFpEF, due to increased 
filling pressures, functional capacity is severely impaired, and patients can develop symptoms 
with light exercise. As a result, the ability to perform activities of daily living is deteriorated. 
Therefore, KCCQ is a meaningful endpoint to evaluate the clinical benefit of tirzepatide in 
patients with HFpEF and obesity.  
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Given the significant weight loss, and associated cardiometabolic improvements, achieved with 
tirzepatide, assessment of CV death and HF events, in addition to KCCQ-CSS as a primary 
endpoint, offers the unique opportunity to evaluate tirzepatide for the benefit of HFpEF patients 
with obesity.  
4.2.1. 
Patient Input into Design  
The sponsor involved patients in the design of this study by engaging patients in virtual 
collaborative events. The insights gained from these events were used to ensure that the study 
design is supportive of the well-being of the study participants and that the study procedures can 
be implemented effectively at the investigative sites. 
4.3. 
Justification for Dose  
Tirzepatide doses of up to 15 mg administered SC QW will be evaluated in this study.  
Participants may be treated with lower maintenance doses of 5 mg or 10 mg if they do not 
achieve full dose escalation to 15 mg and/or do not tolerate 15 mg. 
These doses and associated escalation schemes were selected based on assessment of safety, 
efficacy (glycemic and weight loss benefit), and GI tolerability data followed by exposure 
response modeling of data in participants with T2DM in Phase 1 and Phase 2 studies. Dosing 
algorithms starting at a low dose of 2.5 mg accompanied by dose escalation of 2.5 mg increments 
every 4 weeks should permit time for development of tolerance to GI events and are predicted to 
minimize GI tolerability concerns. 
The dose selection of tirzepatide is based on the findings of the Phase 2 study results. Tirzepatide 
doses of 5 mg, 10 mg, and 15 mg QW have been tested and compared with dulaglutide 1.5 mg 
QW or placebo in a Phase 2 study (Frias et al. 2018). While all 3 doses of tirzepatide 
significantly improved the glycemic control versus dulaglutide, the largest difference was 
observed in the 15-mg tirzepatide treatment group. Moreover, the reduction in body weight with 
tirzepatide was also dose-dependent and greatest in the 15 mg QW treatment group.  
4.4. 
End of Study Definition  
The end of study will occur approximately 52 weeks after the last participant has been 
randomized to the study globally. The study end will occur based on this definition and is not 
impacted by the status of the last randomized participant.  
The criteria used to determine if a participant has completed the study will be described in 
the SAP. 
 
 
 
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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. Participant must be at least 40 years of age inclusive, at the time of signing the ICF. 
Type of Participant and Disease Characteristics 
2. 6MWD ≤465 meters at both Visit 1 tests, between ≥100 meters and ≤425 meters at 
Visit 2 and change from the preceding qualifying 6MWD is <20% and <40 meters. 
See Section 10.10.1 for the flow diagram of the below qualifiers. 
 If Visit 2a 6MWD is both between 100 and 425 meters and…  
 <20% AND <40 meter change from the higher of the two 6MWDs 
conducted at Visit 1, then participant meets this inclusion criterion.  
 ≥20% OR ≥40 meter change from the higher of the two 6MWDs at 
Visit 1, then participant must attend Visit 2b. If at Visit 2b, the 6MWD is 
between 100 and 425 meters and <20% AND <40 meter change from 
preceding (Visit 2a) 6MWD, then participant meets this inclusion 
criterion.  
3. Chronic HF (NYHA Class II-IV) diagnosed for at least 3 months before Visit 1. 
4. LVEF ≥50% demonstrated by echocardiogram performed at Visit 1 or within 6 months 
of Visit 1. 
5. At least 1 of the following to document evidence of HF: 
 Elevated NT-proBNP >200 pg/mL for participants without atrial AF or 
>600 pg/mL for participants with AF, as analyzed at the central laboratory at 
Visit 1  
OR 
 Evidence of structural heart disease:  
 LA enlargement (any of the following: LAV index ≥29 mL/m2, or LAV 
>58 mL in male participants and >52 mL in female participants, or LA 
area >20 cm2, or LA diameter >40 mm in male and >38 mm in female 
participants) determined by echocardiogram at Visit 1 or within 6 months 
of Visit 1 
OR 
 Evidence of elevated filling pressure:  
 At rest (PCWP ≥15 mmHg or LVEDP ≥15 mmHg) or with exercise 
(PCWP ≥25 mmHg) (based on historical record, not associated with 
hospitalization for decompensation of HF, within 2 years of Visit 1), or  
 E/e’ ratio >15 (septal) or >13 (average of septal and lateral) determined by 
echocardiogram at Visit 1 or within 6 months of Visit 1 
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Note: Supporting medical documentation is required in all instances. 
6. Either one of:  
 eGFR <70 mL/min/1.73 m2 at Visit 1, OR 
 HF decompensation within 12 months of Visit 1, defined as hospitalization for HF 
requiring IV diuretic treatment or urgent HF visit requiring IV diuretic treatment 
Note: Supporting medical documentation is required in all instances. 
7. Stable dose of all concomitant HF medications (these may include beta blockers, 
ACEis, ARBs, MRAs, ARNI, and/or SGLT2is), except for oral diuretics, for at least 4 
weeks prior to Visit 1 and throughout the screening period. 
8. If treated with oral diuretics, dose must be stable for at least 2 weeks prior to Visit 1 and 
throughout the screening period; volume control must be optimally achieved in the 
opinion of the investigator. 
9. KCCQ-CSS ≤80 at Visit 1. 
Weight 
10. BMI ≥30.0 kg/m2 at Visit 1. 
Sex 
11.  At the time of signing the ICF: 
a. Male participants: Male participants with partners of childbearing potential should 
be willing to use reliable contraceptive methods for the duration of the trial and for 
4 months thereafter (see Appendix 4 [Section 10.4]). 
b. Female participants:  
o Female participants not of childbearing potential may participate and include 
those who are infertile due to surgical sterilization and/or postmenopausal. Please 
refer to Appendix 4 (Section 10.4) for definitions.  
o Female participants of childbearing potential (not surgically sterilized and 
between menarche and 1-year postmenopausal) must: 
▪ test negative for pregnancy at Visit 1 based on a serum pregnancy test 
followed by a negative urine pregnancy test within 24 hours prior to 
exposure and agree to use 2 forms of effective contraception, if sexually 
active, where at least 1 form is highly effective, for the duration of the trial 
and for 2 months after the last injection, and  
▪ not be breastfeeding. 
Contraceptive use by men or women of childbearing potential should be consistent with local 
regulations regarding the methods of contraception for those participating in clinical trials. 
See Appendix 4 (Section 10.4) for guidance. 
Informed Consent 
12. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1), 
which includes compliance with the requirements and restrictions listed in the ICF and 
in this protocol. 
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5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
13. Myocardial infarction, coronary artery bypass graft surgery, or other major CV 
surgery/intervention, stroke or transient ischemic attack in past 90 days, or unstable 
angina pectoris in past 30 days, prior to Visit 1 or during screening; Have NYHA Class 
I heart failure at either Visit 1 or Visit 2. 
14. Dominant contribution of noncardiac causes to exercise impairment or symptoms 
 Lung disease: pulmonary arterial hypertension, chronic thromboembolic 
pulmonary hypertension (CTEPH), or severe pulmonary disease including (COPD) 
 Other medical conditions: severe anemia (hemoglobin level <9 g/dL) at Visit 1, 
untreated thyroid disease or TSH >4.78 mU/L at Visit 1, or significant 
musculoskeletal disease 
 Orthopedic conditions that limit the ability to walk, such as severe arthritis in the leg, 
knee, hip injuries, hemiplegia, or amputation with artificial limb without stable 
prosthesis function for the past 3 months 
 Any condition that in the opinion of the investigator would interfere with the 
assessment of 6MWT 
15. LVEF <40% by local echocardiography, MRI or other modalities documented any 
time within 2 years of Visit 1. 
16. Acute decompensated HF (exacerbation of HF) requiring IV diuretics, IV inotropes, or 
IV vasodilators, or left ventricular assist device (LVAD) within 4 weeks prior to Visit 
1, and/or during the screening period until randomization. 
17. Impaired renal function, defined as eGFR <15 mL/min/1.73 m2 (CKD-EPI) or 
requiring dialysis at Visit 1. 
18. Any one of the following: 
 Systolic blood pressure (SBP) ≥180 mmHg at Visit 1 
 SBP >160 mmHg both at Visit 1 and at Visit 2 
 Have symptomatic hypotension or SBP <100 mmHg at Visit 1 or Visit 2 
19. Resting heart rate (sinus rhythm) ≥100 bpm at either Visit 1 or Visit 2. 
20. Atrial fibrillation or atrial flutter with a resting heart rate >110 bpm documented by 
ECG at either Visit 1 or Visit 2. 
21. Cardiac amyloidosis or cardiomyopathy based on accumulation disease (for example, 
haemochromatosis, Fabry disease), muscular dystrophy, cardiomyopathy with 
reversible causes (for example, stress cardiomyopathy), hypertrophic cardiomyopathy, 
Chagas cardiomyopathy or known pericardial constriction, or any severe (obstructive 
or regurgitant) valvular heart disease likely to lead to surgery during the study period.  
22. Completed prior surgical treatment for obesity or had liposuction or abdominoplasty 
within 1 year prior to Visit 1. Participants who plan to have surgical treatment for 
obesity or liposuction or abdominoplasty during the duration of the study are excluded.  
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23. Participation in a structured exercise training program in the 1 month prior to Visit 1 
or planning to start a program during the study.  
24. Have T1DM. 
25. For participants with T2DM: 
 Have uncontrolled diabetes requiring immediate therapy (such as diabetic 
ketoacidosis) at Visit 1 or Visit 2, in the judgement of the physician  
 Have had 1 or more events of severe hypoglycemia and/or 1 or more events of 
hypoglycemia unawareness within 6 months prior to Visit 1 (see Section 10.5.1.1 for 
definition of hypoglycemia) 
 Have HbA1c ≥9.5% (80 mmol/mol) at Visit 1, as analyzed at the central laboratory 
 Have a history of proliferative diabetic retinopathy or diabetic maculopathy. Patients 
with severe nonproliferative diabetic retinopathy that requires acute treatment are also 
excluded.  
 
Treated with premix or prandial insulins or intensified insulin regimens (multiple 
daily injection with basal and prandial insulins or insulin pump therapy) at Visit 1. 
26. History of acute or chronic pancreatitis or at high risk for acute pancreatitis (for 
example, serum triglyceride level >500 mg/dL [5.65 mmol/L]). 
27. Have acute or chronic hepatitis, signs and symptoms of any other liver disease other 
than nonalcoholic fatty liver disease, or any of the following, as determined by the 
central laboratory during Visit 1: 
 ALT or AST levels >2.5X the ULN for the reference range. 
Note: Participants with nonalcoholic fatty liver disease are eligible to participate in this 
trial if their ALT level is ≤3.0X the ULN for the reference range. 
28. Have a calcitonin level at Visit 1 of: 
 ≥20 ng/L, if eGFR is ≥60 mL/min/1.73 m2 
 ≥35 ng/L, if eGFR is <60 mL/min/1.73 m2 
29. Have a family or personal history of medullary thyroid carcinoma (MTC) or Multiple 
Endocrine Neoplasia (MEN) Syndrome type 2. 
30. Have a history of an active or untreated malignancy or are in remission from a 
clinically significant malignancy (other than basal- or squamous-cell skin cancer, in 
situ carcinoma of the cervix, or in situ prostate cancer) for less than 5 years. 
31. Have a history of any other condition (such as known drug or alcohol abuse, diagnosed 
eating disorder, or other psychiatric disorder) that, in the opinion of the investigator, 
may preclude the participant from following and completing the protocol. 
32. Have a known clinically significant gastric emptying abnormality (for example, severe 
diabetic gastroparesis or gastric outlet obstruction) or chronically take drugs that 
directly affect GI motility. 
Prior/Concomitant Therapy 
33. Treatment with any incretin, GLP-1 RA, or pramlintide in the 3 months prior to 
Visit 1. 
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34. Discontinuation of any incretin, GLP-1 RA, or pramlintide due to intolerability any 
time prior to Visit 1. 
35. Have any other condition not listed in this section (for example, hypersensitivity or 
intolerance) that is a contraindication to GLP-1 RA. 
36. Implantable cardioverter defibrillator (ICD) implantation within 1 month prior to 
Visit 1 or planned implantation during the course of the study. 
37. Currently implanted left ventricular assist device (LVAD). 
38. Cardiac resynchronization therapy (CRT) implanted within 6 months prior to Visit 1 
or planned implantation during the course of the trial. 
39. Current use of medication associated with weight gain or weight loss, except when on 
stable dose for at least 3 months prior to Visit 1, and expected to be stable during the 
study period. 
Prior/Concurrent Clinical Study Experience 
40. Have participated within the last 6 months in a clinical study involving an 
investigational product. 
Other Exclusions 
41. 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. 
42. Lilly employees. 
5.3. 
Lifestyle Considerations  
Study participants should be instructed not to donate blood or blood products during the study 
and for 8 weeks following the study.  
5.4. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study drug. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any SAE.  
Individuals who do not meet certain criteria for participation in this study (screen failure) may be 
rescreened once. Additionally, individuals who do not complete screening within 12 weeks from 
ICF date should be screen failed and may be rescreened. Rescreened participants should sign a 
new ICF and be assigned a new participant number. The interval between rescreenings should be 
at least 2 weeks. For participants who may have screen failed due to HbA1c criterion not met, 
the time to permit rescreening is at least 8 weeks. If, in the opinion of the investigator, an 
ineligible laboratory test result is the result of an error or extenuating circumstance, then that 
parameter can be retested once without the participant having to be rescreened. For rescreened 
participants, a repeat echocardiogram is not permitted. 
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Participants may be rescreened for the following reasons:  
 Have become eligible to enroll in the study as the result of a protocol amendment 
 Status has changed such that the eligibility criterion that caused the participant to screen 
fail would not cause the participant to screen fail again 
 Completed screening and met all inclusion and exclusion requirements but are unable to 
be enrolled due to extenuating circumstances (such as severe weather, death in family, or 
child illness) 
 
 
 
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6. 
Study Intervention  
Study drug is defined as any investigational intervention(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to/used by a study participant according to the 
study protocol. For this study, ‘study intervention’ and ‘study drug’ are equivalent.   
6.1. 
Study Interventions Administered  
Intervention Name 
Placebo 
Tirzepatide (LY3298176) 
Type  
Drug (placebo) 
Drug 
Dose Formulation 
Single-dose pen 
Single-dose pen 
Unit Dose Strengths 
Not applicable  
2.5 mg, 5 mg, 7.5 mg, 10 mg, 
12.5 mg, 15 mg 
Dosage Levels 
Not applicable 
15 mg QW  
(or maximum tolerated dose of 
5 mg QW or 10 mg QW) 
Route of 
Administration 
Subcutaneous 
Subcutaneous 
Use 
Placebo 
Experimental 
IMP and NIMP 
IMP 
IMP 
Sourcing 
Provided centrally by the sponsor and dispensed via IWRS 
Packaging and 
Labeling 
Study drug will be provided in autoinjectors (single-dose pens), 
packaged in cartons to be dispensed.  
Clinical study materials will be labeled according to country 
regulatory requirements.  
Abbreviations:  QW = weekly; IMP = investigational medicinal product; IWRS = interactive web-response system; 
NIMP = non-investigational medicinal product. 
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The following table shows the randomized study drugs for the entire study. 
Treatment Group 
Treatment Period Interval 
Weeks 
0 to 3 
Weeks 
4 to 7 
Weeks 
8 to 11 
Weeks 
12 to 15 
Weeks 
16 to 19 
Weeks 
20 to End of Treatment 
Period 
Tirzepatide  
2.5 mg 
5 mg 
7.5 mg 
10 mg 
12.5 mg 
15 mg or MTD 
Placebo 
 
Abbreviation: MTD = maximum tolerated dose. 
There are no restrictions on the time of day each weekly dose of study drug is given, but it is 
advisable to administer the SC injections on the same day and same time each week. The actual 
date, time, and injection site location of all dose administrations will be recorded in the diary by 
the participant. If a dose of study drug is missed, the participant should take it as soon as 
possible, unless it is within 72 hours of the next dose, in which case that dose should be skipped, 
and the next dose should be taken at the appropriate time. The day of weekly administration can 
be changed if necessary, as long as the last dose was administered 72 or more hours previously. 
All participants will inject study drug subcutaneously in the abdomen or thigh using the injection 
supplies provided; a caregiver may also administer the injection in the participant’s upper arm. 
The injection site location of all dose administrations will be recorded by the participant. A new 
autoinjector will be used for each injection. If study drug is to always be injected in the same 
body region, participants should be advised to rotate injection sites each week. 
6.1.1. 
Medical Devices  
The combination product provided for use in the study is a tirzepatide or matching placebo 
autoinjector.  
6.2. 
Preparation/Handling/Storage/Accountability  
 The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study drug received and any discrepancies are reported 
and resolved before use of the study drug. 
 Only participants enrolled in the study may receive study drug. Only study personnel may 
supply study drug.  
 All study drug 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, institution, or the head of the medical institution (where applicable) is 
responsible for study drug (includes study drug and autoinjector or single-dose pen) 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and 
final disposition of records). 
 Study site staff must regularly assess whether the participant is correctly administering 
the assigned study drug and storing study drug according to the provided instructions. 
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Further guidance and information for the final disposition of unused study drugs are 
provided in the study training materials. 
The investigator or designee is responsible for the following: 
 Explaining the correct use of the study drug to the participant 
 Verifying that instructions are followed properly 
 Maintaining accurate records of study drug dispensing and collection as well as records of 
interruptions in study drug administration 
 Instructing the participant to discard all used autoinjectors for study drug in a closeable, 
puncture-resistant container and dispose according to local regulations, and  
 Considering dose adjustment of antihyperglycemic medications (see Section 6.5) at Visit 2 
from first administration of study drug. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is a double-blind study. 
Participants who meet all criteria for enrollment will be randomized to one of the study treatment 
groups at the end of Visit 2. Assignment to treatment groups will be determined by a computer-
generated, random sequence using an IWRS. Participants will be randomized in a 1:1 ratio to 
receive tirzepatide or placebo. The randomization will be stratified by HF decompensation 
(hospitalization for HF requiring IV diuretic treatment or urgent HF visit requiring IV diuretic 
treatment) within 12 months of screening (Y/N), diagnosed T2DM (Y/N), and BMI ≥35 kg/m2 
(Y/N). 
Before the study is initiated, the log in information and directions for the IWRS will be provided 
to each site. 
Study drug will be dispensed at the study visits shown in the SoA.  
Returned unused study drug should not be re-dispensed to the participants. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s drug 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If a participant’s drug assignment is unblinded, the sponsor must be notified 
immediately after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and CRF, as applicable. 
If an investigator, site personnel performing assessments, or participant is unblinded, the 
participant must be discontinued from the study. In cases where there are ethical reasons to have 
the participant remain in the study, the investigator must obtain specific approval from a sponsor 
CRP for the participant to continue in the study. 
6.4. 
Study Intervention Compliance  
Participant compliance with study drug and adherence to study visits and procedures will be 
vitally important to meet the study objectives. This will be emphasized through comprehensive 
site training and consistently monitoring participant retention throughout the duration of the 
study.  
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Study drug compliance will be determined by the following: 
 Study drug administration data will be recorded by the participants in the participant 
study diary and reviewed by the investigator at each study visit. 
 The participants will be instructed to return any unused study drug and/or empty cartons 
at the next visit to the study site for the purpose of performing drug accountability. 
Treatment compliance is defined as taking at least 75% of the required doses of study drug. 
Similarly, a participant will be considered significantly noncompliant if he or she is judged by 
the investigator to have intentionally or repeatedly taken more than the prescribed amount of 
medication (more than 125%).  
In addition to the assessment of a participant’s compliance with the study drug administration, 
other aspects of compliance with the study drug will be assessed at each visit based on the 
participant’s adherence to the visit schedule, completion of study diaries, and any other 
parameters the investigator considers necessary.  
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol. 
6.5. 
Concomitant Therapy  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) or other specific categories of interest that the participant is receiving 
at the time of enrollment or receives during the study must be recorded along with: 
● Reason for use 
● Dates of administration including start and end dates 
● Dosage information including dose and frequency for concomitant therapy of 
special interest (drugs used for diabetes, diuretics, drugs used for obesity, and 
cardiovascular drugs) 
The sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Initial doses of tirzepatide delay gastric emptying and have the potential to transiently impact the 
rate of absorption of concomitantly administered oral medicinal products. Tirzepatide should be 
used with caution in participants receiving oral medicinal products that require rapid GI 
absorption following the initial doses of tirzepatide, as exposure to oral medications may 
be increased. 
Prevention of Hypoglycemia 
Similar to GLP-1 RAs, tirzepatide does not generally cause hypoglycemia, but it is 
recommended to decrease the dose of concomitant sulfonylurea or insulin to reduce the risk of 
hypoglycemic episodes in patients with T2DM. For participants with T2DM, specific, 
individually tailored adjustments of the respective antihyperglycemic medications should be 
considered during the entire study.  
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At Visit 2, with the initiation of study drug, the dose adjustments to the following concomitant 
glucose lowering medications are recommended. 
Sulfonylureas: Sulfonylurea dose is recommended to be reduced at least 50% or discontinued, 
especially if the participant is receiving a low dose at randomization. 
Insulins: For participants on basal insulin and with screening HbA1c ≤8.5%, the daily dose is 
recommended to be reduced by at least 20%.  
During the dose escalation period, consider adjusting the total daily dose of insulin, if required 
for controlling worsening hyperglycemia and its acute complications. 
During the maintenance period, further insulin dose reduction for the prevention of 
hypoglycemia is to be considered at the investigator’s discretion. 
Standard of Care for T2DM  
The standard of care for diabetes may be adjusted at the discretion of the investigator as 
clinically indicated in accordance with local standard of care and professional society guidelines.  
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 drug. Prohibited medications include all GLP-1 RAs and pramlintide. 
Discontinuation of dipeptidyl peptidase 4 inhibitors at randomization is recommended in line 
with guidelines. Similarly, the use of dipeptidyl peptidase 4 inhibitor therapies during the study 
is also discouraged (Davies et al. 2018).  
Regarding the use of insulin, participants can be included if treated with basal insulin only; and 
are allowed to use prandial insulin if needed during the study to attain optimal glucose control.  
Hyperglycemia Rescue 
Other medications for glycemic control for participants with T2DM meeting severe, persistent 
hyperglycemia criteria for rescue may be added during the study at the investigator’s discretion. 
Rescue therapy with glucose-lowering agents, including basal and prandial insulins, may be 
medically indicated in situations after randomization due to severe, persistent hyperglycemia or 
early discontinuation of study drug. 
Hyperglycemia rescue criteria will be determined from values recorded in T2DM participant 
diaries. If a diary value equal to or greater than the glycemic threshold for rescue (see definitions 
below) is recorded, that value should be confirmed by a repeat fasting glucose text within 
48 hours (for example, local laboratory). Intensification of T2DM therapy should be initiated if 
confirmed fasting glucose values are: 
 ≥15.0 mmol/L (270 mg/dL) from baseline to Week 6 over at least a 2-week period (at 
least 2 consecutive values) after randomization 
 ≥13.3 mmol/L (240 mg/dL) from Week 6 to Week 12 over at least a 2-week period (at 
least 2 consecutive values) 
 ≥11.1 mmol/L (200 mg/dL) from Week 12 to end of trial over at least a 2-week period 
(at least 2 consecutive values) 
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In addition, if HbA1c is >9.0% at Week 12 or >8.0% at Week 24 or later in the study, 
glucose-lowering therapy should be adjusted to improve glycemic control as outlined above. In 
the event a participant’s HbA1c values are less than these thresholds but are higher than what the 
investigator feels comfortable leaving untreated, glucose-lowering medication can be adjusted. In 
addition, if participants develop symptoms of hyperglycemia (for example, polyuria and 
polydipsia), the investigator should implement measures to determine glycemic control and 
adjust as necessary. For participants newly diagnosed with T2DM during the trial, appropriate 
glucose-lowering therapy should be initiated per standard of care. 
Standard of Care for Heart Failure 
Anticipated treatment for heart failure should be decided prior to randomization. 
Both American College of Cardiology/American Heart Association and European Society of 
Cardiology guidelines recommend symptom management with diuretic agents in patients with 
excess volume, as well as aggressive risk factor management for comorbidities for the treatment 
of HFpEF (van der Meer JACC 2019). Optimization of volume status and proactive adjustment 
of diuretic doses will help control symptoms and volume overload. 
Participants should remain on stable doses of medications to treat heart failure condition and 
comorbidities such as hypertension. With the exception of diuretics, dose modification or 
alteration of such background therapies should be avoided unless all other measures fail to 
improve the participant’s condition. However, if the participant’s condition warrants a change in 
any of these medications, it will be allowed at the discretion of the investigator.  
Management of Participants with Gastrointestinal Symptoms 
In the Phase 2 program, the most commonly reported TEAEs for participants receiving 
tirzepatide were nausea, vomiting, and diarrhea. To mitigate GI symptoms and manage 
participants with intolerable GI AEs, the investigator should: 
 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. Also, participants may be 
informed that lower-fat meals could be better tolerated. 
 Prescribe symptomatic medication (for example, anti-emetic or antidiarrheal medication) 
per local country availability and individual participant needs. Use of symptomatic 
medication should be captured as concomitant medication in the eCRF. 
 Temporarily interrupt study drug. See Section 6.6.1. The data related to temporary 
interruption of study drug should be documented in source documents and entered on 
the eCRF. 
 After the interruption, follow the guidance for restarting study drug (Section 6.6.2). 
If intolerable GI symptoms or events persist despite the above measures, other dose 
modifications (see Section 6.6) may be considered. 
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6.6. 
Dose Modification  
Interventions to optimize study drug tolerance and adherence may be employed throughout the 
study and include, but are not limited to, brief temporary interruptions and use of additional 
medications to manage symptoms.  
Dose modifications, including temporary interruption and de-escalation may occur to manage 
issues with tolerability. It is preferred to attempt a temporary dose interruption (at any time) 
(Section 6.6.1) to manage tolerability issues. After a temporary dose interruption, participants 
may resume study drug at the same dose, re-escalate to the prior dose level (if re-escalation is 
desired or required), or resume at a lower MTD dose level, as tolerated. Guidance for resuming 
study drug after a temporary dose interruption should be followed (Section 6.6.2). 
Unwarranted excessive weight reduction: Dose interruption is preferred over de-escalation 
for slowing unwarranted excessive weight loss; however, the method used is at the 
investigator’s discretion. After the dose escalation period and at the investigator’s discretion, 
when excessive weight reduction is not warranted due to safety concerns, the investigator may 
choose to adjust the study drug dose without first attempting a temporary dose interruption. The 
participant’s study drug dose will be permanently reduced to 5 mg, in a blinded fashion for the 
remainder of the study and the dose cannot be re-escalated. A dose adjustment for unwarranted 
excessive weight reduction is completed through the IWRS. Participants on 5 mg will have 
blinded study drug temporarily interrupted (Section 6.6.1).  
Dose reductions for unwarranted excessive weight loss may occur at scheduled and unscheduled 
visits. 
6.6.1. 
Temporary Interruption  
Temporary study drug interruption should be utilized to manage tolerability issues. After 
randomization, the investigator may interrupt study drug, for example, due to an AE (such as 
nausea vomiting, excessive unwarranted weight loss or a clinically significant laboratory value). 
Guidance for resuming study drug after a temporary dose interruption should be followed 
(Section 6.6.2). If study drug interruption is due to an AE, the event is to be followed and 
documented.  
For cases where increased ALT, AST, or ALP occurs, study drug may be interrupted (Section 
6.6.2), and close hepatic monitoring must be initiated (Section 8.2.5.1). The interruption of study 
drug is not equivalent to discontinuation from study treatment. Any interruption of study drug 
does not affect the study visit structure/schedule per the SoA (Section 1.3). Even if study drug is 
interrupted, study procedures should continue during the dose interruption. Every effort should 
be made by the investigator to maintain participants in the study and to restart study drug 
promptly after any interruption, as soon as it is safe to do so (see Section 6.6.2. for restarting 
study drug). Dose interruptions are managed through the IWRS. The data related to interruption 
of study drug will be documented in source documents and entered on the eCRF, however 
participant noncompliance should not be recorded as interruption of study drug on the eCRF. 
Participants who have a temporary interruption of the study drug will continue participating in 
the trial according to the protocol to collect all planned efficacy and safety measurements 
(Section 1.3). 
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6.6.2. 
Restarting Study Drug after Interruption  
In certain situations, the investigator may need to temporarily interrupt study drug. Every effort 
should be made by the investigator to maintain participants on study drug and to restart study 
drug after any temporary interruption, as soon as it is safe to do so. Distribution of study drug at 
the correct dose will be per IWRS instructions. 
If study drug interruption is… 
then… 
1 or 2 consecutive doses 
Participant restarts study drug at last administered 
dose, per escalation schedule. If the participant has 
reached maintenance dose level, the study drug 
dose level will restart at the same prior achieved 
maintenance dose level. 
3 or more consecutive doses 
Participant restarts study drug (at 5 mg, managed 
by IWRS) and repeats dose escalation scheme until 
maintenance dose is reached. If maintenance dose 
has previously been established, the dose escalation 
cannot not exceed the prior achieved maintenance 
dose level. 
Due to an AE 
The event is to be documented and followed 
according to the procedures in Section 8.3. 
Due to intolerable persistent GI AE 
Participants should be treated as suggested in 
Section 6.5. 
Abbreviations: AE = adverse event; GI = gastrointestinal; IWRS = interactive web response service. 
Investigators should inform the sponsor that study drug has been temporarily interrupted.  
Participants are not required to re-escalate to the prior maintenance dose level if a tolerability 
issue recurs during dose re-escalation.  
If this attempted dose re-escalation to the prior maintenance dose level is not tolerated, the dose 
should be reduced to the next lower 5 mg incremental dose that was tolerated (for example, 5 mg 
or 10 mg). The participant will remain at that dose level for the duration of the study. During re-
escalation after a temporary dose interruption, participants should be followed every 4 weeks 
until either a new lower maintenance dose level or prior maintenance dose level is reached.  
For participants receiving 5 mg maintenance dose, no dose de-escalation is permitted. Only dose 
interruption is permitted to manage tolerability issues (Section 6.6.2). This can be performed 
through IWRS.    
In the event that a participant has a temporary interruption that requires extending the escalation 
beyond Visit 8, unscheduled visits are allowed in the IWRS to facilitate a 4-week dispensing 
schedule to complete the escalation. 
If an unscheduled visit occurs in the same week or date of a regular scheduled visit per the SoA, 
the site should complete all procedures included for the regular scheduled visit. Unscheduled 
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visits either in the clinic or by telephone may be conducted to provide support and guidance to 
participants as needed.  
6.7. 
Intervention after the End of the Study  
Tirzepatide will not be made available to participants after conclusion of the study. Due to the 
double-blind study drug assignment, it is not known if a participant received active study drug or 
placebo. Participants will not be unblinded until study end and the final analyses are complete. 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1. 
Discontinuation of Study Intervention  
7.1.1. 
Permanent Discontinuation from Study Drug  
Before permanently discontinuing study drug, attempts to maintain the participant should be 
documented (see Dose Modification, Section 6.6 and Temporary Dose Interruption, Section 
6.6.1). Contact the sponsor before study treatment discontinuation occurs to discuss potential 
options to maintain the participant on study drug until final study ends. It is the goal for 
participants to remain on study drug treatment until study ends.  
Permanent discontinuation of study drug will not automatically lead to discontinuation from the 
study. If study drug is permanently discontinued, the participant will remain in the study and 
attend all scheduled visits to be evaluated for safety and efficacy as described in the SoA.  
Possible reasons leading to permanent discontinuation of study drug: 
 Participant decision 
o The participant or the participant’s designee (for example, legal guardian) requests to 
discontinue study drug  
 Investigator Decision 
o The investigator decides that the participant should be discontinued from study drug 
 Discontinuation due to a hepatic event or liver test abnormality  
Please refer to Section 8.2.5.1 for liver chemistry stopping criteria and Section 8.2.5.4 for 
study drug interruption or discontinuation due to an hepatic event. Participants who 
experience a hepatic event or liver test abnormality should have additional hepatic safety 
data collected via CRF (see Section 8.2.5.1 for details). 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. 
 
 In addition, participants will be permanently discontinued from the study drug in 
the following circumstances:  
o acute or chronic pancreatitis (see Section 10.5.1.2) 
o if a participant is diagnosed with thyroid C-cell hyperplasia, MEN-2, or MTC, or 
pancreatic cancer after randomization 
o if any other TEAE, SAE, or clinically significant laboratory value for which the 
investigator believes that permanent study drug discontinuation is the appropriate 
measure to be taken 
o if a participant is diagnosed with T1DM 
o if a female participant becomes pregnant 
o if an investigator, site personnel performing assessments, or participant is unblinded 
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o if the investigator, after consultation with the sponsor-designated medical resource, 
determines that a clinically significant systemic hypersensitivity reaction has 
occurred. A clinically significant systemic hypersensitivity reaction is one that occurs 
after administration of the study drug (for example, drug-related symptomatic 
bronchospasm, allergy-related edema/angioedema, or hypotension) and requires 
parenteral medication, does not respond to symptomatic medication, results in clinical 
sequelae, or is an anaphylactic reaction. 
o if the participant undergoes any bariatric surgery during the study 
o if the participant begins treatment with a GLP-1RA during the study, 
o in the opinion of the investigator, the participant should permanently discontinue the 
study intervention for safety reasons. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
In order to minimize the amount of missing data and to enable assessment of study objectives as 
planned in the study protocol, every attempt will be made to keep participants in the study, 
irrespective of the following: 
 compliance to study drug 
 adherence to visit schedule 
 missing assessments 
 study drug discontinuation due to AE (Section 7) 
 development of comorbidities, and 
 development of clinical outcomes. 
The circumstances listed above are not valid reasons for participant discontinuation from 
the study.  
Participant will be discontinued from study in the following circumstances:  
 enrollment in any other clinical study involving a study drug or enrollment in any other 
type of medical research judged not to be scientifically or medically compatible with 
this study 
 participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and GCP, and  
 if the participant becomes pregnant.  
A participant may discontinue from the study:  
 at any time at his/her own request  
 at the request of his/her designee (for example, legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
 if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study, or 
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 if the participant, for any reason, requires treatment with a therapeutic agent that 
is prohibited by the protocol and has been demonstrated to be effective for 
treatment of the study indication. In this case, discontinuation from the study 
occurs prior to introduction of the new agent. 
Study discontinuation is expected to be rare and participants should be provided with options for 
alternative follow-up methods and/or end of study vital status/endpoint ascertainment.   
If the participant is unwilling or unable to return for all scheduled follow-up visits in person, the 
site will attempt to collect as much follow-up information as possible via telephone or other 
virtual methods of direct patient contact with the patient. Sites are expected to conduct these 
alternative visit methods according to the visit interval outlined in the Schedule of Activities.  
 An ET visit should be conducted, as shown in the SoA. If the participant refuses to have an ET 
visit in the clinic, efforts should be made to collect data via telephone. See the SoA for data to be 
collected at the time of ET visit. 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, he/she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records.  
7.2.1. 
Inadvertently Enrolled Participants  
If the sponsor or investigator identifies a participant who did not meet enrollment criteria and 
was inadvertently enrolled, then the participant should remain in the study and be discontinued 
from study drug when continued treatment would not be medically appropriate. If the 
investigator and the sponsor CRP agree it is medically appropriate to continue the study drug, the 
investigator must obtain documented approval from the sponsor Chief Medical Officer (CMO) to 
allow the inadvertently enrolled participant to continue study drug. Safety follow-up should be 
performed as outlined in Section 8.2 (Safety Assessments) and Section 8.3 (Adverse Events and 
Serious Adverse Events) of the protocol.  
7.3. 
Lost to Follow up  
A participant will be considered high risk for lost to follow-up if he or she repeatedly fails to 
return for scheduled visits. 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. If a participant refuses all means of completing study visits, contact with 
the patient’s family or the patient’s primary physician or medical record review during the study 
and at the end of the study to ascertain vital status and record safety and efficacy endpoints is 
required.  
The disposition of lost to follow-up will be documented in the eCRF at the time of study end. 
Site personnel should continue to enter missed visits into both IWRS and eCRF. A patient will 
be considered as lost to follow-up only if the patient is unable to be contacted by the study site 
during the study close-out period, and no data on vital status (alive or dead) is available through 
accepted methods for ascertainment, including query of public databases, contact with patient’s 
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family or designee/personal contact (e.g., friend), family doctor, or attempt to determine vital 
status and endpoints via other means (if not prohibited by local laws) (e.g., national 
registries/databases, medical records, voter records, and third-party patient locator services).   
If vital status is determined, this will be documented and the patient will not be considered lost to 
follow-up. If no final visit is available, and vital status is not determined during the study 
close-out period, this will be documented and the patient will be considered lost to follow-up. 
Note:  If the investigator site personnel are unable to contact the patient, they may give the 
patient’s name and last known contact information to a patient locator service to try to find 
current information, if not prohibited by local laws and regulations. The patient locator service 
will not contact the patient directly and any new information they find will be shared with 
investigator site personnel.  
Sponsor personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1)
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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 drug. 
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. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.  
Other visit methods (i.e. remote, telephone) may be considered at the discretion of the 
investigator if a participant is unable to come to their scheduled on-site visit. Alternative options 
to visit procedures must be considered with prior consultation and written approval of the 
sponsor.  
8.1. 
Efficacy Assessments  
8.1.1. 
Primary Efficacy Assessment  
The primary efficacy endpoints are  
 change from baseline to Week 52 in KCCQ-CSS. 
 occurrence of the composite endpoint of CV death and/or HF events over time, and 
Death and heart failure events will be recorded by the investigator at the time of event discovery. 
An independent CEC will adjudicate death (CV, non-CV, unknown cause) and HF events. The 
CEC charter will contain the final detailed event definitions for all adjudicated events. 
8.1.1.1. 
Kansas City Cardiomyopathy Questionnaire  
The KCCQ is a 23-item, participant self-administered questionnaire that assesses impacts of HF 
“over the past 2 weeks” on the following 7 domains (Green et al. 2000; Joseph et al. 2013): 
 Physical Limitation (6 items) 
 Symptom Stability (1 item) 
 Symptom Frequency (4 items) 
 Symptom Burden (3 items) 
 Self-Efficacy (2 items) 
 Quality of Life (3 items), and  
 Social Limitation (4 items). 
Each of the 23 individual items are answered on Likert scales of varying lengths (5-point, 
6-point, or 7-point scales). Domain scores are obtained by averaging the associated individual 
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items and transforming the score to a 0 to 100 range. Higher scores indicate better health status. 
Summary scores are obtained by combining select domain scores: 
 Total Symptom Score: mean of the Symptom Frequency and Symptom Burden scores 
 Clinical Summary Score: mean of the Physical Limitation and Total Symptom 
scores, and 
 Overall Summary Score: mean of the Physical Limitation, Total Symptom, Quality of 
Life, and Social Limitation scores. 
The Clinical Summary Score will be used for the primary and key secondary endpoints.  
KCCQ collections are required per the SoA at Visits 8 and 12 for all participants in the study 
regardless study drug status (on or off study drug).  
If Visit 12 is missed or not performed within the SoA window of the Visit 12 KCCQ 
(52 ± 7 days from Visit 2), it is requested that the KCCQ be performed within 30 days of missed 
Visit 12 date. If a participant discontinues study before reaching Visit 12, a KCCQ must be 
conducted at the early termination visit.  
The KCCQ and all other self-reported questionnaires will be translated into the native language 
of the region, linguistically validated, and administered according to the SoA (Section 1.3). At 
these visits, the questionnaires should be completed before the participant has discussed their 
medical condition or progress in the study with the investigator and/or site staff. 
8.1.1.2. 
Definition of Heart Failure Events  
The heart failure event definition within the protocol includes worsening symptoms or signs of 
HF, which are meaningful to the participant and require intensification of treatment characterized 
by one or more of the following: hospitalization for heart failure regardless of duration or 
treatment received; use of intravenous drug, usually an intravenous diuretic, but may include 
intravenous vasodilators or positive inotropic drugs; or augmentation or increase in oral diuretic 
therapy.  
8.1.2. 
Secondary Efficacy Assessments  
8.1.2.1. 
Six-Minute Walk Test  
Participants will perform an exercise capacity assessment using the 6MWT. Testing of the 
6MWT should be performed as directed in the SoA (Section 1.3). The 6MWT is to be performed 
indoors on a straight, flat, hard surface that is at least 30 meters in length.  
The 6MWTs at Visits 1 and 2 will be performed to assess participant eligibility. The Visit 1 tests 
will also serve as the training test to familiarize participants with the procedure. Additional 
details can be found in Section 10.10.1.  
Prior to and at the end of each 6MWT, participants will be asked to rate their breathing 
discomfort and overall fatigue using the Borg Scale, separately, at each timepoint.  
6MWT are required per the SoA at Visits 8 and 12 for all participants in the study regardless 
study drug status (on or off study drug).  
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If Visit 12 is missed or not performed within the SoA window of the Visit 12 6MWT 
(52 ± 7 days from Visit 2), it is requested that the 6MWT be performed within 30 days of missed 
Visit 12 date.    
If a participant discontinues study before reaching Visit 12, a 6MWT must be conducted at the 
early termination visit.  
8.1.2.2. 
Body Weight and hsCRP  
Body weight will be assessed as described in Section 8.2.1. hsCRP will be assessed as described 
in Section 8.2.4. 
8.1.3. 
Exploratory Efficacy Assessments  
8.1.3.1. 
Patient Global Impression of Status   
Three patient global impression items will be assessed and are described below. 
8.1.3.1.1. Patient Global Impression of Status – Overall  
Study participants will be asked to complete a Patient Global Impression of Status – Overall item 
specifically developed for this study. This is a participant-rated assessment of their overall health 
“in the past 2 weeks” and is rated on a 5-point scale ranging from “1-Excellent” to “5-Poor.” 
8.1.3.1.2. Patient Global Impression of Status – Physical Function  
Study participants will be asked to complete a Patient Global Impression of Status – Physical 
Function item specifically developed for this study. This is a participant-rated assessment of 
the overall impact of HF symptoms on their ability to perform physical activities “in the past 
2 weeks” and is rated on a 5-point scale ranging from “1- Not impacted” to “5- Extremely 
impacted, cannot perform physical activities.” 
8.1.3.1.3. Patient Global Impression of Status – Symptom Severity  
Study participants will be asked to complete a Patient Global Impression of Status – Symptom 
Severity item specifically developed for this study. This is a participant-rated assessment of the 
overall severity of their HF symptoms “in the past 2 weeks” and is rated on a 5-point scale 
ranging from “1- No symptoms” to “5- Very severe.” 
8.1.3.2. 
EQ-5D-5L  
Generic health-related quality of life will be assessed using the EQ-5D-5L (EuroQoL Research 
Foundation 2019). The EQ-5D-5L is a standardized 5-item instrument for use as a measure of 
health outcome. It provides a simple descriptive profile and a single index value for health status 
that can be used in the clinical and economic evaluation of health care as well as population 
health surveys. The EQ-5D-5L comprises 5 dimensions of health (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression). The 5L version, introduced in 2005, scores 
each dimension at 5 levels (no problems, slight problems, moderate problems, severe problems, 
and unable to perform/extreme problems), for a total of 3125 possible health states. In addition to 
the health profile, a single health state index value can be derived based on a formula that 
attaches weights to each of the levels in each dimension. This index value ranges between less 
than 0 (where 0 is a health state equivalent to death; negative values are valued as worse than 
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dead) to 1 (perfect health). In addition, the EQ Visual Analog Scale records the respondent’s 
self-rated health status on a vertical graduated (0 to 100) visual analog scale. In conjunction with 
the health state data, it provides a composite picture of the respondent’s health status. 
The EQ-5D-5L is used worldwide and is available in more than 170 languages. Details on the 
instrument, scoring, organizing, and presenting the data collected can be found in the EQ-5D-5L 
User Guide (EuroQoL Research Foundation 2019). 
8.1.3.3. 
NYHA Classification  
The NYHA classification will be assessed and recorded at the time points indicated in the SoA 
(Section 1.3) by an independent, blinded assessor. The NYHA classification is provided in 
Appendix 11 (Section 10.11). 
8.2. 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Physical Examinations  
● A complete physical examination will include, at a minimum, assessments of the 
CV, respiratory, GI and neurological systems, as well as a thyroid examination.  
o Body weight, waist circumference, and height should be measured. All 
weights for a given participant should be measured in a consistent manner 
using a calibrated scale (mechanical or digital scales are acceptable), using the 
same scale whenever possible, and after the participant has emptied their 
bladder. Participants should be lightly clothed but not wearing shoes while 
their weight is measured.  
● Symptom-directed physical examinations will be conducted as described in 
the SoA. 
o Investigators should pay special attention to clinical signs and symptoms 
related to HF as well as related to previous serious illnesses. Particular interest 
would include dyspnea, orthopnea, paroxysmal nocturnal dyspnea, edema, 
jugular venous distension, and rales.  
The physical examination should be performed before the first 6MWT, if more than one 6MWTs 
are done.  
8.2.2. 
Vital Signs  
For each participant, vital signs measurements should be conducted according to the SoA 
(Section 1.3). An apical heart rate should be assessed during the collection of vital signs. The 
vital signs collection associated with the 6MWT should be separate and may be performed using 
automated equipment.  
Any clinically significant findings from vital signs measurements that result in a diagnosis and 
that occur after the participant receives the first dose of study drug should be reported to the 
sponsor or its designee as an AE via the eCRF. 
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8.2.3. 
Electrocardiograms  
Single 12-lead ECGs will be obtained locally as outlined in the SoA (see Section 1.3).  
All ECGs should be recorded after the participant has been supine for 5 minutes in a quiet room.   
The ECGs must be interpreted by a qualified physician (the investigator or 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 qualified 
designee) is responsible for determining if any change in participant management is needed, and 
must document his/her review of the ECG printed at the time of evaluation. 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 
investigator must report the presence of AF on the eCRF. 
The original ECG must be retained at the investigative site.  
The investigator or qualified designee’s interpretation will prevail for immediate participant 
management purposes. 
8.2.4. 
Clinical Safety Laboratory Assessments  
With the exception of laboratory test results that may unblind the study, the sponsor or its 
designee will provide the investigator with the results of laboratory tests analyzed by a central 
vendor, if a central vendor is used for the clinical trial. 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed. The SoA 
describes the timing and frequency. 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results must be 
retained with source documents unless a Source Document Agreement or comparable document 
cites an electronic location that accommodates the expected retention duration. Clinically 
significant abnormal laboratory findings are those that are not associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the participant's 
condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline levels or are no 
longer considered clinically significant by the investigator or medical monitor. 
 If such values do not return to normal/baseline levels within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor notified. 
 All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the SoA, standard collection requirements, and 
laboratory manual. 
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.  
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All urine pregnancy tests will be performed locally according to the SoA. Guidance for 
contraception and definitions are defined in Appendix 4 (Section 10.4).  
8.2.5. 
Safety Monitoring  
The sponsor will periodically review evolving aggregate safety data within the study by 
appropriate methods. The study team will review safety reports in a blinded fashion according to 
the schedule provided in the Trial-Level Safety Review Plan. The sponsor will also review SAEs 
within time frames mandated by company procedures. The Sponsor CRP will, as appropriate, 
consult with the functionally independent Global Patient Safety therapeutic area physician or 
clinical scientist. 
8.2.5.1. 
Hepatic Safety Monitoring, Evaluation, and Criteria for Study Drug 
Interruption or Discontinuation  
 
The following tables summarize actions to take based on abnormal hepatic laboratory or clinical 
changes. 
 
Participants with normal or near-normal baseline (ALT, AST, or ALP <1.5x ULN) 
If this laboratory value is observed… 
Then… 
Initiate or 
continue 
close hepatic 
monitoring 
Initiate  
comprehensive 
evaluation 
Interrupt or 
discontinue  
study drug 
ALT or AST ≥3x ULN 
X 
 
 
ALP ≥2x ULN  
X 
 
 
TBL ≥2x ULNb 
X 
 
 
ALT or AST ≥5x ULN 
X 
X 
 
ALP ≥2.5x ULN 
X 
X 
 
ALT or AST ≥3x ULN with hepatic signs or symptomsa  
X 
X 
X 
ALT or AST ≥5x ULN for more than 2 weeks  
X 
X 
X 
ALT or AST ≥8x ULN 
X 
X 
X 
ALT or AST ≥3x ULN and TBL ≥2x ULNb or INR≥ 1.5 
X 
X 
X 
ALP ≥3x ULN  
X 
X 
X 
ALP ≥2.5x ULN and TBL ≥2x ULNb 
X 
X 
X 
ALP ≥2.5x ULN with hepatic signs or symptomsa 
X 
X 
X 
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
b In participants with Gilbert’s syndrome, the threshold for TBL may be higher. 
 
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Participants with elevated baseline (ALT, AST, or ALP ≥ 1.5x ULN) 
If this laboratory value is observed… 
Then… 
Initiate or 
continue 
close hepatic 
monitoring 
Initiate  
comprehensive 
evaluation 
Interrupt 
or 
discontinue  
study drug 
ALT or AST ≥2x baseline  
X 
 
 
ALP ≥2x baseline  
X 
 
 
TBL ≥2x ULNb 
X 
 
 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) 
X 
X 
 
ALP ≥2.5x baseline 
X 
X 
 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) with hepatic signs or symptomsa  
X 
X 
X 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) for more than 2 weeks  
X 
X 
X 
ALT or AST ≥4x baseline or ≥400 U/L (whichever occurs 
first) 
X 
X 
X 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) and TBL ≥2x ULNb or INR ≥1.5 
X 
X 
X 
ALP ≥3x baseline  
X 
X 
X 
ALP ≥2.5x baseline and TBL ≥2x ULNb 
X 
X 
X 
ALP ≥2.5x baseline with hepatic signs or symptomsa 
X 
X 
X 
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
b In participants with Gilbert’s syndrome, the threshold for TBL may be higher. 
 
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: 
1. 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 
2. 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 
3. Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5X ULN) 
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o In participants with baseline ALP ≥1.5X ULN, the threshold is ALP ≥2X 
baseline on 2 or more consecutive blood tests 
4. Hepatic event considered to be an SAE 
5. Discontinuation of study drug due to a hepatic event 
Note: the interval between the two consecutive blood tests should be at least 2 days. 
 
8.2.5.2. 
Close Hepatic Monitoring  
Close hepatic monitoring should include these actions: 
 
Laboratory tests (Appendix 8 [Section 10.8]), including ALT, AST, ALP, TBL, D. Bil, 
GGT, CK, and CBC with differential, should be checked within 48 to 72 hours of the 
detection of elevated liver tests to confirm the abnormality and to determine if it is 
increasing or decreasing. 
 
If the abnormality persists, clinical and laboratory monitoring should continue at a 
frequency of 2-3 times weekly until levels normalize or return to approximate baseline 
values.  
 
In addition to lab tests, basic 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 current symptoms, recent illnesses (for example, heart failure, 
systemic infection, hypotension, or seizures), recent travel, concomitant medications 
(including over-the-counter), herbal and dietary supplements, history of alcohol drinking 
and other substance abuse. 
 
8.2.5.3. 
Comprehensive Hepatic Evaluation  
Comprehensive hepatic evaluation should include these actions: 
 
At a minimum, comprehensive hepatic 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, and E; tests for autoimmune hepatitis; and an abdominal imaging 
study, for example, ultrasound or CT scan.  
 
Based on the participant’s history and initial results, further testing should be considered 
in consultation with the Lilly-designated medical monitor, including tests for hepatitis D 
virus (HDV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), 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, and additional tests including magnetic resonance 
cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography 
(ERCP), cardiac echocardiogram, or a liver biopsy.   
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 
Clinical and laboratory monitoring should continue at a frequency of 1-2 times weekly 
until levels normalize or return to approximate baseline values.  
 
All the medical information and test results related to the hepatic monitoring and 
comprehensive hepatic evaluation should be collected and recorded in a hepatic safety 
case report form (CRF).  
 
8.2.5.4. 
Study Drug Interruption or Discontinuation due to a Hepatic Event  
Interruption or discontinuation of study drug should include these actions: 
 
While the participant is not receiving the study drug, clinical and laboratory monitoring 
should continue at a frequency of 1 to 2 times weekly until liver tests normalize or return 
to approximate baseline values.  
 
If the hepatic event continues past the anticipated end of the study (that is, data lock), the 
investigator should consult with the Lilly-designated medical monitor to determine the 
need for further data collection beyond the end date of the study (that is, data lock date). 
 
All the medical information and test results related to the close hepatic monitoring and 
comprehensive hepatic evaluation should be collected and recorded in a hepatic safety 
case report form (CRF).  
 
Resumption of the study drug after interruption for a hepatic reason can be considered 
only in consultation with the Lilly-designated medical monitor and only if the liver test 
results returned to near baseline and if a self-limited non-study-drug etiology is 
identified. Otherwise, the study drug should be permanently discontinued. 
 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Appendix 3 (Section 10.3): 
 Adverse events (AEs) 
 Serious adverse events (SAEs) 
 Product complaints (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 drug or study procedures, or that caused the 
participant to discontinue the study drug or study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs 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).  
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For product complaints, the investigator is responsible for ensuring that follow-up includes any 
supplemental investigations as indicated to elucidate the nature and/or causality. Further 
information on follow-up procedures is provided in Appendix 3 (Section 10.3).  
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study drug or procedure. United States 
21 CFR 312.32, European Union Clinical Trial Directive 2001/20/EC, and the associated 
detailed guidance or national regulatory requirements in participating countries require the 
reporting of SUSARs. The sponsor has procedures that will be followed for the identification, 
recording, and expedited reporting of SUSARs that are consistent with global regulations and the 
associated detailed guidance. 
8.3.1. 
Timing and Mechanism for Collecting Events  
This table describes the timing, deadlines, and mechanism for collecting events. 
 
Event 
Collection 
Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-up 
Method 
of 
Reporting 
Adverse Event 
AE 
Signing of 
the 
informed 
consent 
form (ICF)  
Participation in study has ended 
As soon as 
possible upon 
site awareness 
AE eCRF 
N/A 
Serious Adverse Event 
SAE and 
SAE 
updates – 
prior to start 
of study 
drug and 
deemed 
reasonably 
possibly 
related with 
study 
procedures 
Signing of 
the 
informed 
consent 
form (ICF) 
Start of study drug 
Within 24 
hours of 
awareness 
SAE eCRF  
SAE 
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 
SAE* and 
SAE 
updates – 
after start of 
study drug 
Start of 
study drug 
Participation in study has ended 
Within 24 
hours of 
awareness 
SAE eCRF  
SAE 
paper 
form 
SAE* – 
after 
participant’s 
study 
participation 
has ended 
and the 
investigator 
becomes 
aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper 
form 
N/A 
Pregnancy 
Pregnancy 
in female 
participants 
and female 
partners of 
male 
participants 
After the 
start of 
study drug 
Four months after the last injection 
for female partners of male 
participants and 2 months after the 
last injection for female participants 
Within 24 
hours of 
learning of the 
pregnancy 
Pregnancy 
paper form 
eCRF  
Pregnancy 
paper 
form 
Product Complaints 
PC 
associated 
with an 
SAE or 
might have 
led to an 
SAE 
Start of 
study drug 
End of study drug 
Within 24 
hours of 
awareness 
Product 
Complaint 
form 
N/A 
PC not 
associated 
with an 
SAE 
Start of 
study drug 
End of study drug 
Within 1 
business day 
of awareness 
Product 
Complaint 
form 
N/A 
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Event 
Collection 
Start 
Collection Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-up 
Method 
of 
Reporting 
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 
N/A 
Abbreviations: eCRF = electronic case report form; N/A = not applicable; PC = product complaint; SAE = serious 
adverse event. 
*Serious adverse events, including death, caused by disease progression as described in Section 8.3.2 should not be 
reported unless the investigator deems them to be possibly related to study drug. 
8.3.2. 
Primary, Secondary, and Additional Study Endpoint Reporting  
The following investigator-reported events are considered potential endpoints and must be 
reported first as an AE on the AE eCRF (with the appropriate designation for seriousness). They 
must then be reported as an endpoint on the eCRF with all required source documents provided 
for adjudication to the CEC. These potential endpoints (even if they meet criteria for a serious 
event) are not to be reported on the SAE eCRF unless considered as possibly related to study 
drug, the drug delivery system, or study procedure. Potential endpoints that are serious and 
considered as possibly related to study drug, the drug delivery system, or study procedure must 
also be reported as an SAE using the SAE eCRF: 
 all-cause mortality (death), and 
 HF events. 
In the case where 1 of the above endpoint events is reported but does not meet a prespecified 
event definition detailed in the CEC charter, as reviewed by the independent CEC, no further 
action will be taken by the study site. 
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8.3.3. 
Adverse Events of Special Interest  
The following are AESI and will be adjudicated by an external adjudication committee. This 
committee will be blinded to treatment assignment. 
 pancreatitis 
 major adverse CV events (see Section 10.5.1.5), and 
 deaths 
The following are additional AESI for this program that will not be adjudicated by an external 
committee: 
 hepatobiliary disorders 
 severe hypoglycemia  
 thyroid malignancies and C-cell hyperplasia  
 supraventricular arrhythmias and cardiac conduction disorders 
 allergic/hypersensitivity reactions, including injection site reactions and ADA formation 
 severe GI AEs, and  
 acute renal events. 
Sites should collect additional details and data regarding AESI, as instructed on the applicable 
eCRFs, and detailed in Section 10.5. 
The details on the definition of AESI will be provided in SAP. 
8.4. 
Treatment of Overdose  
Considering the mechanism of action of tirzepatide, potential overdose effects can be GI 
disorders and hypoglycemia. In the event of overdose, appropriate supportive treatment should 
be initiated according to the participant’s clinical signs and symptoms.  
Study drug overdose (defined as injection of study drug more than 1 time within 72 hours) will 
be reported as an AE. 
In the event of an overdose, the investigator should 
 contact the medical monitor immediately 
 evaluate the participant to determine, in consultation with the medical monitor, whether 
study intervention should be interrupted or whether the dose should be reduced, and 
 closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate. 
8.5. 
Pharmacokinetics  
Pharmacokinetic samples will be collected from all participants in this study. 
Tirzepatide plasma concentrations will be determined from blood samples obtained from 
participants receiving tirzepatide treatment. Blood samples collected from participants assigned 
to the placebo arm will not be included in the bioanalysis of drug concentrations.  
Blood samples for PK assessment will be collected prior to the dose administration and at the 
same time as the planned immunogenicity samples (that is, at Week 0 and then at Weeks 4, 12, 
24, and 52 per the Study Schedule or additionally at follow-up and ET (reference SoA). 
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Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.  
Concentrations of tirzepatide will be assayed using a validated liquid chromatography mass 
spectrometry method. Bioanalytical samples collected to measure tirzepatide concentrations will 
be retained for a maximum of 1 year following last participant visit for the study 
(Section 10.1.10). During this time, samples remaining after the bioanalyses may be used for 
exploratory analyses such as metabolism work, protein binding, and/or bioanalytical method 
cross-validation. 
8.6. 
Pharmacodynamics  
Pharmacodynamic parameters will not be evaluated in this study. 
8.7. 
Genetics  
A whole blood sample will be collected for pharmacogenetic analysis where local regulations 
allow.  
See Appendix 2, Clinical Laboratory Tests (Section 10.2), and Section 1.3 (SoA) for sample 
collection information. 
See Section 10.6 for genetic research, custody, and sample retention information. 
8.8. 
Biomarkers  
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of participant response 
(including safety), and clinical outcome. Sample collection is incorporated into clinical studies to 
enable examination of these questions through measurement of biomolecules including DNA, 
RNA, proteins, lipids, and other cellular elements. 
Serum and plasma for exploratory biomarker research will be collected at the time specified in 
the SoA (Section 1.3) where local regulations allow. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigator site personnel. 
Samples will be stored and analysis may be performed on biomarkers thought to play a role in 
disease processes, mechanism of action of tirzepatide, pathways associated with HFpEF, and/or 
research methods validating diagnostic tools or assay(s) related to HFpEF and associated 
diseases. Biomarkers may be evaluated to determine their association with observed clinical 
responses to tirzepatide and the disease state. 
Samples will be retained at a facility selected by the sponsor or its designee for the duration 
detailed in Section 10.1.10, or for a shorter period if local regulations and ERBs impose shorter 
time limits. This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in the 
development of tirzepatide or after tirzepatide becomes commercially available. 
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8.9. 
Immunogenicity Assessments  
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
to determine antibody production against tirzepatide. Antibodies may be further characterized for 
cross-reactive binding to endogenous counterparts (native GIP and GLP-1) and their ability to 
neutralize the activity of tirzepatide and endogenous counterparts. To interpret the results of 
immunogenicity, a venous blood sample will be collected at the same time points to determine 
the plasma concentrations of tirzepatide. All samples for immunogenicity should be taken 
predose when applicable and possible. 
 
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and ERBs allow, at a facility selected by the sponsor. The 
duration allows the sponsor to respond to future regulatory requests related to tirzepatide. Any 
samples remaining after 15 years will be destroyed. 
8.10. 
Medical Resource Utilization and Health Economics  
Not applicable.
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9. 
Statistical Considerations  
9.1. 
Statistical Hypotheses  
Two primary hypotheses will be tested in this study: 
 Tirzepatide MTD is superior to placebo for the change from baseline to Week 52 in 
KCCQ-CSS.  
 Tirzepatide MTD is superior to placebo for the occurrence of the composite endpoint of 
CV death and/or HF events over time.  
Key secondary hypotheses (all under multiplicity control) are that tirzepatide MTD is superior to 
placebo with regards to 
 change from baseline to Week 52 in 6MWD 
 percent change from baseline to Week 52 in body weight, and 
 change from baseline to Week 52 in hsCRP. 
 
All primary and key secondary hypotheses will be tested with the overall family-wise type I error 
rate at a 2-sided alpha level of 0.05 through the multiplicity control approach based on the 
graphical multiple testing procedure. For the primary hypotheses, the HF outcome will be tested 
at a 2-sided alpha level of 0.04, and change in KCCQ-CSS will be tested at a 2-sided alpha level 
of 0.01 in parallel for statistical significance. If significant, the respective alpha of the primary 
endpoints will be propagated to test the key secondary endpoints. If any of the primary endpoints 
is not significant, then the appropriate alpha after the key secondary endpoints testing will be 
recycled to that primary endpoint. The detailed graphical testing scheme will be outlined in the 
SAP. 
9.2. 
Sample Size Determination  
A sample size of 700 participants (350 in each treatment group) will provide roughly 80% power 
for the change from baseline to Week 52 in KCCQ-CSS using Wilcoxon rank sum test under the 
assumptions that the change from baseline to Week 52 in KCCQ-CSS follows normal 
distribution with mean of 5 and standard deviation of 19 in placebo and mean of 10 and standard 
deviation of 19 in tirzepatide group at a 2-sided alpha of 0.01 significance level. The expected 
events at the end of the study will provide roughly 80% power to demonstrate the superiority of 
tirzepatide MTD to placebo in occurrence of the composite endpoint of CV death and/or HF 
events at a 2-sided alpha of 0.04 significance level under the treatment effect estimate 
assumption of 0.5. The study power is calculated using nQuery Version 9.1. 
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9.3. 
Populations for Analyses  
The following populations are defined: 
Analysis Population 
Description 
Entered 
All participants who sign the informed consent form 
Randomized/Intent-to-Treat 
(ITT) Population 
All participants assigned to treatment, regardless of whether 
they take any doses of study treatment, or if they took the 
correct treatment. Participants will be analyzed according to the 
treatment group to which they were assigned. 
Safety Population 
All participants in ITT population who take at least 1 dose of 
study treatment. Participants will be analyzed according to the 
treatment group to which they were assigned. 
9.4. 
Statistical Analyses  
9.4.1. 
General Considerations  
Statistical analysis of this study will be the responsibility of sponsor or its designee. 
Unless specified otherwise, all tests of treatment effects will be conducted at a 2-sided alpha 
level of 0.05 and all confidence intervals will be given at a 2-sided 95% level. Efficacy will be 
assessed using ITT Population and safety will be assessed using the Safety Population.  
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP and the CSR. Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
The SAP will be completed prior to first unblinding and any subsequent amendments will be 
documented, with final amendments finalized prior to final database lock. The SAP 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. 
9.4.2. 
Primary Endpoint(s)  
The primary estimand for primary endpoints is to assess the treatment difference between 
tirzepatide and placebo relative to the efficacy measures for all randomized participants, and 
treatment policy strategy will be used to handle all intercurrent events, which is, all the observed 
values for the variable of interest are used regardless of whether the intercurrent event occurs. 
The endpoint and population-level summary for the estimand is described in Section 9.4.2.1 and 
Section 9.4.2.2 for each primary endpoint. 
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9.4.2.1. 
Change from Baseline in KCCQ-CSS  
For the primary endpoint of change from baseline to Week 52 in KCCQ-CSS, a stratified 
Wilcoxon (Van Elteren) test will be used as the primary analysis method, controlling for the 
stratification factors of HF decompensation within 12 months of screening (Y/N), diagnosed 
T2DM (Y/N), and baseline BMI ≥35 kg/m2 (Y/N). Population-level summary of Hodges-
Lehmann estimate for the median difference and corresponding confidence interval will be 
reported. 
The last measurement prior to randomization KCCQ-CSS will be used as baseline. Missing 
KCCQ-CSS at Week 52 will be imputed through multiple imputations based on the reason of 
missingness with details described in the SAP. The statistical inference over multiple 
imputations will be guided by the method proposed by Rubin (1987). 
9.4.2.2. 
Occurrence of CV Death and/or HF Event over time  
The primary analysis model will include fixed factors of treatment and the stratification factors 
of HF decompensation within 12 months of screening (Y/N), diagnosed T2D (Y/N), and baseline 
BMI ≥35 kg/m2 (Y/N). The analysis model with a full list of covariates will be specified in the 
SAP. The censoring date for a participant is the date of participant’s end of follow-up. The 
missing data due to censoring will be implicitly handled by the model, assuming censoring is 
independent of the outcome. The treatment effect estimate, with its 95% CI and p-value, will be 
provided using the primary analysis model. 
The estimated cumulative event curve over time will be provided. Counts and proportions of 
participants who experience a primary endpoint event will be calculated as well as counts of 
primary endpoint events. The total person-years of follow-up, the incidence rate per 100 person-
years of follow-up, and the absolute risk difference will be provided. 
9.4.3. 
Key Secondary Endpoint(s)  
Analyses for the key secondary endpoints will also be guided by the treatment policy strategy.  
Change from baseline in 6MWD at Week 52 will be analyzed using the same nonparametric 
approach as described in Section 9.4.2.1.  
Percent change from baseline in body weight will be analyzed using an analysis of covariance 
(ANCOVA) analysis. The ANCOVA model will include the categorical effect of treatment, 
stratification factors, and the continuous covariate of baseline body weight value. Missing data 
will be imputed through multiple imputations based on the reason of missingness with details 
described in the SAP.  
Change from baseline in hsCRP will be analyzed using an ANCOVA model. The ANCOVA 
model will include the categorical effect of treatment, stratification factors, and the continuous 
covariate of baseline hsCRP value. The ANCOVA model will be based on the log-transformed 
values of hsCRP. Missing data will be imputed through multiple imputations based on the reason 
of missingness with details described in the SAP.  
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9.4.4. 
Tertiary/Exploratory Endpoint(s)  
The analyses for exploratory endpoints will be described in the SAP. Statistical tests will be 
performed at the two-sided significance level of 0.05. There will be no multiplicity adjustment 
for any analysis of exploratory variables unless specified otherwise. Missing values will not be 
explicitly imputed unless specified otherwise. 
9.4.5. 
Other Safety Analyses  
Safety will be assessed by summarizing and analyzing AEs, special safety topics, laboratory 
analytes, and vital signs. All safety analyses will be made on the Safety Population. Unless 
specified otherwise, all data obtained during study period from Safety Population, regardless of 
adherence to study drug, will be used for safety analyses. The details for safety analysis will be 
described in the SAP. 
Adverse events will be coded from the actual term using MedDRA and reported with preferred 
terms and system organ class.  
9.4.5.1. 
Evaluation of Immunogenicity  
The frequency and percentage of participants with preexisting ADAs and with treatment-
emergent ADAs to tirzepatide will be tabulated. Treatment-emergent ADAs are defined as those 
with a titer 2-fold (1 dilution) greater than the minimum required dilution of the ADA assay if no 
ADAs were detected at baseline (treatment-induced ADA), or those with a 4-fold (2 dilutions) 
increase in titer compared with baseline if ADAs were detected at baseline (treatment-boosted 
ADA). The details of analyses for immunogenicity will be specified in SAP. 
9.4.6. 
Subgroup Analyses  
Subgroup variables to be evaluated for the primary efficacy endpoint may include demography 
(for example, race, ethnicity), baseline disease characteristics (for example, diagnosed T2DM) 
and others. Subgroup analyses may also be performed for selected secondary efficacy endpoints. 
Details for the subgroup analyses will be provided in the SAP. 
9.5. 
Interim Analyses  
Based on the projected enrollment, approximately 4 interim analyses of safety will be conducted. 
The first interim analysis is planned to occur when approximately 20% of the anticipated number 
of participants are randomized or 6 months after the first participant is randomized, whichever 
occurs later, followed by subsequent reviews approximately every 6 months throughout 
the study. 
The DMC is authorized to evaluate unblinded interim analyses. Study sites will receive 
information about interim results only if they need to know for the safety of their participants.  
Unblinding details are specified in a separate unblinding plan document. 
The DMC charter will describe the planned interim analyses in detail. 
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9.6. 
Data Monitoring Committee  
An independent DMC with members all external to the sponsor will be used to monitor 
participant safety in an unblinded fashion. For details on the DMC, refer to the DMC charter.
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines, 
including the Declaration of Helsinki and CIOMS International Ethical 
Guidelines 
o Applicable ICH GCP guidelines 
o International Organization for Standardization (ISO) 14155 
o 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: 
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
 Investigator sites are compensated for participation in the study as detailed in the clinical 
trial agreement. 
10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
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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 his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant or his/her legally authorized representative and answer all 
questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA requirements, where 
applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the participant was entered in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Participants must be re-consented 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 his/her data to be used as 
described in the informed consent.  
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The sponsor has processes in place to ensure data protection, information security, and data 
integrity. These processes include appropriate contingency plan(s) for appropriate and timely 
response in the event of a data security breach. 
10.1.5. 
Dissemination of Clinical Study Data  
Report Preparation 
An investigator will sign the final CSR for this study, indicating agreement that, to the best of his 
or her knowledge, the report accurately describes the conduct and results of the study. 
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Public Access to Reports and 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. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of PK, immunogenicity, or genetic data. Data are available to 
request 6 months after the indication studied has been approved in the United States and after 
primary publication acceptance, whichever is later. No expiration date of data requests is 
currently set once they 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.  For details on submitting a request, see the instructions provided at 
www.clinicalstudydatarequest.com. 
Publications/Publication Policy 
The publication policy is described in Section 10.1.9. 
10.1.6. 
Data Quality Assurance  
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (for example, laboratory data or an 
electronic source, such as eCOA). 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. 
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. 
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Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the clinical trial agreement unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
In addition, the sponsor or its representatives will periodically check a sample of the participant 
data recorded against source documents at the study site. The study may be audited by the 
sponsor or its representatives, and/or regulatory agencies at any time. Investigators will be given 
notice before an audit occurs. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An EDC system will be used in this study for the collection of CRF data. The investigator 
maintains a separate source for the data entered by the investigator or designee into the 
sponsor-provided EDC system. The investigator is responsible for the identification of any data 
to be considered source and for the confirmation that data reported are accurate and complete by 
signing the CRF. 
Additionally, eCOA data (patient-reported outcomes instruments) will be directly recorded by 
the participant, into a device (for example, hand-held 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 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 system(s). Prior to decommissioning, the investigator will receive 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 (as applicable) will be provided to the 
investigator for review and retention. Data will subsequently be transferred from the central 
vendor to the sponsor data warehouse. 
Data from complaint forms submitted to the sponsor will be encoded and stored in the global 
product complaint management system. 
10.1.7. 
Source Documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents, or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
Definition of what constitutes source data can be found in Section 10.1.6.  
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10.1.8. 
Study and Site Start and Closure  
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 open and will be the study start date. 
The sponsor 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: 
 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 of participants by the investigator 
 Discontinuation of further study drug development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and assures 
appropriate participant therapy and/or follow-up. 
10.1.9. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of this study will be submitted 
for publication by a peer-reviewed journal. 
10.1.10. 
Long-Term 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 the 
intervention or after the intervention becomes commercially available. 
This table describes the retention period for potential sample types. 
Sample Type  
Custodian  
Retention Period After Last 
Participant Visit 
Genetics sample 
Sponsor or designee 
up to 15 years 
Exploratory biomarker sample 
Sponsor or designee 
up to 15 years 
Immunogenicity (antidrug antibody) sample 
Sponsor or designee 
up to 15 years 
Pharmacokinetic sample 
Sponsor or designee 
up to 1 years 
 
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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 
10.2. 
Appendix 2: Clinical Laboratory Tests  
● Clinical laboratory testing will be performed according to the SoA (Section 1.3). 
● Central and local laboratories will be used. The table below describes when the 
local or central laboratory will be used  
● 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. 
● Pregnancy testing will be performed according to the SoA.  
● Investigators must document their review of the laboratory safety results. 
Laboratory results that will not be reported to investigative sites or other blinded 
personnel are noted in the table below. 
Refer to Section 10.7 for recommended laboratory testing for hypersensitivity events. 
Clinical Laboratory Tests  
Comments   
Hematology 
Assayed by Lilly-designated laboratory.  
Hemoglobin 
  
Hematocrit 
  
Erythrocyte count (RBCs [red blood cells]) 
  
Mean cell volume  
  
Mean cell hemoglobin concentration 
  
Leukocytes (WBCs [white blood cells])  
  
Differential 
  
   Neutrophils, segmented 
  
   Lymphocytes 
  
   Monocytes 
  
   Eosinophils 
  
   Basophils 
  
Platelets 
  
Clinical Chemistry 
Assayed by Lilly-designated laboratory.  
Sodium 
  
Potassium 
  
Chloride 
  
Bicarbonate 
  
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Clinical Laboratory Tests  
Comments   
Total bilirubin 
  
Direct bilirubin 
  
Alkaline phosphatase (ALP) 
  
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 
Glucose 
  
Lipids 
 
Total cholesterol 
 
Direct LDL-C 
 
HDL-C 
 
VLDL-C 
 
Triglycerides 
 
Pancreas (Exocrine) 
Assayed by Lilly-designated laboratory.  
Pancreatic amylase 
 
Lipase 
 
Special Chemistry 
Assayed by Lilly-designated laboratory. 
Hemoglobin A1c (HbA1c) 
 
Calcitonin 
 
Cystatin C 
 
N-terminal pro b-type natriuretic peptide (NT-
proBNP) 
 
Cardiac troponin T (cTnT) 
 
C-reactive protein, high-sensitivity (hsCRP) 
 
Thyroid stimulating hormone 
 
Urine Chemistry 
Assayed by Lilly-designated laboratory.  
Albumin 
 
Creatinine 
 
Calculation 
 
eGFR (calculated by CKD-EPI equation) 
Will be calculated by the Lilly-designated laboratory at all visits.  
Urine albumin, creatinine, UACR 
 
Hormones (female) 
Urine Pregnancy 
Local laboratory 
Serum Pregnancy 
Assayed by Lilly-designated laboratory.  
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Clinical Laboratory Tests  
Comments   
Follicle Stimulating Hormone (FSH) 
Assayed by Lilly-designated laboratory.  
Pharmacokinetic Samples   
 
Assayed by Lilly-designated laboratory.  
 
Results will not be provided to the investigative sites. 
 
In the event of systemic drug hypersensitivity reactions 
(immediate or nonimmediate), additional blood samples will be 
collected including ADA, PK, and exploratory biomarker 
samples. PK samples for immunogenicity must be taken prior 
to drug administration. 
Genetics sample 
Whole blood (EDTA) 
 
Assayed by Lilly-designated laboratory.  
 
Results will not be provided to the investigative sites. 
Exploratory Biomarker Samples  
 
Assayed by Lilly-designated laboratory.  
 
Results will not be provided to the investigative sites. 
Serum 
  
EDTA Plasma 
  
P800 Plasma 
 
Immunogenicity Samples 
 
Anti-tirzepatide antibodies 
Anti-tirzepatide neutralizing antibodies 
 
 
 
Assayed by Lilly-designated laboratory.  
 
Results will not be provided to the investigative sites. 
 
In the event of systemic drug hypersensitivity reactions 
(immediate or nonimmediate), additional blood samples will be 
collected including ADA, PK, and exploratory biomarker 
samples. PK samples for immunogenicity must be taken prior 
to drug administration.  
Abbreviations: ADA = antidrug antibody; CKD-EPI = Chronic Kidney Disease-Epidemiology Collaboration; 
EDTA = ethylenediaminetetraacetic acid; eGFR = estimated glomerular filtration rate; HDL-C = high-density 
lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lilly = Eli Lilly and company; 
PK = pharmacokinetic; UACR = urine albumin/creatinine ratio; VLDL-C = very low-density lipoprotein 
cholesterol. 
 
 
 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting  
The definitions and procedures detailed in this appendix are in accordance with ISO 14155. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study. See Section 6.1.1 for the list of sponsor 
medical devices). 
10.3.1. 
Definition of AE  
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study drug. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory finding) in study participants, users, or 
other persons, whether or not related to the investigational medical device. This 
definition includes events related to the investigational medical device or comparator 
and events related to the procedures involved except for events in users or other 
persons, which only include events related to investigational devices.  
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, 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 conditions detected or diagnosed after study drug administration even though they 
may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug 
or a concomitant medication. Overdose per se will not be reported as an AE/SAE 
unless it is an intentional overdose taken with possible suicidal/self-harming intent. 
Such an overdose should be reported regardless of sequelae.  
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
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However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as an 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 which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (for example, endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 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  
If an event is not an AE per the definition above, then it cannot be an SAE even if serious 
conditions are met (for example, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease). 
SAE is defined as any untoward medical occurrence that, at any dose: 
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 the 
hospital 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. 
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d. Results in persistent disability/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/birth defect 
 Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. 
f. 
Other situations: 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers; intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization; or development of drug dependency or 
drug abuse.  
g. Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.  
Definition of Serious Adverse Device Effect (SADE) 
An SADE is defined as an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event. 
Definition of Unanticipated Adverse Device Effect (UADE) 
An UADE is a serious adverse effect on health or safety or any life-threatening problem or 
death caused by or associated with a device, if that effect, problem, or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
application (including a supplementary plan or application) or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of the participant. 
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10.3.3. 
Definition of Product Complaints  
Product Complaint 
 A product complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
or performance of a study drug. When the ability to use the study drug safely is 
impacted, the following are also product complaints: 
o Deficiencies in labeling information, and 
o Use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 Product complaints related to study drugs used in clinical trials are collected in order to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a product complaint or problem with the study drug so that the situation can be 
assessed. 
 An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and Product Complaint Recording 
When an AE/SAE/product complaint occurs, it is the responsibility of the investigator to 
review all documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
The investigator will then record all relevant AE/SAE/product complaint information in the 
participant’s medical records, in accordance with the investigator’s normal clinical practice. 
AE/SAE information is reported on the appropriate eCRF page and product complaint 
information is reported on the Product Complaint Form. 
Note: An event may meet the definition of both a product complaint and an AE/SAE. In such 
cases, it should be reported as both a product complaint and as an AE/SAE. 
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the eCRF page for AE/SAE and the 
Product Complaint Form for product complaints. 
There may be instances when copies of medical records for certain cases are requested by 
sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission to 
sponsor or designee. 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.  
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Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to one of the following categories:  
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
 Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with an SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.  
Assessment of Causality 
 The investigator is obligated to assess the relationship between study drug and each 
occurrence of each AE/SAE. 
 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. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study drug administration 
will be considered and investigated. 
 The investigator will also consult the IB in his/her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change his/her 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.  
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Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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. 
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 paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken offline to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the sponsor by telephone. 
 Contacts for SAE reporting can be found in the study training.  
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 towards the safety of participants and the 
safety of a study drug 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 drug under clinical investigation. 
The sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (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.  
 As required by local regulations, the investigator will report to their IRB/IEC any 
UADE (unanticipated problem that resulted in an SAE), or any product complaint that 
could have led to an SAE had precautions not been taken. 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information  
10.4.1. 
Male participants:  
Men, regardless of their fertility status, with nonpregnant WOCBP partners must agree to either 
remain abstinent (if this is their preferred and usual lifestyle) or use condoms, as well as 1 
additional highly effective (˂1% failure rate) method of contraception (such as combination oral 
contraceptives, implanted contraceptives, or intrauterine devices) or effective method of 
contraception (such as diaphragms with spermicide or cervical sponges) for the duration of the 
study and until their plasma concentrations are below the level that could result in a relevant 
potential exposure to a possible fetus, predicted to be 90 days plus 5 half-lives following the last 
dose of study drug, which is approximately 4 months after the last injection. 
a) Men and their partners may choose to use a double-barrier method of contraception. 
(Barrier protection methods without concomitant use of a spermicide are not an effective 
or acceptable method of contraception. Thus, each barrier method must include use of a 
spermicide. It should be noted, however, that the use of male and female condoms as a 
double-barrier method is not considered acceptable due to the high failure rate when 
these barrier methods are combined.) 
b) Periodic abstinence (for example, calendar, ovulation, symptothermal, or postovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
Men with pregnant partners should use condoms during intercourse for the duration of the study 
and until the end of the estimated, relevant potential exposure in WOCBP (4 months). 
Men should refrain from sperm donation for the duration of the study and until their plasma 
concentrations are below the level that could result in a relevant potential exposure to a possible 
fetus, predicted to be 90 days plus 5 half-lives following the last dose of study drug, which is 
approximately 4 months.  
Men who are in exclusively same-sex relationships (as their preferred and usual lifestyle) are not 
required to use contraception.  
10.4.2. 
Female participants:  
Women of childbearing potential who are abstinent (if this is complete abstinence, as their 
preferred and usual lifestyle) or in a same-sex relationship (as part of their preferred and usual 
lifestyle) must agree to either remain abstinent or stay in a same-sex relationship without sexual 
relationships with males. Periodic abstinence (for example, calendar, ovulation, symptothermal, 
or postovulation methods), declaration of abstinence just for the duration of a trial, and 
withdrawal are not acceptable methods of contraception. 
Otherwise, WOCBP participating must agree to use 2 forms of effective contraception, where at 
least 1 form is highly effective (˂than 1% failure rate), for the entirety of the study. 
Contraception must continue following completion of study drug administration for the entirety 
of the study and for 4 weeks after the last injection.  
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a) WOCBP participating must test negative for pregnancy prior to initiation of treatment as 
indicated by a negative serum pregnancy test at the screening visit followed by a negative 
urine pregnancy test within 24 hours prior to exposure.  
b) Two forms of effective contraception, where at least 1 form is highly effective (such as 
combination oral contraceptives, implanted contraceptives, or intrauterine devices) will 
be used for the duration of the trial and for 2 months after the last injection. Effective 
contraception (such as male or female condoms with spermicide, diaphragms with 
spermicide, or cervical sponges) may be used as the second therapy. Barrier protection 
methods without concomitant use of a spermicide are not a reliable or acceptable method. 
Thus, each barrier method must include use of a spermicide (that is, condom with 
spermicide, diaphragm with spermicide, or female condom with spermicide). It should be 
noted that the use of male and female condoms as a double-barrier method is not 
considered acceptable due to the high failure rate when these methods are combined. 
c) Not be breastfeeding. 
Women not of childbearing potential may participate and include those who are: 
a) Infertile due to surgical sterilization, or 
b) Postmenopausal. 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (for example, amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study drug, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(for example, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
Note: Determination can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female is defined as follows: 
a. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy with or 
without hysterectomy, confirmed by operative note  
b. A woman at least 40 years of age and up to 55 years old with an intact uterus, not on 
hormone therapy*, who has had cessation of menses for at least 12 consecutive 
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months without an alternative medical cause, AND with a follicle-stimulating 
hormone >40 mIU/mL; or  
c. A woman 55 or older not on hormone therapy, who has had at least 12 months of 
spontaneous amenorrhea, or 
d. A woman at least 55 years of age with a diagnosis of menopause prior to starting 
hormone replacement therapy. 
* Women should not be taking medications during amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormone, anti-estrogens, selective estrogen receptor modulators 
(SERMs), or chemotherapy that could induce transient amenorrhea. 
Contraception Guidance: 
Highly Effective Methods of Contraception: 
 Combined oral contraceptive pill and mini pill 
 NuvaRing® 
 Implantable contraceptives 
 Injectable contraceptives (such as Depo-Provera®) 
 Intrauterine device (such as Mirena® and ParaGard®) 
 Contraceptive patch – ONLY women <198 pounds or 90 kg 
 Total abstinence (if this is their preferred and usual lifestyle) or in a same-sex relationship 
with no sexual relationship with males (as part of their preferred and usual lifestyle). 
Note: periodic abstinence (for example, calendar, ovulation, symptothermal, postovulation 
methods), declaration of abstinence just for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
Note: Implantable contraceptives and injectable contraceptives (such as Depo-Provera) are only 
permitted if started prior to screening. Participants should not start these methods of 
contraception after being enrolled in the study. 
 Vasectomy - for men in clinical trials 
Effective Methods of Contraception (must use combination of 2 methods): 
 Male condom with spermicide 
 Female condom with spermicide 
 Diaphragm with spermicide 
 Cervical sponge 
 Cervical cap with spermicide 
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. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
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submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. 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 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 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 drug 
by the investigator will be reported to the sponsor as described in protocol Section 8.3.1. 
While the investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
 Any female participant who becomes pregnant while participating in the study will 
discontinue study drug and be withdrawn from the study.  
 
 
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10.5. 
Appendix 5: Adverse Events of Special Interest: Definitions and 
Procedures for Recording, Evaluating, Follow-Up, and Reporting.  
10.5.1. 
Special Safety Topics  
10.5.1.1. Hypoglycemia  
Upon ICF signing, all participants will be educated about signs and symptoms of hypoglycemia, 
how to treat hypoglycemia, and how to collect appropriate information for each episode of 
hypoglycemia.  
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by BG samples collected 
during study visits.  
All participants with T2DM and who develop diabetes during the study will be provided with 
glucometers. 
Participants with T2DM will be provided a diary to record relevant information (for example, 
glucose values, symptoms). 
All hypoglycemic episodes are to be recorded on a specific eCRF and should not be otherwise 
recorded as AEs unless the event meets severe criteria. If a hypoglycemic event meets severe 
criteria (see definition below), it should be recorded as serious on the AE eCRFs, and reported to 
the sponsor as an SAE. 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). 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the BG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine blood-equivalent glucose meters and strips) in accordance with the 2020 American 
Diabetes Association position statement on glycemic targets (ADA 2020): 
Glucose Alert Value (Level 1): 
 Documented symptomatic hypoglycemia is defined as any time a participant feels that he 
or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
BG level of <70 mg/dL (<3.9 mmol/L). 
 Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia, but with a measured BG <70 mg/dL (<3.9 mmol/L). 
 Documented unspecified hypoglycemia is defined as any event with no information about 
symptoms of hypoglycemia available, but with a measured BG <70 mg/dL 
(<3.9 mmol/L). 
Clinically Significant Hypoglycemia (Level 2): 
 Documented symptomatic hypoglycemia is defined as any time a participant feels that he 
or she is experiencing symptoms and/or signs associated with hypoglycemia and has a 
BG level of <54 mg/dL (<3.0 mmol/L). 
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 Documented asymptomatic hypoglycemia is defined as any event not accompanied by 
typical symptoms of hypoglycemia but with a measured BG <54 mg/dL (<3.0 mmol/L). 
 Documented unspecified hypoglycemia is defined as any event with no information about 
symptoms of hypoglycemia available but with a measured BG <54 mg/dL 
(<3.0 mmol/L). 
Severe Hypoglycemia (Level 3): 
 Severe hypoglycemia is defined as an episode with severe cognitive impairment requiring 
the assistance of another person to actively administer carbohydrate, glucagon, or other 
resuscitative actions. These episodes may be associated with sufficient neuroglycopenia 
to induce seizure or coma. Blood glucose measurements may not be available during such 
an event, but neurological recovery attributable to the restoration of BG to normal is 
considered sufficient evidence that the event was induced by a low BG concentration. 
Nocturnal Hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that occurs at 
night, presumably during sleep. 
10.5.1.2. Pancreatitis  
Acute pancreatitis is defined as an AE of interest in all trials with tirzepatide, including this trial. 
Acute pancreatitis is an acute inflammatory process of the pancreas that may also involve 
peripancreatic tissues and/or remote organ systems (Banks and Freeman 2006). The diagnosis of 
acute pancreatitis requires 2 of the following 3 features: 
 abdominal pain, characteristic of acute pancreatitis (generally located in the epigastrium 
and radiates to the back in approximately half the cases) (Banks and Freeman 2006; 
Koizumi et al. 2006); the pain is often associated with nausea and vomiting 
 serum amylase (total and/or pancreatic) and/or lipase ≥3X ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
If acute pancreatitis is suspected, appropriate laboratory tests (including levels of pancreatic 
amylase and lipase) should be obtained via the central laboratory (and locally, if needed). 
Imaging studies, such as abdominal CT scan with or without contrast, MRI, or gallbladder 
ultrasound, should be performed. Abdominal ultrasound may be used as an alternative method 
only if CT and MRI cannot be performed. If laboratory values and/or abdominal imaging support 
the diagnosis of acute pancreatitis, the participant must discontinue therapy with tirzepatide but 
will continue in the study. A review of the participant’s concomitant medications should be 
conducted to assess any potential causal relationship with pancreatitis. 
Each AE of pancreatitis must be reported. If typical signs and/or symptoms of pancreatitis are 
present and confirmed by laboratory values (lipase or amylase [total and/or pancreatic]) and 
imaging studies, the event must be reported as an SAE. For a potential case that does not meet all 
of these criteria, it is up to the investigator to determine the seriousness of the case (AE or SAE) 
and the relatedness of the event to study drug(s). 
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Each participant will have measurements of p-amylase and lipase (assessed at the central 
laboratory) as shown on the SoA (Section 1.3) to assess the effects of the investigational doses of 
tirzepatide on pancreatic enzyme levels. Serial measurements of pancreatic enzymes have limited 
clinical value for predicting episodes of acute pancreatitis in asymptomatic participants (Nauck 
et al. 2017; Steinberg et al. 2017a, 2017b). Thus, further diagnostic follow-up of cases of 
asymptomatic pancreatic hyperenzymemia (lipase and/or pancreatic amylase ≥3X ULN) is not 
mandated but may be performed based on the investigator’s clinical judgment and assessment of 
the participant’s overall clinical condition. 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. 
All suspected cases of acute or chronic pancreatitis will be adjudicated by an independent 
clinical endpoint committee. In addition, AEs of severe or serious abdominal pain of unknown 
etiology will also be submitted to the adjudication committee to assess for possible pancreatitis 
or other pancreatic disease. Relevant data from participants with acute or chronic pancreatitis and 
those with severe or serious abdominal pain will be entered into a specifically designed eCRF 
page. The adjudication committee representative will enter the results of adjudication in a 
corresponding eCRF page. 
10.5.1.3. Thyroid Malignancies and C-Cell Hyperplasia  
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the 
study. Participants who are diagnosed with MTC and/or MEN-2 during the study will have study 
drug stopped and should continue follow-up with an endocrinologist. 
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy (including MTC and papillary carcinoma) and measurements of calcitonin. This data 
will be captured in specific eCRFs. The purpose of calcitonin measurements is to assess the 
potential of tirzepatide to affect thyroid C-cell function, which may indicate development of 
C-cell hyperplasia and neoplasms. 
10.5.1.4. Calcitonin Measurements  
If an increased calcitonin value (see definitions below) is observed in a participant who has been 
administered a medication that is known to increase serum calcitonin, then this medication 
should be stopped, and calcitonin levels should be measured after an appropriate washout period. 
For participants who require additional endocrine assessment because of increased calcitonin 
concentration as defined in this section, data from the follow-up assessment will be collected in 
the specific section of the eCRF. 
Calcitonin Measurements in Participants with eGFR ≥60 mL/min/1.73 m2 
A significant increase in calcitonin for participants with eGFR ≥60 mL/min is defined below. If a 
participant’s laboratory results meet these criteria, these clinically significant laboratory results 
should be recorded as an AE. 
 calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the screening value. 
o These participants will be asked to repeat the measurement within 1 month. If this 
repeat value is increasing (≥10% increase), study drug should be stopped, and the 
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participant encouraged to undergo additional endocrine assessment and longer-
term follow-up by an endocrinologist to exclude any serious adverse effect on the 
thyroid. 
 calcitonin value ≥35 ng/L AND ≥50% over the screening value. 
o In these participants, study drug should be stopped, and the participant 
recommended to immediately undergo additional endocrine assessments and 
longer-term follow-up by an endocrinologist. 
Calcitonin Measurement in Participants with eGFR <60 mL/min/1.73 m2 
A significant increase in calcitonin for participants with eGFR <60 mL/min/1.73 m2 is defined as 
a calcitonin value ≥35 ng/L AND ≥50% over the screening value. If a participant’s labs meet 
these criteria, these clinically significant labs should be recorded as an AE. 
In these participants, study drug should be discontinued (after first confirming the value), and the 
participant recommended to immediately undergo additional endocrine assessments and longer-
term follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid. 
10.5.1.5. Major Adverse Cardiovascular Events  
Deaths and nonfatal CV AEs will be adjudicated by a committee of physicians external to the 
sponsor with cardiology expertise. This committee will be blinded to treatment assignment. The 
nonfatal CV AEs to be adjudicated include: 
 myocardial infarction 
 hospitalization for unstable angina 
 coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack. 
10.5.1.6. Supraventricular Arrhythmias and Cardiac Conduction Disorders  
Participants who develop any event from these groups of disorders should undergo an ECG, 
which will be retained at the site as a source document. Additional diagnostic tests to determine 
exact diagnosis should be performed, as needed. The specific diagnosis will be recorded as an 
AE. Events that meet criteria for serious conditions as described in Section 10.3.2 must be 
reported as SAEs. If a clinically significant finding is identified by ECG (including, but not 
limited to, AF or changes from baseline in corrected QT 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 should be reported as an AE. 
10.5.1.7. Hypersensitivity Events  
All allergic or hypersensitivity reactions will be reported by the investigator as either AEs, or if 
any serious criterion is met, as SAEs. 
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In the event of suspected drug hypersensitivity reactions (immediate or nonimmediate) in 
subjects who experience moderate-to-severe reactions as assessed by the investigator, 
unscheduled blood samples will be collected as outlined in Appendix 7 (Section 10.7). 
Additional data, such as type of reaction and treatment received, will be collected on any AEs or 
SAEs that the investigator deems related to study drug via the eCRF created for this purpose. 
Study drug should be temporarily interrupted in any individual suspected of having a severe or 
serious allergic reaction to study drug. Study drug may be restarted when/if it is safe to do so, in 
the opinion of the investigator. 
10.5.1.8. Injection Site Reactions  
Injection site reactions will be collected on the eCRF separate from the hypersensitivity reaction 
eCRF. At the time of AE occurrence, samples will be collected for measurement of tirzepatide 
ADA and tirzepatide concentration. 
10.5.1.9. Antidrug Antibodies  
The occurrence of ADA formation will be assessed as outlined in Section 8.9. 
10.5.1.10. Hepatobiliary Disorders  
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed. In 
cases of elevated liver markers, hepatic monitoring should be initiated as outlined in Appendix 8 
(Section 10.8). 
10.5.1.11. Severe Gastrointestinal Adverse Events  
Tirzepatide may cause severe GI AEs such as nausea, vomiting, and diarrhea. Information about 
severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the eCRF/AE form. For 
detailed information concerning the management of GI AEs, please refer to Section 6.5. 
10.5.1.12. Acute Renal Events  
Renal safety will be assessed based on repeated renal function assessment as well as assessment 
of AEs suggestive of acute or worsening of chronic renal failure. Gastrointestinal AEs have been 
reported with tirzepatide, including nausea, diarrhea, and vomiting. This is consistent with other 
GLP-1 RAs (Aroda and Ratner 2011). The events may lead to dehydration, which could cause a 
deterioration in renal function, including acute renal failure. 
Participants should be advised to notify investigators in case of severe nausea, frequent vomiting, 
or symptoms of dehydration. 
 
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10.6. 
Appendix 6: Genetics  
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study drug, susceptibility 
to, severity, and progression of disease. Variable response to study drug may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, 
and excretion; mechanism of action of the drug; disease etiology; and/or 
molecular subtype of the disease being treated. Therefore, where local regulations 
and IRB/IEC allow, a blood sample will be collected for DNA analysis from 
consenting participants. 
● DNA samples will be used for research related to tirzepatide or HF and related 
diseases. They may also be used to develop tests/assays including diagnostic tests 
related to tirzepatide or HF. Genetic research may consist of the analysis of one or 
more candidate genes, the analysis of genetic markers throughout the genome, or 
analysis of the entire genome (as appropriate). 
● DNA sample analysis may be performed on pharmacogenetic variants thought to 
play a role in T2DM or CV disease to evaluate their association with observed 
clinical outcomes to tirzepatide in this study. In the event the observation of a 
study drug response, the samples may be genotyped, and analysis may be 
performed to evaluate a genetic association with response to tirzepatide. These 
investigations may be limited to a focused, candidate-gene study or, if 
appropriate, genome-wide association studies may be performed to identify 
regions of the genome associated with the variability observed in drug response. 
Samples may be used for investigations related to the disease, drug, or class of 
drugs under study in the context of this clinical program; however, samples may 
not be used for broad, exploratory, unspecified disease or population genetic 
analysis. Additional analyses may be conducted if it is hypothesized that this may 
help further understand the clinical data. 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to tirzepatide or study drugs of this class to 
understand the study disease or related conditions. 
● The results of genetic analyses may be reported in the CSR or in a separate 
study summary. 
● The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
● The samples will be retained while research on tirzepatide continues but no longer 
than 15 years or another period as per local requirements (see Section 10.1.10).  
 
 
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10.7. 
Appendix 7: Recommended Laboratory Testing for Hypersensitivity 
Events  
Laboratory testing should be performed at the time of a systemic hypersensitivity event. The 
management of the AE may warrant lab testing beyond that described below and should be 
performed as clinically indicated. Laboratory assessments should be performed if the participant 
experiences generalized urticaria or if anaphylaxis is suspected. 
 Collect the sample after the participant has been stabilized and within 1 to 2 hours of the 
event; however, samples may be obtained as late as 12 hours after the event as analytes 
can remain altered for an extended period of time. Record the time at which the sample 
was collected. 
 Obtain a follow-up sample at the next regularly scheduled visit or after approximately 
4 weeks, whichever is later. 
 
 
 
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Clinical Laboratory Tests for Hypersensitivity Events 
Hypersensitivity Tests 
Notes 
Selected test may be obtained in the event of anaphylaxis or systemic 
allergic/hypersensitivity reactions.  
Tirzepatide antidrug antibodies 
(immunogenicity/ADA) 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Tirzepatide concentrations (PK) 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Tryptase 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Urine N-methylhistamine testing is performed in addition to tryptase testing. 
Collect the first void urine sample following the event. Collect a follow-up 
urine sample after approximately 4 weeks. 
Note: If a tryptase sample is obtained more than 2 hours after the event (that 
is, within 2-12 hours), or is not obtained because more than 12 hours have 
lapsed since the event, collect a urine sample for N-methylhistamine testing.  
N-methylhistamine 
Will be performed if validated assay is available.  
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Drug-specific IgE 
Will be performed if a validated assay is available. 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Basophil activation test 
Will be performed if a validated assay is available. 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
NOTE: The basophil activation test is an in vitro, cell-based assay that only 
requires a serum sample. It is a surrogate assay for drug specific-IgE but is 
not specific for IgE. 
Complement (C3, C3a and C5a) 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Cytokine panel: IL‐6, IL‐1β, IL‐10 
Assayed by Lilly-designated laboratory.  
Results will not be provided to the investigative sites. 
Abbreviations: ADA = antidrug antibody; IgE = immunoglobulin E; IL = interleukin; PK = pharmacokinetic. 
 
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10.8. 
Appendix 8: Liver Safety: Suggested Actions and Follow-Up 
Assessments  
Hepatic Evaluation Testing 
See Section 8.2.5.1 for guidance on appropriate test selection. 
The Lilly-designated central laboratory must complete the analysis of all selected testing except 
for microbiology testing. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (red blood cells [RBCs]) 
Alkaline phosphatase (ALP) 
Leukocytes (white blood cells [WBCs]) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Antinuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA)a 
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    HBV DNAb 
Anti-actin antibodyc 
Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNAb 
    EBV DNAb 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNAb 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNAb 
    HSV (Type 1 and 2) DNAb 
Microbiologyd 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
 
    Blood 
 
    Urine 
 
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio; PT = prothrombin time. 
a Not required if anti-actin antibody is tested. 
b Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c Not required if anti-smooth muscle antibody (ASMA) is tested. 
d Assayed ONLY by investigator-designated local laboratory; no central testing available. 
 
 
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10.9. 
Appendix 9: Medical Device Adverse Events (AEs), Adverse Device   
Effects (ADEs), Serious Adverse Events (SAEs) and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting  
 
Refer to Section 10.3 for definitions and procedures for recording, evaluating, follow-up, and 
reporting of all events. 
 
 
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10.10. 
Appendix 10: Six-Minute Walk Test Screening Procedures  
10.10.1. 
Screening Procedures and Flow Diagram  
The flow diagram below details the participant flow and eligibility with the 6MWT. 
 
Abbreviations: 6MWD = 6-minute walk test distance; 6MWT = 6-minute walk test; V1 = Visit 1; V2a = Visit 2a; 
V2b = Visit 2b. 
a Rescreening is not allowed 
b Use the higher value of the two Visit 1 6MWD as a reference for Visit 2a. 
c Continue with other Visit 2 assessments according to the SoA. 
d Participants excluded on 6MWT may be re-screened after a minimum of 2 weeks. 
 
 
 
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10.11. 
Appendix 11: New York Heart Association Classification of Heart 
Failure  
 
Class 
Symptomatology  
I 
No symptoms. Ordinary physical activity such as walking and climbing stairs does not cause 
fatigue or dyspnea. 
II 
Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking uphill, 
walking or stair climbing after meals, in cold weather, in wind or when under emotional stress 
causes undue fatigue or dyspnea. 
III 
Symptoms with less than ordinary physical activity. Walking 1-2 blocks on the level and 
climbing more than one flight of stairs in normal conditions causes undue fatigue or dyspnea. 
IV 
Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea. 
 
 
 
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10.12. 
Appendix 12: Abbreviations  
Term 
Definition 
6MWD 
6-minute walk test distance 
6MWT 
6-minute walk test 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse events of special interest 
AF 
atrial fibrillation 
ALP  
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
blinding/masking 
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the participant is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
BG 
blood glucose 
BMI 
body mass index 
CEC 
clinical endpoint committee 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form  
CRP 
clinical research physician: Individual responsible for the medical conduct of the study. 
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer. 
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Term 
Definition 
CSR  
clinical study report 
CT 
computed tomography 
CV 
cardiovascular 
D Bil 
direct bilirubin 
DMC 
data monitoring committee 
Device Deficiencies 
Equivalent to product complaint 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
ERB 
ethical review board 
ET 
early termination 
EV 
extended visit 
GCP 
good clinical practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GLP-1 
glucagon-like peptide-1 
HbA1c 
hemoglobin A1c 
HF 
heart failure 
HFpEF 
heart failure with preserved ejection fraction 
HIPAA 
Health Insurance Portability and Accountability Act 
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Term 
Definition 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
independent ethics committee 
informed consent 
A process by which a participant voluntarily confirms his or her 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. 
INR 
international normalized ratio 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
IRB 
institutional review board 
ISO 
International Organization for Standardization 
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 allocated 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. 
IV 
intravenous 
IWRS 
interactive web-response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KCCQ-CSS 
Kansas City Cardiomyopathy Questionnaire – Clinical Summary Scale 
LA 
left atrial 
LAV 
left atrial volume 
LVDEP 
left ventricular end-diastolic pressure 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN-2 
multiple endocrine neoplasia type 2 
MMRM 
mixed model repeated measures  
MRI 
magnetic resonance imaging 
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Term 
Definition 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NT-proBNP 
N-terminal pro b-type natriuretic peptide 
NYHA 
New York Heart Association 
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 
PCWP 
pulmonary capillary wedge pressure 
PK 
pharmacokinetics 
PT 
prothrombin time 
QTc 
corrected QT interval 
QW 
weekly 
RA 
receptor agonist 
SADE 
serious adverse device effect 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
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.  
SoA 
schedule of activities 
study intervention 
for this study, study intervention may be interpreted/synonymous with study drug 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TBL 
total bilirubin 
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Term 
Definition 
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. 
UADE 
unanticipated adverse device effect 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
 
 
 
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10.13. 
Appendix 13: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment b: 21 January 2022 
Overall Rationale for the Amendment: 
The purpose of this protocol amendment is to incorporate feedback received from the FDA on 
exclusion criterion and concomitant therapy. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion Criteria 
Criterion #7: removed “and/or” wording; 
added “or” between ARNI and SGLT2is  
For clarification  
Section 5.2 Exclusion Criteria 
Criterion #13: for NYHA Class, added 
word “or” in sentence to ensure 
participants with NYHA Class I are 
excluded from the study  
Criterion #20: for AF, changed “and” to 
“or” between “Visit 1” and “Visit 2”  
For clarification  
Section 6.5 Concomitant 
Therapy 
Removed sentence on use of SGLT2i for 
treatment of T2DM 
Per FDA feedback 
Section 7.1.1 Permanent 
Discontinuation from Study Drug 
A sentence inadvertently added and then 
was removed 
For clarification  
 
 
 
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Amendment a: 15 December 2021 
Overall Rationale for the Amendment: 
The purpose of this protocol amendment is to clarify dosing information to allow for more 
participant retention and clarity on the dosing regimen, add additional unscheduled visits, and 
make inclusion/exclusion criteria updates. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
 In Intervention Groups and 
Duration, changed 15 mg to QW 
 Added wording to Study Period 1 
to specify timing 
 To Clarify dose  
 
 For Clarification 
in timing 
Section 1.2 Schema 
Adjusted wording in Note for screening 
procedures timing  
To Clarify screening 
period timing  
Section 1.3 Schedule of 
Activities (SoA) 
 Added 3 columns to Unscheduled 
Visits (UV): UV, Dosing UV, and 
Phone follow up Dosing UV, 
added Xs for specific tests   
 Footnote “a” added in regard to 
Unscheduled Visits; subsequent 
footnotes adjusted 
 For Telephone Visit, X added to 
Phone Follow-Up Dosing UV 
 To specify UV  
 
 
 
 To explain UV; 
for accuracy  
 
 For Accuracy  
Section 3 Objectives and 
Endpoints 
 Added Other Secondary title & 
moved Incidence HF events and 
CV Death from Exploratory 
 Added timing to first occurrence 
and recurrent events for HF events 
and CV death 
 The Endpoint wording for the 
exploratory Objective Atrial 
fibrillation is updated 
 Change in 
Endpoints 
 
 To specify 
timings 
 
 Correction  
Section 4.1 Overall Design 
 For Study Period 1, timing period 
adjusted  
 For Screening, sentence added to 
clarify time period for V1  
 
 
For Treatment, dose escalation 
described; paragraphs added to 
specify that participant be 
 Correction 
 
 Clarification for 
timing for 
duration of V1  
 
 New information 
added to clarify 
dose escalation, 
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maintained on study drug; some 
sentences regarding dose and 
discontinuation removed  
 
maintenance on 
study drug; To 
reduce 
redundancy 
Section 5.1 Inclusion 
Criteria 
 For Inclusion Criterion #7 added 
additional HF medications 
 Clarification for 
Concomitant 
Medication use  
Section 5.2 Exclusion 
Criteria 
 For Exclusion Criterion #13, 
NYHA Class information added  
 For Exclusion Criterion #15 
changed wording to include MRI 
or other local modalities  
 For Exclusion Criterion #21 added 
sentence on participants with 
Chagas disease 
 For Exclusion Criterion #25 
removed sentence regarding 
fundoscopic examination and 
clarified definition of 
nonproliferative diabetic 
retinopathy 
 Additional 
information 
 For Clarification 
 
 
 For Clarification 
 
 
 Correction and 
Clarification  
 
 
 
 
Section 5.4 Screen 
Failures 
Added upper limit of screening period to 
clarify screen failure 
For Clarification 
Section 6.4 Study 
Intervention Compliance 
Wording added to clarify participant 
compliance 
For Clarification 
Section 6.5 Concomitant 
Therapy 
 Added information on ARNI, 
SGLT2i, and GLP-1/GIPR use in 
the study 
 Changed Hyperglycemia Rescue 
at Week 26 to Week 24  
 Wording added in Standard of 
Care for Heart Failure 
 Wording changed to Clarify 
dosing modification for GI 
Symptoms 
 Clarification of 
Concomitant 
Medication Use 
 Correction  
 
 For Clarification  
 
 For Clarification 
Section 6.6 Dose 
Modification 
Information changed to clarify dose 
modification 
For Clarification 
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Section 6.7 Intervention 
after the End of the Study 
Wording added in regard to unblinding 
information  
For Clarification 
Section 7.1.1 Permanent 
Discontinuation from Study 
Drug 
 Wording added to clarify 
permanent discontinuation of 
study drug 
 Wording changed to specific 
criteria when participant has 
Pancreatic Cancer 
 For Clarification 
 
 For Clarification  
Section 7.1.2 Temporary 
Interruption  
Wording changed to clarify that study 
interruption, is not study discontinuation; 
Moved to Section 6.6.1 
For Clarification 
Section 7.1.3 Restarting 
Study Drug after 
Interruption 
Added wording on Maintenance dose 
levels; Moved to Section 6.6.2   
For Clarification 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the Study 
Wording changed to clarify participant 
retention in the study 
For Clarification 
Section 7.2.1 Inadvertently 
Enrolled Participants 
Wording Changed to clarify medical 
appropriateness of treatment 
For Clarification  
Section 8 Study 
Assessments and 
Procedures 
Information added regarding remote visits 
For Clarification 
Section 8.1.1.3 Six-Minute 
Walk Test 
Clarified wording on Borg Scale  
For Clarification 
Section 8.2.3 
Electrocardiograms 
Clarified on use of ECG machine type 
For Clarification 
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments  
Urine pregnancy wording added 
For Clarification 
Section 10.1.1 
Regulatory and Ethical 
Considerations 
Added bullet point, International 
Organization for Standardization (ISO) 
14155 and wording on substantiality of 
amendments  
To align with current 
Harmonized Protocol 
Template v10 
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Section 10.1.11 
Investigator Information  
Added Investigator Information Section  
To align with current 
Harmonized Protocol 
Template v10 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Removed Lactate dehydrogenase 
Error Correction 
Section 10.5.1.5 Major 
Adverse Cardiovascular 
Events 
Removed hospitalization for HF 
This is an efficacy point 
Section 10.10 Appendix 
10: Six Minute Walk Test 
Screening Procedures 
Flow Diagram corrected for 6MWD 
Error Correction 
 
 
 
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