A Phase 2 Study of Once-Weekly LY3437943 Compared With Placebo in Participants Who Have Obesity or Are Overweight With Weight-Related Comorbidities
Phase: PHASE2
Conditions: Obesity, Overweight
Sponsor: Eli Lilly and Company

 
 J1I-MC-GZBF (b) Clinical Protocol 
 
 
 A Phase 2 Study of Once-Weekly LY3437943 Compared with Placebo in Participants Who Have 
Obesity or Are Overweight with Weight-Related Comorbidities 
 
NCT04881760 
 
Approval Date: 29-Aug-2022 
 
 

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J1I-MC-GZBF (b) 
 
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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 LY3437943, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its 
subsidiaries.  
 
Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information 
exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. 
In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or 
otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. 
Protocol Title: A Phase 2 Study of Once-Weekly LY3437943 Compared with Placebo in 
Participants Who Have Obesity or Are Overweight with Weight-Related 
Comorbidities  
Protocol Number: J1I-MC-GZBF 
Amendment Number: b 
Compound: LY3437943  
Study Phase: Phase 2 
Short Title: Effect of LY3437943 versus Placebo in Participants Who Have Obesity or Are 
Overweight 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 154659 
Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-072320 
 
 
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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 a 
21-May-2021 
Original Protocol 
26-Feb-2021 
Amendment [b] 
This amendment is considered to be nonsubstantial. 
 
Overall Rationale for the Amendment: 
The overall changes and rationale for the changes made in this amendment are described in the 
following table.  
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities 
Pharmacokinetic (PK) sample 
row: Updated sample taken at 
Visit 17 from Predose to 
Postdose 
Dosing does not occur at Visit 
17 (Week 48); therefore, time 
point is now described as 
approximately 1 week post the 
last dose (Week 47). 
Pharmacokinetic Schedule of 
Events table 
Sample #10 row: Updated 
collection time point from 
“Predose (up to -8 hours)” to 
“Postdose (approximately 1 
week)” 
Dosing does not occur on Week 
48. This sample collection time 
point is approximately 1 week 
following the last dose. 
Pharmacokinetic Schedule of 
Events table 
Sample #11 row: Updated Week 
Relative to Randomization from 
“End of Treatment” to “Safety 
follow-up” 
Treatment period ends at Week 
48 visit. Updated wording to 
accurately describe visit.   
Pharmacokinetic Schedule of 
Events table 
Sample #11 row: Updated 
collection time point from “4 
weeks post last dose” to “5 
weeks post last dose” 
Since the last dose is on 
Week 47, the Sample #11 
collected at the Safety follow-up 
visit is 5 weeks post the last 
dose. 
Section 7.1 
Discontinuation of 
Study Intervention 
Information about inadvertent 
enrollment has been removed. 
Deleted as internal process will 
be followed for inadvertent 
enrollment. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2.1 
Discontinuation of 
Inadvertently Enrolled 
Participants 
This section has been removed. 
Deleted as internal process will 
be followed for inadvertent 
enrollment. 
 
 
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Table of Contents 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................11 
1.3. 
Schedule of Activities (SoA) ..........................................................................................12 
2. 
Introduction ...................................................................................................................21 
2.1. 
Study Rationale ...............................................................................................................21 
2.2. 
Background .....................................................................................................................21 
2.3. 
Benefit/Risk Assessment ................................................................................................22 
2.3.1. 
Risk Assessment .............................................................................................................22 
2.3.2. 
Benefit Assessment .........................................................................................................23 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................23 
3. 
Objectives and Endpoints ............................................................................................24 
4. 
Study Design ..................................................................................................................26 
4.1. 
Overall Design ................................................................................................................26 
4.1.1. 
Overview of Study Periods .............................................................................................27 
4.1.2. 
Study Procedures ............................................................................................................31 
4.2. 
Scientific Rationale for Study Design ............................................................................32 
4.3. 
Justification for Dose ......................................................................................................33 
4.4. 
End of Study Definition ..................................................................................................33 
5. 
Study Population ...........................................................................................................34 
5.1. 
Inclusion Criteria ............................................................................................................34 
5.2. 
Exclusion Criteria ...........................................................................................................35 
5.3. 
Lifestyle Considerations .................................................................................................41 
5.3.1. 
Diet and Physical Activity Counseling ...........................................................................41 
5.4. 
Screen Failures ................................................................................................................41 
6. 
Study Intervention ........................................................................................................42 
6.1. 
Study Interventions Administered ..................................................................................42 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................43 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................43 
6.4. 
Study Intervention Compliance ......................................................................................44 
6.5. 
Concomitant Therapy .....................................................................................................44 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms .......................................45 
6.5.2. 
Definition and Management of Incident Diabetes ..........................................................45 
6.6. 
Dose Modification ..........................................................................................................47 
6.6.1. 
Temporary Interruption of Study Drug ...........................................................................47 
6.6.2. 
Dose Reductions Indicated to Ensure Participant Safety ................................................49 
6.7. 
Intervention after the End of the Study ...........................................................................49 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................50 
7.1. 
Discontinuation of Study Intervention ............................................................................50 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................52 
7.3. 
Lost to Follow-Up ...........................................................................................................52 
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8. 
Study Assessments and Procedures.............................................................................53 
8.1. 
Efficacy Assessments .....................................................................................................53 
8.2. 
Safety Assessments .........................................................................................................53 
8.2.1. 
Physical Examinations ....................................................................................................54 
8.2.2. 
Vital Signs .......................................................................................................................54 
8.2.3. 
Electrocardiograms .........................................................................................................54 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................54 
8.2.5. 
Safety Monitoring ...........................................................................................................55 
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring ...........................................................57 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................58 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................58 
8.3.2. 
Adverse Events of Special Interest .................................................................................61 
8.4. 
Treatment of Overdose ...................................................................................................68 
8.5. 
Pharmacokinetics ............................................................................................................68 
8.5.1. 
Bioanalysis ......................................................................................................................68 
8.6. 
Pharmacodynamics .........................................................................................................69 
8.7. 
Genetics ..........................................................................................................................69 
8.8. 
Biomarkers ......................................................................................................................69 
8.9. 
Immunogenicity Assessments.........................................................................................70 
8.10. 
Health Economics ...........................................................................................................70 
9. 
Statistical Considerations .............................................................................................71 
9.1. 
Statistical Hypotheses .....................................................................................................71 
9.2. 
Sample Size Determination ............................................................................................71 
9.3. 
Populations for Analyses ................................................................................................71 
9.4. 
Statistical Analyses .........................................................................................................72 
9.4.1. 
General Considerations ...................................................................................................72 
9.4.2. 
Treatment Group Comparability .....................................................................................73 
9.4.3. 
Primary Endpoint(s) ........................................................................................................73 
9.4.4. 
Secondary Endpoint(s) ....................................................................................................74 
9.4.5. 
Exploratory Endpoints ....................................................................................................75 
9.4.6. 
Other Safety Analyses.....................................................................................................75 
9.4.7. 
Other Analyses ................................................................................................................75 
9.4.8. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................75 
9.5. 
Interim Analyses .............................................................................................................76 
9.6. 
Data Monitoring Committee (DMC) ..............................................................................76 
10. 
Supporting Documentation and Operational Considerations ..................................77 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................77 
10.1.1. Regulatory and Ethical Considerations ...........................................................................77 
10.1.2 
Informed Consent Process ..............................................................................................77 
10.1.3 
Data Protection................................................................................................................78 
10.1.4 
Committees Structure......................................................................................................78 
10.1.5 
Dissemination of Clinical Study Data.............................................................................78 
10.1.6 
Data Quality Assurance ..................................................................................................79 
10.1.7 
Source Documents ..........................................................................................................80 
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10.1.8 
Study and Site Start and Closure ....................................................................................80 
10.1.9 
Publication Policy ...........................................................................................................82 
10.1.10 Investigator Information .................................................................................................82 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................83 
10.3. 
Appendix 3: Laboratory Assessments for Hypersensitivity 
Events..............................................................................................................................87 
10.4. 
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting ........................................................89 
10.4.1 
Definition of AE .............................................................................................................89 
10.4.2 
Definition of SAE ...........................................................................................................90 
10.4.3 
Definition of Product Complaints ...................................................................................91 
10.4.4 
Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................92 
10.4.5 
Reporting of SAEs ..........................................................................................................93 
10.4.6 
Regulatory Reporting Requirements ...............................................................................94 
10.5. 
Appendix 5: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................95 
10.6. 
Appendix 6: Genetics....................................................................................................100 
10.7. 
Appendix 7: Diet and Physical Activity Counseling ....................................................101 
10.7.1 
Diet ................................................................................................................................101 
10.7.2 
Physical Activity ...........................................................................................................102 
10.8. 
Appendix 8: Protocol GZBF Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, and Vital 
Signs..............................................................................................................................104 
10.9. 
Appendix 9: Liver Safety: Suggested Actions and Follow-Up 
Assessments ..................................................................................................................107 
10.10. 
Appendix 10: Metabolic Mechanistic Biomarkers .......................................................109 
10.11. 
Appendix 11: Patient-Reported Outcomes ...................................................................111 
10.12. 
Appendix 12: Provisions for Changes in Study Conduct during 
Exceptional Circumstances ...........................................................................................113 
10.13. 
Appendix 13: Abbreviations .........................................................................................118 
10.14. 
Appendix 14: Protocol Amendment History ................................................................122 
11. 
References ....................................................................................................................124 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2 Study of Once-Weekly LY3437943 Compared with Placebo in 
Participants Who Have Obesity or Are Overweight with Weight-Related 
Comorbidities  
Short Title: Effect of LY3437943 versus Placebo in Participants Who Have Obesity or Are 
Overweight 
Rationale: 
Obesity is a chronic disease and its increasing prevalence is a public health concern associated 
with rising incidence of type 2 diabetes (T2D), increased risk for premature death, and increased 
risk for some cancers (AMA 2013; Council on Science and Public Health 2013; Lauby-Secretan 
et al. 2016). There remains an unmet need in the pharmacologic treatment of obesity for drugs 
that are safe, efficacious, and well tolerated. 
LY3437943 is a novel synthetic peptide, which shows potent agonist action at glucose-dependent 
insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon (Gcg) 
receptors (GIPR, GLP-1R, and GcgR). It includes a linear peptide component of 39 amino acid 
residues conjugated to a C20 fatty acid moiety. In nonclinical pharmacology models, 
LY3437943 demonstrated greater weight loss in diet-induced obese (DIO) mice compared with 
an existing GLP-1 receptor agonist (GLP-1RA). The body weight reduction in DIO mice was 
primarily due to loss of fat mass and was associated with lowered total plasma cholesterol and 
reduced liver fat content. In addition, LY3437943 demonstrated a greater effect on glucose-
dependent insulin secretion compared with an existing GLP-1RA, as demonstrated by 
intravenous glucose tolerance test in lean rats. Data from the Phase 1 program in patients with 
T2D demonstrated that LY3437943 has the potential to induce clinically meaningful weight loss 
(that is, 5%-10% or more) with a safety profile consistent with other GLP-1 and GIP/GLP-1RAs.  
Study J1I-MC-GZBF (Study GZBF) will investigate the safety and efficacy of 48 weeks of 
treatment with LY3437943, administered subcutaneously once weekly (QW), in participants who 
have obesity (BMI ≥ 30 kg/m2) or are overweight (BMI ≥ 27 kg/m2 and < 30 kg/m2) with 
weight-related comorbidities but without T2D. The primary objective will be the effect on 
percent change in body weight at 24 weeks. These data will support dose selection for Phase 3 
studies in participants who have obesity or are overweight with weight-related comorbidities. 
 
 
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Intervention Groups and Duration: 
Study participants will be randomly assigned in a 2:1:1:1:1:2:2 ratio (LY3437943 1 mg QW, 
LY3437943 4 mg QW [with starting dose at 2 mg], LY3437943 4 mg QW [with starting dose at 
4 mg], LY3437943 8 mg QW [with starting dose at 2 mg], LY3437943 8 mg QW [with starting 
dose at 4 mg], LY3437943 12 mg QW [with starting dose at 2 mg], placebo QW) and stratified 
by sex and BMI ≥ 36 kg/m2.  
All participants will receive diet and physical activity counseling using a standardized approach 
throughout the study. 
Study GZBF will consist of 3 periods: a 6-week screening period, a 48-week double-blind, 
placebo-controlled treatment period (consisting of an up to 12-week dose-escalation period and a 
36-week maintenance period), and a 4-week safety follow-up period. 
Data Monitoring Committee: No
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1.2. 
Schema 
 
 
 
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Abbreviations: ABPM = ambulatory blood pressure monitoring; ADA = anti-drug antibody; BP = blood pressure; CKD-EPI = Chronic Kidney Disease-
Epidemiology; ECG = electrocardiogram; ED = early discontinuation of treatment; eGFR = estimated glomerular filtration rate; HbA1c = hemoglobin A1c; 
IWRS= Interactive Web Response Systems; MRI = magnetic resonance imaging; NAFLD = non-alcoholic fatty liver disease; PK = pharmacokinetics; PR = 
pulse rate; SF-36v2 acute form = Short Form-36 Version 2 Health Survey acute form; TXP = treatment period. 
 
General Notes: 
 
Telephone visits are shaded. 
 
Visit 4 baseline assessments must be completed before processing the randomization in the interactive web-response system (IWRS). 
 
The interval between Visit 1 and Visit 4 can be accomplished in less than 6 weeks and will not be considered as a protocol deviation. If the ABPM 
needs to be repeated at Visit 3 (per criteria specified in Section 4.1.2.3), then the screening period may exceed 6 weeks and this will not be considered a 
protocol deviation. 
 
Participants who do not qualify for the MRI should move from Visit 1 to Visit 3.   
 
The visit date is determined in relation to the date of Visit 4 (randomization). 
 
Participants who are unable or unwilling to continue the study drug for any reason will perform an ED visit. If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as an ED visit.  
 
Visit 99 is only applicable to participants who discontinue the double-blind study treatment prematurely and decline to complete the remaining 
scheduled study visits. If the participant is unwilling to complete all the study visits, then the participant should be encouraged to come back for a Visit 
99, 48 weeks ± 7 days after randomization, primarily for body weight measurement and assessment of adverse events. If the participant is unwilling to 
attend Visit 99, it should be documented in the participant medical record that the participant has refused to attend. 
 
Visit 801 (safety follow-up visit) should be performed 4 weeks after the last visit during the study treatment period or Visit 99.  
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 Pharmacokinetic Schedule of Events 
Sample # 
Week Relative to Randomization 
Collection Timepoint Relative to LY3437943 Weekly Dose 
1 
0 
Predose (up to -8 hours)* 
2 
1 
1 to 24 hours postdose 
3 
4 
Predose (up to -8 hours)* 
4 
8 
24 to 72 hours postdose 
5 
12 
Predose (up to -8 hours)* 
6 
16 
72 to 168 hours postdose 
7 
20 
Any time during this week 
8 
24 
Predose (up to -8 hours)* 
9 
36 
Any time during this week 
10 
48 
Postdose (approximately 1 week)* 
11 
Safety follow-up 
5 weeks post last dose 
12 
Early discontinuation 
Any time 
* Immunogenicity (ADA) samples collected with PK at these visits. 
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Summary of clinical studies 
Study J1I-MC-GZBA (GZBA) was a first-in-human, single-ascending dose study investigating 
the safety, tolerability, and pharmacokinetic/pharmacodynamic (PK/PD) of LY3437943 
administered as a SC injection in 45 healthy participants.  
The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (GI) 
events, including vomiting (with higher doses), abdominal distention, and nausea, which were 
dose dependent, mostly mild in severity, occurred within 4 days of dosing, and resolved within a 
week of onset. Dose-dependent increases in heart rate (HR) and decreases in systolic blood 
pressure (BP) were observed, which returned to near baseline by Day 29.  
Across dose levels, the maximum observed drug concentration (Cmax) occurred between ~1 and 
3 days postdose, while the mean terminal half-life was ~5 to 7 days, thus supporting a QW 
dosing regimen.  
Study J1I-MC-GZBB (GZBB) is a Phase 1, randomized, investigator- and participant-blind 
study that assessed the safety, tolerability, and PK/PD effects of multiple doses of LY3437943 
when administered QW in participants with T2D. Trulicity® (dulaglutide) 1.5 mg was used as an 
active comparator. Participants in Cohorts 1 to 3 received fixed doses of LY3437943 (0.5, 1.5, 
and 3 mg QW) or placebo for 12 weeks. Participants in Cohorts 4 and 5 received placebo or 
LY3437943 titrated from a starting dose of 3 mg QW to maximum doses of 6 mg QW (Cohort 4) 
and 12 mg QW (Cohort 5) over the 12-week treatment period. 
Based on preliminary data from this ongoing study, 72 participants received study treatment, and 
43 completed the study to date. Gastrointestinal adverse events (AEs) (nausea, abdominal 
distention, and diarrhea) and decreased appetite were the most frequently reported events, mostly 
mild in severity and dose dependent. A dose dependent increase in HR was noted. The HR 
effects were consistent with those of the GLP-1 or GIP/GLP-1RA class, as was seen in Phase 1 
clinical development. There were no reports of severe hypoglycemia or AEs related to the site of 
injection. Overall, data from early phase clinical trials support further development of 
LY3437943 in Phase 2 studies.  
2.3. 
Benefit/Risk Assessment  
This section summarizes the key observations from the completed or ongoing Phase 1 trials with 
LY3437943. More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of LY3437943 may be found in the Investigator’s Brochure (IB). 
Information on AEs expected to be related to the investigational product may be found in Section 
6.2 (Developmental Core Safety Information) of the IB. Information on serious adverse events 
(SAEs) that are expected in the study population independent of drug exposure will be assessed 
by the sponsor in aggregate, periodically during the course of the study, and may be found in 
Section 7 (Reference Safety Information for Assessment of Expectedness of Serious Adverse 
Reactions) of the IB. 
2.3.1. 
Risk Assessment 
The most common AEs observed in the LY3437943 clinical trials in healthy participants and 
participants with T2D have been GI effects. There are safety topics of special interest identified 
from other GLP-1 and GIP/GLP-1RA clinical programs, including pancreatic safety, 
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cardiovascular events, hypoglycemia, hypersensitivity reactions, and thyroid C-cell effects; refer 
to Section 8.3.2 for further details. Most of these AEs have not been observed with LY3437943 
in the current stage of clinical development. Please refer to the IB Section 6 for more details. 
2.3.2. Benefit Assessment 
LY3437943 is a triple-agonist of the GIP, GLP-1, and glucagon receptors that is currently in 
early clinical development. Full assessment of its potential benefits has not been completed. The 
purpose of this Phase 2 trial is to provide an initial efficacy assessment in participants who have 
obesity or are overweight with weight-related comorbidities, in addition to safety and PK/PD 
assessments.  
2.3.3. 
Overall Benefit: Risk Conclusion 
The data from Phase 1 studies indicate that the safety profile of LY3437943 is consistent with 
the safety profile of other GLP-1 and GIP/GLP-1RAs. No additional risks are anticipated. 
Considering the measures to minimize risk to participants included in the study protocol, 
potential risks identified in association with LY3437943 are considered acceptable in this study. 
No benefits of LY3437943 can be assumed because LY3437943 is in the early phase of clinical 
development. All participants in this study will receive diet and physical activity counseling.  
 
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Objectives 
Estimands/Endpoints 
 
Lipid parameters  
 
Mean change in fasting 
o 
total cholesterol  
o 
HDL cholesterol 
o 
LDL cholesterol  
o 
VLDL cholesterol  
o 
triglycerides  
 
Glycemic control 
 
Mean change in 
o 
fasting glucose  
o 
HbA1c 
 
Proportion of participants with incident T2D  
 
 
Mechanistic biomarkers 
 
Mean change in mechanistic biomarkers (see 
detailed list of parameters in Section 10.10) 
 
Patient-reported outcomes 
 
Proportion of participants with change in 
PGIS-Physical Function  
 
Mean change in  
o 
SF-36v2 acute form domain scores  
o 
Eating Inventory domain scores 
 
To assess the PK of LY3437943 and potential 
participant factors that may influence its PK 
 
LY3437943 plasma concentrations 
 
To assess the relationship between 
LY3437943 dose and/or exposure and key 
efficacy and safety measures and potential 
participant factors that may influence these 
relationships 
 
Dose–response and concentration–response 
analyses for key efficacy and safety 
parameters 
Abbreviations: ABPM = ambulatory blood pressure modeling; BMI = body mass index; HbA1c = hemoglobin A1c; 
HDL = high-density lipoprotein; LDL = low-density lipoprotein; PGIS = Patient Global Impression of Status; 
SF-36v2 acute form = Short Form-36 Version 2 Health Survey acute form; VLDL = very low-density lipoprotein. 
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4. 
Study Design 
4.1. 
Overall Design 
Study GZBF is a 48-week, Phase 2, multicenter, randomized, double-blind, placebo-controlled 
study designed to examine the safety and efficacy of 4 dose levels of QW subcutaneously 
administered LY3437943 compared with QW subcutaneously administered placebo in 
participants who have obesity (BMI ≥ 30 kg/m2) or are overweight (BMI ≥ 27 kg/m2 and < 30 
kg/m2) with weight-related comorbidities but without T2D. The primary objective will be the 
effect of LY3437943 on percent change in body weight at 24 weeks. These data will support 
dose selection for Phase 3 studies in participants who have obesity or are overweight with 
weight-related comorbidities. 
All participants will receive diet and physical activity counseling using a standardized approach 
throughout the study (Section 5.3.1). 
Participants with high probability of non-alcoholic fatty liver disease (NAFLD) and for liver fat 
≥10% as determined by the screening liver fat algorithm (see Section 4.1.2.1) will undergo liver 
fat assessment by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF). 
Participants with baseline liver fat equal to or higher than 10% as assessed by MRI-PDFF will be 
invited to participate in an addendum study in which the effect of LY3437943 on liver fat and 
serum biomarkers of nonalcoholic steatohepatitis will be evaluated. Approximately 100-125 
participants will be included in this addendum study. 
Four maintenance doses of LY3437943 will be evaluated in the trial: 1, 4, 8, and 12 mg. Dose 
escalation to improve GI tolerability will occur in certain treatment groups up to Week 12 by 
increasing the volume of administered study drug (or placebo). For maintenance doses equal to 
or greater than 4 mg, the initial dose will be 2 or 4 mg followed by additional escalation steps. 
For 2 of the maintenance dose arms (4 and 8 mg), participants will be randomly assigned into 2 
subgroups, designated by (a) and (b), with different dose escalation schemes. This is described in 
detail in Section 4.1.1. 
Study participants will be randomly assigned in a 2:1:1:1:1:2:2 ratio (LY3437943 1 mg QW, 
LY3437943 4 mg QW [a], LY3437943 4 mg QW [b], LY3437943 8 mg QW [a], LY3437943 8 
mg QW [b], LY3437943 12 mg QW, placebo QW) and stratified by sex and BMI ≥ 36 kg/m2. 
An upper limit of 60% enrollment of women will be used to ensure a sufficiently large sample of 
men. 
Study GZBF will consist of 3 periods: a 6-week screening period, a 48-week double-blind, 
placebo-controlled treatment period (consisting of an up to 12-week dose-escalation period and a 
36-week maintenance period), and a 4-week safety follow-up period.  
 
 
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4.1.1. 
Overview of Study Periods 
4.1.1.1. 
Main Study Period 
Screening Period 
Visit 1 
The purpose of screening procedures at Visit 1 is to establish initial eligibility and to obtain 
blood samples for laboratory assessments needed to confirm eligibility. The participant must sign 
the informed consent form (ICF) before the study procedures are performed, as outlined in the 
SoA, Section 1.3. Since some screening procedures need to be completed in the fasting state 
(approximately 8 hours without eating, drinking [except water], or performing any significant 
physical activity), Visit 1 may be conducted over more than 1 day to ensure necessary conditions 
are met. Participants who meet all applicable inclusion criteria and none of the applicable 
exclusion criteria (Sections 5.1 and 5.2) at Visit 1 will continue in the study. Participants who do 
not qualify for the magnetic resonance imaging (MRI) should move directly from Visit 1 to Visit 
3. 
Visit 2 
Participants identified with a high probability for liver fat ≥10% as determined by the screening 
algorithm at Visit 1 will undergo liver fat and body composition assessment by MRI. Liver fat 
and body composition assessment will be performed after a fast of at least 6 hours. Participants 
can take necessary medications and small quantities of water during the fast.  
Visit 3 
Eligible participants (individuals who meet all applicable inclusion criteria and none of the 
applicable exclusion criteria) will receive education about ambulatory blood pressure monitoring 
(ABPM) and will be trained in its use at Visit 3. Ambulatory monitoring of HR and BP should be 
performed prior to Visit 4. Details on ABPM are described in Section 4.1.2.3. Diet and physical 
activity counseling will begin at Visit 3 so that participants will be familiar with the program 
prior to randomization (Section 5.3.1). This counseling will be provided at all subsequent visits 
until Week 44 (Visit 16). 
Treatment Period  
Randomization (Visit 4) 
At Visit 4, ABPM results will be analyzed to ensure that at least 70% of the readings are valid as 
described in Section 4.1.2.3. Eligible participants with acceptable ABPM data (as described 
Section 4.1.2.3) will perform all required procedures prior to randomization and prior to taking 
the first dose of study drug. If the ABPM results are not acceptable, randomization (Visit 4) 
should be rescheduled, and ABPM needs to be performed again within 1 week and prior to the 
rescheduled Visit 4. At Visit 4, study participants are required to report after approximately 8 
hours without eating, drinking (except water), or performing any significant physical activity. 
When collected, patient-reported outcomes questionnaires should be administered as early as 
possible in the visit, prior to randomization. Preferred administration order is  
1. Patient Global Impression of Status for Physical Activity  
2. SF-36v2 acute form, and  
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3. Eating Inventory. 
The mental health questionnaires (PHQ-9, C-SSRS, and Self-Harm Form) should be completed 
after the assessment for AEs. 
Following randomization, study site personnel will demonstrate study drug preparation and 
injection technique using a vial and syringe and observe the study participant inject the first dose 
of LY3437943 or placebo. The date, time, and location of the first dose of study drug will be 
recorded on the electronic case report form (eCRF). Beginning at randomization, all participants 
will receive study drug according to the randomized treatment arm for the duration of the 
48-week treatment period.  
Visit 5 
Visit 5 needs to take place 5-9 days after Visit 4. Study participants are required to report after 
approximately 8 hours without eating, drinking (except water), or performing any significant 
physical activity. The mental health questionnaires (PHQ-9, C-SSRS, and Self-Harm Form) 
should be completed after the assessment for AEs during visits as indicated in the SoA, Section 
1.3. Study site personnel will review the study drug preparation and injection technique using a 
vial and syringe and then observe the study participant inject the second dose of LY3437943 or 
placebo. The date, time, and location of the second dose of study drug will be recorded on the 
eCRF. 
Dose-Escalation Period (Visits 6-8) 
Dose escalation will occur in certain treatment groups up to Week 12 of treatment. On Visit 6 
through Visit 8, study participants are required to report after approximately 8 hours without 
eating, drinking (except water), or performing any significant physical activity. The mental 
health questionnaires (PHQ-9, C-SSRS, and Self-Harm Form) should be completed after the 
assessment for AEs during visits as indicated in the SoA, Section 1.3. For maintenance doses 
equal to or greater than 4 mg, the initial dose will be 2 or 4 mg followed by additional escalation 
steps as appropriate and described below. The dose will be increased at 4-week increments until 
the maintenance dose is achieved (Section 6.1 for details), as follows: 
 Maintenance dose of 1 mg: no dose escalation 
 Maintenance dose of 4 mg will be randomized 1:1 into 2 subgroups:  
o Subgroup (a): 2 mg (Visit 4)  4 mg (Visit 6) 
o Subgroup (b): 4 mg (no dose escalation) 
 Maintenance dose of 8 mg will be randomized 1:1 into 2 subgroups:  
o Subgroup (a): 2 mg (Visit 4)  4 mg (Visit 6)  8 mg (Visit 7) 
o Subgroup (b): 4 mg (Visit 4)  8 mg (Visit 6) 
 Maintenance dose of 12 mg:  
o 2 mg (Visit 4)  4 mg (Visit 6)  8 mg (Visit 7)  12 mg (Visit 8). 
Maintenance dose will be continued for the remainder of the study. Study site personnel will 
review the study drug preparation and injection technique using a vial and syringe at each visit. 
Refer to Section 6.5.1 and 6.6 for guidance on management of participants who experience GI 
symptoms. 
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Maintenance Period (Visits 9-17) 
During the maintenance period, visits will occur monthly through 48 weeks. Telephone visits 
will occur at Weeks 28, 32, 40, and 44. For office visits, study participants are required to report 
after approximately 8 hours without eating, drinking (except water), or performing any 
significant physical activity. Office and telephone visit procedures should be conducted 
according to the SoA (Section 1.3). At Visit 11 and Visit 17, when collected, patient-reported 
outcomes questionnaires should be administered as early as possible in the visit. Preferred 
administration order is  
1. Patient Global Impression of Status for Physical Activity 
2. SF-36v2 acute form, and 
3. Eating Inventory.  
The mental health questionnaires (PHQ-9, C-SSRS, and Self-Harm Form) should be completed 
after the assessment for AEs during visits as indicated in the SoA, Section 1.3.  
ABPM will be repeated at Week 24 (Visit 11) and Week 36 (Visit 14) as described in Section 
4.1.2.3. Study drug and injection supplies will be returned per the SoA (Section 1.3) and 
according to local requirements. New supplies will be dispensed as needed. Study site personnel 
will review the study drug preparation and injection technique using a vial and syringe at each 
office visit. Participants should be instructed to contact the investigative site for assistance as 
soon as possible if they experience any difficulties administering their study drug. Additional 
unscheduled visits may be scheduled if the participant needs additional support for the study 
drug injection technique.  
Participants should also be advised about the appropriate course of action if study drug is not 
taken at the required time (for details on late/missing doses, see Sections 6.1 and 6.6). Study 
participants will be permitted to use concomitant medications that they require during the study, 
except certain excluded medications (see Section 6.5) that may interfere with the assessment of 
efficacy and safety characteristics of the study treatments.  
Early Discontinuation of Treatment Visit 
Participants unable or unwilling to continue the study treatment for any reason will perform an 
early discontinuation of treatment (ED) visit. If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as an ED visit. A study 
participant who discontinues study drug permanently should be encouraged to continue in the 
study and to complete all study visits, including Visit 801 (See Participant Disposition and 
Timing of Safety Follow-Up figure below). Procedures should be completed according to the 
SoA (Section 1.3). When collected, patient-reported outcomes questionnaires should be 
administered as early as possible in the visit. Preferred administration order is  
1. Patient Global Impression of Status for Physical Activity  
2. SF-36v2 acute form, and 
3. Eating Inventory.  
Mental health questionnaires (PHQ-9, C-SSRS, and Self-Harm Form) should be completed after 
the assessment for AEs.  
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Visit 99 
A study participant who discontinues study drug permanently should be encouraged to continue 
in the study and to complete all study visits. If the participant is unwilling to complete all the 
study visits, then the participant should be encouraged to come back for a study visit 48 weeks (± 
7 days) after randomization, which is designated as Visit 99 in the SoA (See Participant 
Disposition and Timing of Safety Follow-Up figure below). This visit is critical to ensure 
complete data collection for the Week 48 secondary endpoints. Refer to the SoA, Section 1.3, for 
procedures to be completed. 
For participants unwilling to attend this visit, their refusal to attend should be documented in the 
participant medical record. 
Safety Follow-Up Period (Visit 801) 
Participants who complete the study treatment period should perform a Visit 801 (safety follow-
up visit) 4 weeks after the last treatment visit (Visit 17). Participants who complete a Visit 99 
should perform a Visit 801 four weeks after Visit 99. Participants who stop study drug early, and 
decline to complete visits to 48 weeks (including Visit 99), should perform a Visit 801 (safety 
follow-up visit) 4 weeks after the last visit of the treatment period and then discontinue the study 
(See Participant Disposition and Timing of Safety Follow-Up figure below). During the safety 
follow-up period, participants will not receive study drug.  
Mental health questionnaires (PHQ-9, C-SSRS, and Self-Harm Form) should be completed after 
the assessment for AEs. 
Participants are also required to return any remaining study diaries to the study site at the end of 
this period. 
Participant Disposition and Timing of Safety Follow-Up 
 
Abbreviations: ED = early discontinuation of treatment; Wks = weeks 
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Ambulatory BP measurements 
 should be collected on a typical workday, not on a non-working day  
 will be recorded every 30 minutes during daytime hours (0700 to 2200 hours), and 
 will be recorded every 60 minutes during nighttime hours (2200 to 0700 hours). 
A 24-hour session of ambulatory monitoring produces technically acceptable measurements if 
≥70% of the readings are valid. Between Visit 3 and Visit 4 (Week 0) and within 7 days 
following Visit 11 (Week 24) and Visit 14 (Week 36), participants will undergo a 24-hour 
ambulatory monitoring session. Upon return of the ABPM device, the recordings must be 
transmitted to the Core Laboratory and reviewed for validity of the readings before the 
participant leaves the site. If a technically satisfactory result is not achieved (less than 70% of 
readings are valid), the investigator should review the device settings and placement and the 
participant’s activity track to correct any user error or device malfunctions. Another 24-hour 
ambulatory monitoring session should be conducted prior to Visit 4 (Randomization) or within 
14 days following Visit 11 and Visit 14, respectively. If the second session also provides 
technically unsatisfactory results, data will be considered missing and the participant may 
continue in the study.  
4.2. 
Scientific Rationale for Study Design 
Data from the Phase 1 program in patients with T2D demonstrated that LY3437943 has the 
potential to induce clinically meaningful weight loss (that is, 5%-10% or more) with a safety 
profile consistent with other GLP-1 and GIP/GLP-1RAs.  
The placebo arm is included to determine whether any efficacy or safety effects of LY3437943 
are different in magnitude from no treatment (that is, placebo). Although it will not be feasible to 
blind the participant and the investigator to the injection volume of study drug, they will not 
know whether the participant is receiving LY3437943 or placebo. To preserve the blind, 
participants randomized to placebo will be randomly assigned to follow the injection dose 
schedule for 1 of the LY3437943 treatment arms. 
Consistent with current guidelines for weight management, all participants will receive diet and 
physical activity counseling throughout the study, which will be based on guidelines published 
by the U.S. Department of Agriculture and U.S. Department of Health and Human Services 
(HHS 2018; USDA and HHS 2020).  
The primary efficacy measure, mean percent change in body weight, is an accepted Phase 2 
endpoint for investigational drugs being developed for weight management (FDA 2007). In 
addition, the protocol includes other parameters relevant to assessment of the effects of 
LY3437943 on safety, BP, HR, lipids, glycemic control, mechanism of action, PK parameters, 
and patient-reported outcomes.  
The primary objective will be evaluated at 24 weeks because this period is considered adequate 
for evaluation of weight loss efficacy in a Phase 2 trial and sufficient to assess the dose–
exposure–response of LY3437943 efficacy for selection of doses to be included in Phase 3 
testing. The planned 48-week treatment period should be sufficient to capture the maximal or 
near-maximal weight loss effects of LY3437943. The putative mechanism of action of 
LY3437943 suggests that treatment with LY3437943 will result in continued weight loss over 
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33 
this treatment period. In addition, safety and tolerability over a wide dose range of LY3437943 
versus placebo will be assessed to enable robust benefit–risk characterizations in treatment of 
participants who have obesity or are overweight. 
LY3437943 was well tolerated up to a 3 mg dose in the single ascending dose study (Study 
GZBA) and up to a 12 mg dose with gradual dose escalation in the multiple ascending dose 
study (Study GZBB). Therefore, the highest dose in this study will be 12 mg. In addition, 2 dose 
escalation schemes, starting with either 2 mg or 4 mg doses, are designed to provide information 
on optimal dose escalation schemes for Phase 3 clinical development. 
To minimize the potential confounding effect of changes to concomitant medications, 
participants will be permitted to use concomitant medications that do not interfere with the 
assessment of efficacy or safety characteristics of the study treatments. 
The sample size is determined based on data from Study GZBB that provided preliminary PD 
data for LY3437943 in participants with T2D over a 12-week treatment period, and on data from 
the semaglutide Phase 2 obesity study (O’Neil et al. 2018). 
4.3. 
Justification for Dose 
LY3437943 doses of 1, 4, 8, and 12 mg, administered subcutaneously QW, were selected based 
on the following 
 Safety and tolerability of LY3437943 in healthy participants and participants with T2D in 
the Phase 1 studies GZBA (0.1 to 6 mg dose range) and GZBB (0.5 to 12 mg dose range). 
 PK/PD modeling of preliminary data from Study GZBB. 
 Acceptable margin of safety for the 12-mg maximum dose in this study relative to the no-
observed-adverse-effect level in rats and monkeys in the 6-month toxicology studies. 
 A maintenance dosage of 1 mg is predicted to achieve LY3437943 concentration levels 
that will demonstrate greater body weight loss compared with placebo and is being 
investigated in this study to enable full characterization of exposure–response 
relationships.  
 Maintenance dosages of 4, 8, and 12 mg are expected to provide clinically relevant 
weight loss relative to placebo with increasing weight loss with increasing dose. For these 
doses, a starting dose of 2 or 4 mg prior to dose escalation will be investigated to evaluate 
the impact on tolerability and safety findings. 
 The selected dose levels and dose range will support a robust dose–exposure–response 
analysis of multiple safety and efficacy measures to support selection of dose(s) of 
LY3437943 with optimal benefit/risk ratio for further clinical development. 
4.4. 
End of Study Definition 
A participant is considered to have completed the study if he or she has completed all required 
phases of the study including the last visit or the last scheduled procedure shown in the SoA. 
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled procedure shown in the SoA for the last participant in the trial globally. 
 
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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 the following criteria apply: 
Age 
1. 
Participant must be 18 to 75 years of age inclusive, at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics 
2. 
Have a BMI of 
 ≥30 kg/m2 and ≤50 kg/m2 
 ≥27 kg/m2 and <30 kg/m2 with at least 1 of the following weight-related 
comorbidities 
o hypertension: on BP-lowering medication or having systolic BP 
≥130 mmHg or diastolic BP ≥80 mmHg at screening 
o dyslipidemia: on lipid-lowering medication or having low-density 
lipoprotein (LDL) ≥160 mg/dL (4.1 mmol/L) or triglycerides ≥150 
mg/dL (1.7 mmol/L), or high-density lipoprotein (HDL) <40 
mg/dL (1.0 mmol/L) for men or HDL <50 mg/dL (1.3 mmol/L) for 
women at screening 
o cardiovascular disease: (for example, ischemic cardiovascular 
disease, New York Heart Association [NYHA] Functional 
Classification Class I-II heart failure)  
3. 
In the investigator’s opinion, are well motivated, capable, and willing to  
 learn how to self-inject study drug, as required for this protocol (visually impaired 
persons who are not able to perform the injections must have the assistance of a 
sighted individual trained to inject the study drug; persons with physical 
limitations who are not able to perform the injections must have the assistance of 
an individual trained to inject the study drug)  
 inject study drug (or receive an injection from a trained individual if visually 
impaired or with physical limitations), and 
 follow study procedures for the duration of the study, including, but not limited 
to, follow lifestyle advice (for example, dietary changes and physical activity 
plan), maintain a study drug administration log, and complete required 
questionnaires. 
In addition, a subgroup of approximately 100-125 participants will meet the following 
inclusion criterion  
4. 
Have liver fat content ≥10% by MRI-PDFF 
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Sex 
5. 
 Male and/or female 
Contraceptive use by men or women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
Males, women of childbearing potential and women not of childbearing potential 
(for definitions, see Section 10.5 [Appendix 5]) can participate in this study 
considering the following: 
 males agree to refrain from sperm donation and to use contraceptive methods as 
described in Section 10.5 (Appendix 5) throughout the study and for 5 half-lives of 
study drug plus 90 days, corresponding to 4 months after the last injection.  
 women of childbearing potential must have negative pregnancy tests at Visit 1 and 
Visit 4 as indicated in the SoA and agree to use contraceptive methods as 
described in Section 10.5 (Appendix 5) throughout the study and for 5 half-lives of 
study drug plus 30 days, corresponding to 2 months after the last injection. Female 
participants should not be breastfeeding. 
Note: Hormone replacement therapy in postmenopausal women and contraceptives 
containing an estrogen and a progestin (oral or transdermal system) in premenopausal 
women are allowed but women must be on stable therapy for 3 months prior to 
screening. 
Informed Consent 
6. 
Capable of giving signed informed consent as described in Section 10.1 (Appendix 
1), which includes compliance with the requirements and restrictions listed in the ICF 
and in this protocol. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
Diabetes Related 
7. 
Have history of diabetes mellitus including T1D or T2D, history of ketoacidosis, or 
hyperosmolar state/coma  
8. 
Have at least 1 laboratory value suggestive of diabetes during screening, including 1 
or more of HbA1c ≥6.5% (48 mmol/mol), fasting serum glucose ≥126 mg/dL 
(7.0 mmol/L), or random glucose ≥200 mg/dL (11.1 mmol/L)  
Obesity Related 
9. 
Have a self-reported change (increase or decrease) in body weight >5 kg within 3 
months prior to screening 
10. 
Have a prior or planned surgical treatment for obesity (excluding liposuction or 
abdominoplasty, if performed >1 year prior to screening) 
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11. 
Have or plan to have endoscopic and/or device-based therapy for obesity or have had 
device removal within the last 6 months prior to screening including but not limited to 
 
mucosal ablation  
 
gastric artery embolization  
 
intragastric balloon, and  
 
duodenal-jejunal endoluminal liner 
Other Medical 
12. 
Have renal impairment measured as estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73 m2, calculated by Chronic Kidney Disease-Epidemiology (CKD-
EPI) as determined by central laboratory during screening  
13. 
Have a known clinically significant gastric emptying abnormality (for example, 
severe gastroparesis or gastric outlet obstruction) or chronically take drugs that 
directly affect GI motility 
14. 
Have a history of acute or chronic pancreatitis. A participant with a history of acute 
pancreatitis caused by gallstones may be included in the study if the participant has a 
cholecystectomy to resolve the problem 
15. 
Have thyroid-stimulating hormone outside of the range of 0.4 to 6.0 mIU/L at 
screening visit 
Note: Participants receiving treatment for hypothyroidism may be included, provided 
their thyroid hormone replacement dose has been stable for at least 6 months. 
Note: Thyroid-stimulating hormone values above the normal range can, in some 
participant, suggest subclinical hypothyroidism. If, in the investigator’s opinion, the 
participant has subclinical hypothyroidism and may require initiation of thyroid 
hormone replacement during the study, the participant should be excluded from the 
study.  
16. 
Have obesity induced by other endocrinologic disorders (for example, Cushing’s 
syndrome) or diagnosed monogenetic or syndromic forms of obesity (for example, 
Melanocortin 4 Receptor deficiency or Prader–Willi Syndrome) 
17. 
Have a history of significant active or unstable Major Depressive Disorder (MDD) or 
other severe psychiatric disorder (for example, schizophrenia, bipolar disorder, or 
other serious mood or anxiety disorder) within the last 2 years 
Note: Participants with MDD or generalized anxiety disorder whose disease state is 
considered stable for the past 2 years and expected to remain stable throughout the 
course of the study, in the opinion of the investigator, may be considered for inclusion 
if they are not on excluded medications 
18. 
Have a lifetime history of suicide attempt  
19. 
Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at Visit 1  
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20. 
On the C-SSRS at Visits 1, 3, or 4, prior to randomization: 
 
a “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS 
or  
 
a “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS  
or  
 
a “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS  
and  
 
the ideation or behavior occurred within the past month  
21. 
Have uncontrolled hypertension (systolic BP above or equal to 160 mmHg and/or 
diastolic BP above or equal to 100 mmHg). If a participant is on anti-hypertensive 
therapies, doses must be stable for 30 days prior to screening. For participants with 
uncontrolled hypertension at the screening visit, antihypertensive medication may be 
started or adjusted. Blood pressure must meet the protocol criterion for hypertension 
control by Visit 3 with stable treatment for at least 30 days 
22. 
Have an elevated resting pulse rate (>100 bpm) at baseline 
23. 
Have any of the following cardiovascular conditions within 3 months prior to 
Screening: 
 acute myocardial infarction  
 cerebrovascular accident (stroke) 
 unstable angina, or  
 hospitalization due to congestive heart failure (CHF) 
24. 
Ongoing or history of frequent intermittent or chronic tachyarrhythmia syndromes 
(such as atrial fibrillation, supraventricular tachycardia, and positional orthostatic 
tachycardia syndrome).  
Note: Participants with history of premature atrial contractions or premature 
ventricular contractions may be included. 
25. 
Have NYHA Functional Classification III or IV CHF  
26. 
Have an electrocardiogram (ECG) considered by the investigator indicative of active 
cardiac disease or with abnormalities that may interfere with the interpretation of 
changes in ECG intervals at screening  
27. 
Have acute or chronic hepatitis, or signs and symptoms of any other liver disease 
other than NAFLD, or any of the following, as determined by the central laboratory 
during screening  
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 
ALT level >3.0X upper limit of normal (ULN) for the reference range 
 
alkaline phosphatase (ALP) level >1.5X ULN for the reference range, or 
 
total bilirubin level (TBL) >1.5X ULN for the reference range (except for 
cases of known Gilbert’s Syndrome)  
28. 
Have a serum calcitonin level (at Visit 1) of 
 ≥20 ng/L, if eGFR ≥60 mL/min/1.73 m2 or 
 ≥35 ng/L if eGFR <60 mL/min/1.73 m2 (as determined by central laboratory at 
Visit 1) 
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 carcinomas of the cervix, or in situ prostate cancer) for less than 5 years 
31. 
Have any other condition not listed in this section (for example, hypersensitivity or 
intolerance) that is a contraindication to GLP-1RA 
32. 
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 
33. 
Alcohol consumption >14 units/week for women and >21 units/week for men 
34. 
Have a history of use of marijuana or tetrahydrocannabinol (THC)-containing 
products within 3 months of enrollment or unwillingness to abstain from marijuana or 
THC-containing products use during the trial 
Note: If a participant has used cannabidiol oil during the past 3 months but agrees to 
refrain from use for the duration of the study, the participant can be enrolled. 
35. 
Have had a transplanted organ (corneal transplants [keratoplasty] are allowed) or are 
awaiting an organ transplant 
36. 
Have any hematological condition that may interfere with HbA1c measurement (for 
example, hemolytic anemias and sickle cell disease) 
37. 
Have had a blood donation of 500 mL within the previous 8 weeks of study 
screening or a blood transfusion or severe blood loss within the prior 3 months, or 
have known hemoglobinopathy, hemolytic anemia, sickle cell anemia, or have a 
hemoglobin value <11 g/dL (males) or <10 g/dL (females), or any other condition 
known to interfere with HbA1c methodology 
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38. 
Have a history of atopy (severe or multiple allergic manifestations) or clinically 
significant multiple or severe drug allergies, or intolerance to topical corticosteroids, 
or severe posttreatment hypersensitivity reactions (including, but not limited to, 
erythema multiforme major, linear immunoglobulin A dermatosis, toxic epidermal 
necrolysis, anaphylaxis, angioedema, or exfoliative dermatitis) 
39. 
Have a fasting serum triglyceride level of >500 mg/dL at screening. If a participant is 
on lipid-lowering therapies, doses must be stable for 30 days prior to screening 
40. 
Have evidence of a significant active, uncontrolled medical condition or a history of 
any medical problem capable of constituting a risk when taking the study medication 
or interfering with the interpretation of data, as judged by the screening investigator at 
screening 
41. 
Have a history of symptomatic gallbladder disease within the past 2 years, defined by 
the presence of gallstones on an imaging study and abdominal pain attributed to the 
gallstones by the participant’s physician; subjects who had a procedure to remove the 
gallstones and/or the gallbladder (cholecystectomy), with no long-term complications, 
are eligible for participation as long as the procedure was completed at least 3 months 
prior to screening 
42. 
Have a history of documented human immunodeficiency virus (HIV) infection 
Prior/Concomitant Therapy 
43. 
Are receiving or have received within 3 months prior to screening chronic (>2 weeks) 
systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, single 
intraarticular injection, or inhaled preparations) or have evidence of a significant, 
active autoimmune abnormality (for example, lupus or rheumatoid arthritis) that has 
required (within the last 3 months) or is likely to require, in the opinion of the 
investigator, concurrent treatment with systemic glucocorticoids (excluding topical, 
intraocular, intranasal, intraarticular, or inhaled preparations) during the course of the 
study 
44. 
Have current treatment with or history of treatment with (within 3 months prior to 
screening) medications that may cause significant weight gain including, but not 
limited to, tricyclic antidepressants, atypical antipsychotics, and mood stabilizers 
Examples: 
 imipramine  
 amitriptyline  
 mirtazapine 
 paroxetine 
 phenelzine 
 chlorpromazine 
 thioridazine 
 clozapine 
 olanzapine 
 valproic acid and its derivatives, and  
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 lithium. 
Note: Selective serotonin reuptake inhibitors other than paroxetine are permitted.  
45. 
Have taken within 3 months prior to screening medications (prescribed or over the 
counter) or alternative remedies intended to promote weight loss 
Examples include, but are not limited to: 
 Saxenda® (liraglutide 3.0 mg) or other GLP-1RA 
 Xenical®/Alli® (orlistat) 
 Meridia® (sibutramine) 
 Acutrim® (phenylpropanolamine) 
 Sanorex® (mazindol) 
 Apidex® or LomairaTM (phentermine) 
 QsymiaTM (phentermine/topiramate combination) 
 Contrave® (naltrexone/bupropion) 
 
46. 
Use of metformin, or any other glucose-lowering medication, whether prescribed for 
polycystic ovarian syndrome or diabetes prevention is not permitted 
47. 
Have started implantable or injectable contraceptives, such as Depo Provera® and 
Nexplanon®, within 18 months prior to screening. Intrauterine devices, including 
levonorgestrel-releasing intrauterine systems, are allowed if the participant has been 
using the device for at least 3 months 
Prior/Concurrent Clinical Study Experience 
48. 
Have known allergies to GLP-1R agonists or LY3437943  
49. 
Are currently enrolled in any other clinical study involving an investigational product 
(IP) or any other type of medical research judged not to be scientifically or medically 
compatible with this study  
50. 
Within the last 30 days, have participated in a clinical study and received treatment, 
whether active or placebo. If the study involved an IP, 5 half-lives or 30 days, 
whichever is longer, should have passed 
51. 
Have previously received LY3437943 as part of this study or any another study 
investigating LY3437943 
Other Exclusions 
58. Are investigator site personnel directly affiliated with this study and/or their immediate 
families. Immediate family is defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted 
59. Are Lilly employees 
Note: The inclusion and exclusion criteria numbered from 52 to 57 are part of J1I-MC-GZBF 
Addendum (1). So, in Section 5.2, the exclusion criteria continue with the next available number 
in the sequence from the last number in the protocol addendum (58–59). 
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5.3. 
Lifestyle Considerations 
Throughout the study, participants may undergo medical assessments and review of compliance 
with requirements before continuing in the study. Participants will report to the clinical research 
site for safety assessments and will remain in the clinic until all procedures for that visit are 
complete and the investigator has deemed it safe to release the participant from the clinic. There 
will be no inpatient stays. In addition, participants will report to the clinical research site for 
pharmacokinetic (PK)-specific visits. 
Meals/Diet – Participants will fast for at least 8 hours overnight prior to each in-person site visit 
where fasting samples are drawn and when weight measurements are taken. 
Physical Activity – Participants will be advised to avoid strenuous exercise within 24 hours 
prior to each study site visit. When certain study procedures are in progress at the site, 
participants may be required to remain supine or seated. 
Alcohol – Alcohol will not be permitted 8 hours prior to the study site visits, until the 
participant has been discharged from the clinical research site. 
Blood Donation – Study participants should be instructed not to donate blood or blood products 
during the study and for 8 weeks following the study.  
5.3.1. 
Diet and Physical Activity Counseling  
Study participants will receive diet and physical activity counseling, using a standardized 
approach, by a dietician/nutritionist or a similar qualified healthcare professional, as specified in 
the SoA (Section 1.3). Based on the counseling provided, participants should follow a healthy 
lifestyle plan throughout the course of the study (HHS 2018; USDA and HHS 2020). Refer to 
Section 10.7 (Appendix 7) for details of the diet and physical activity recommendations.  
To encourage adherence, it is recommended that a 3-day diet and exercise diary be completed 
prior to each counseling visit. During each visit, the participant’s diet is reviewed and advice to 
maximize adherence is provided if needed. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility criteria, 
and any SAE.  
Individuals who do not meet the criteria for participation in this study (screen failures) may be 
rescreened only once at the discretion of the investigator. Before rescreening is performed, the 
participant must sign a new ICF and receive a new identification number. If, in the opinion of the 
investigator, an ineligible lab test result is the result of an error or exceptional circumstance, then 
that parameter can be retested once without the participant having to be rescreened. 
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All participants will inject study drug SC into the abdominal wall, alternating between 4 sites 
weekly, that is right and left upper quadrants and right and left lower quadrants, using the 
injection supplies provided. A caregiver may administer the injection after appropriate training. 
A new syringe will be used for each injection. The actual date, time, and injection-site location 
of all dose administrations will be recorded in the study drug administration log by the 
participant. 
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, prepare, or administer study drug. All study drugs 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-authorized study personnel are responsible for study drug 
accountability, reconciliation, and record maintenance (that is, receipt, 
reconciliation, and final disposition records). 
 Further guidance and information for the final disposition of unused study drug 
interventions are provided in the study training materials.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
This is a double-blind study. 
Participants who meet all criteria for enrollment will be randomly assigned to 1 of the study 
treatment arms at Visit 4. Assignment to treatment arms will be determined by a 
computer-generated random sequence using an IWRS. Participants will be randomly assigned in 
a 2:1:1:1:1:2:2 ratio (LY3437943 1 mg QW, LY3437943 4 mg QW (a), LY3437943 4 mg QW 
(b), LY3437943 8 mg QW (a), LY3437943 8 mg QW (b), LY3437943 12 mg QW, placebo 
QW).  
Although the participant and the investigator will know the injection volume of study drug, they 
will not know whether the participant is receiving LY3437943 or placebo. To preserve the blind, 
participants randomized to placebo will be randomly assigned to follow the injection dose 
schedule for 1 of the LY3437943 treatment arms. 
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete. 
Emergency unblinding may be performed through the IWRS. This option may be used ONLY if 
the participant’s well-being requires knowledge of the participant’s treatment assignment. All 
unblinding events are recorded and reported by the IWRS. 
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 
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clinical research physician (CRP) or clinical research scientist (CRS) for the participant to 
continue in the study. 
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a participant’s treatment assignment is warranted for medical management of the event. The 
participant’s safety must always be the first consideration in making such a determination. If a 
participant’s treatment assignment is unblinded, Lilly must be notified immediately. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.  
6.4. 
Study Intervention Compliance 
Participant compliance with study drug will be assessed at each visit. Compliance will be 
assessed by direct questioning and counting of unused study drug and/or empty vials returned. 
Study drug compliance will be determined by the following:  
 Study drug administration data will be recorded by the participant and reviewed 
by the investigator at each study visit. 
 The participants will be instructed to return any unused study drug and/or empty 
vials at the next visit to the study site for the purpose of performing drug 
accountability. 
Treatment compliance will be assessed every 4 weeks, or every 12 weeks after Visit 11, at the 
time of visits to the study site. Treatment compliance for each 4- to 12-week interval is defined 
as taking at least 75% of the required SC doses of study drugs.  
In addition to the assessment of a participant’s compliance with the study drug administration, 
other aspects of compliance with the study treatments will be assessed at each visit based on the 
participant’s adherence to the visit schedule, completion of study, study drug administration logs, 
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. Additional unscheduled visits may be scheduled 
if study site personnel determine that a participant requires additional training for the study drug 
preparation and injection techniques.  
6.5. 
Concomitant Therapy 
Investigative site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study. This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible.  
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications (for example, other medications for weight management) that may 
interfere with the assessment of efficacy and safety characteristics of the study treatments. 
Treatment with, or initiation of, medications that are excluded in the entry criteria (Section 5.2) 
is not permitted during the study, except for medications required for the management of 
incident diabetes (see Section 6.5.2). Hormone replacement therapy in postmenopausal women 
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and contraceptives containing an estrogen and a progestin (oral or transdermal system) in 
premenopausal women should not be started after entering the study. The sponsor should be 
contacted if a participant starts treatment with a medication that is prohibited by the protocol. 
Doses of other prescription medications for treatment of concurrent medical conditions should 
remain constant during the study unless an adjustment is medically indicated. For example, doses 
of anti-hypertensive medication may be reduced if the participant’s BP declines significantly 
during the study resulting in symptoms of lightheadedness.  
Any medication or vaccine (including over-the-counter or prescription medicines and 
acetaminophen/paracetamol), vitamins, and/or herbal supplements that the participant is 
receiving at the time of enrollment or receives during the study must be recorded in the eCRF. 
Nonsteroidal anti-inflammatory medications (including ibuprofen and aspirin), acetaminophen, 
cough suppressants, antihistamines, antibiotics, and topical ointments may be used on an as-
needed basis without notifying the sponsor and are not restricted by the stable dosing 
requirements listed earlier. Apart from these medications, the sponsor should be contacted to 
clarify if an individual medication is allowed in the study. If the need for additional concomitant 
medication arises, the participant may be continued in the study-on-study drug if, in the 
investigator’s opinion, the addition of the new medication does not pose a safety risk. If an 
additional concomitant medication is started, the sponsor should be informed as soon as possible. 
6.5.1. 
Management of Participants with Gastrointestinal Symptoms 
In the Phase 1 program, the most reported TEAEs for participants receiving LY3437943 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 (omit 1 dose). Refer to Section 6.6.1 for further 
guidance on restarting study drug after temporary discontinuation of study drug. The data 
related to temporary interruption of study treatment should be documented in source 
documents and entered on the eCRF. 
If intolerable GI symptoms or events persist despite the above measures, see Section 6.6. 
6.5.2. 
Definition and Management of Incident Diabetes 
Definition of Incident Diabetes 
Incident diabetes is defined when any 1 of the following occurs after randomization (ADA 
2020): 
 In a participant with classic symptoms of hyperglycemia or hyperglycemic crisis, a 
random serum glucose ≥200 mg/dL (11.1 mmol/L) 
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 Within a 4-week period, any 2 of the following criteria are observed or 1 abnormal value 
is observed and confirmed 
o HbA1c ≥6.5% (48 mmol/mol) 
o Fasting serum glucose ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric 
intake for at least 8 h, and 
o Initiation of any medication for the treatment of diabetes. 
Management of Incident Type 2 Diabetes 
Participants who develop T2D during the study will be 
 provided and trained to use a glucometer (the frequency of self-monitoring of BG will be 
at the discretion of the investigator) 
 educated on the signs and symptoms of hypoglycemia and its treatment, and 
 provided a diary to record hypoglycemic episodes per Section 8.3.2.1. 
Participants will be referred to their usual care provider and provided with a letter showing the 
study results indicative of diabetes. The decision to initiate glucose-lowering medication and the 
choice of glucose-lowering medication will be at the discretion of the participant’s usual care 
provider, except for the following medications that are not allowed in the study: 
 GLP-1RA, and 
 Dipeptidyl peptidase-4 (DPP-4) inhibitors.  
GLP-1RA and DPP-4 inhibitors should not be used in combination with LY3437943 due to 
overlapping pharmacology and the potential for increased GI side effects. Although metformin is 
not allowed upon study entry, it is allowed for treatment of incident T2D and is recommended 
for initial glucose-lowering therapy in this circumstance. Metformin should not be initiated 
during the study for the treatment of other metabolic conditions (for example, polycystic ovary 
syndrome and diabetes prevention). If additional glucose-lowering therapy beyond metformin is 
needed to treat incident T2D, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, 
sulfonylureas, or long-acting basal insulin may be considered. 
Monitoring for hypoglycemia includes capture of events as defined in Section 8.3.2.1. Date of 
diagnosis of diabetes will be captured in the eCRF. If participants are diagnosed with incident 
T1D, discontinuation of study drug should be considered as noted in Section 7.1.  
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
7.1. 
Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study drug. If study drug is definitively discontinued, the participant will remain 
in the study to be evaluated for all planned efficacy and safety measures. In addition, the 
participant may continue to receive diet and physical activity counseling. Participants who are 
unwilling to attend all scheduled visits after stopping study drug will be asked to return for a 
final visit 48 weeks after randomization, primarily for weight measurement and assessment of 
AEs (Visit 99). If participants are unwilling to attend Visit 99, their refusal to attend should be 
documented in the participant medical record. See the SoA for data to be collected at the time of 
discontinuation of study drug and follow-up and for any further evaluations that need to be 
completed.  
Possible reasons leading to permanent discontinuation of study drug: 
 participant decision 
o the participant requests to discontinue study drug 
 clinical considerations 
o initiation of prohibited concomitant medications (see Section 6.5) if 
participants will not or cannot discontinue them 
o intolerable GI symptoms despite management as described in Section 6.5.1 
and Section 6.6.1 
Note: The investigator should contact the Sponsor CRP/CRS to discuss 
whether it is medically appropriate for the participant to continue study 
treatment.  
o if the investigator, after consultation with the sponsor-designated medical 
monitor, determines that a systemic hypersensitivity reaction has occurred 
related to study drug administration, the participant should be permanently 
discontinued from the investigational drug 
o BMI ≤19 kg/m2 is reached at any time during the treatment period  
o diagnosis of T1D 
o diagnosis of MTC or MEN2 after randomization 
o significant elevation of calcitonin (Section 8.3.2.3.1)  
o diagnosis of acute or chronic pancreatitis  
o diagnosis of an active or untreated malignancy (other than basal or squamous 
cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) 
after randomization 
o onset of pregnancy in a female participant  
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o occurrence of any other treatment-emergent AE (TEAE), SAE, or clinically 
significant finding for which the investigator believes that permanent study 
drug discontinuation is the appropriate measure to be taken 
o PHQ-9 score ≥15  
▪ Participants should be referred to a Mental Health Professional (MHP) 
to assist in deciding whether the participant should be discontinued 
from study drug. If a participant’s psychiatric disorder can be 
adequately treated with psycho- and/or pharmacotherapy, then the 
participant, at the discretion of the Investigator (in agreement with the 
MHP), may be continued in the trial on randomized therapy.  
o in addition, study drug may be discontinued if participants 
▪ answered “yes” to either Question 4 (Active Suicidal Ideation with 
Some Intent to Act, Without Specific Plan) on the “Suicidal Ideation” 
portion of the C-SSRS 
or  
▪ answered “yes” to Question 5 (Active Suicidal Ideation with Specific 
Plan and Intent) on the “Suicidal Ideation” portion of the C-SSRS  
or  
▪ answered “yes” to any of the suicide-related behaviors (Actual 
attempt, Interrupted attempt, Aborted attempt, Preparatory act or 
behavior) on the “Suicidal Behavior” portion of the C-SSRS. 
Note: A psychiatrist or appropriately trained professional may assist in the decision to 
discontinue the participant. 
 discontinuation due to a hepatic event or liver test abnormality 
o Participants who are discontinued from study drug due to a hepatic event or liver 
test abnormality should have additional hepatic safety data collected via eCRF. 
o Discontinuation of the study drug for abnormal liver tests should be considered 
by the investigator when a participant meets 1 of the following conditions after 
consultation with the Lilly-designated medical monitor: 
▪ ALT or AST >8X ULN 
▪ ALT >2X baseline value OR ≥300 U/L, whichever occurs first, if 
baseline ALT ≥2X ULN 
▪ ALT or AST >5X ULN for more than 2 weeks 
▪ ALT or AST >3X ULN and TBL >2X ULN or international 
normalized ratio (INR) >1.5  
▪ ALT or AST >3X ULN with the appearance of fatigue, nausea, 
vomiting, right upper-quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (>5%) 
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▪ ALP >3X ULN 
▪ ALP >2.5X ULN and TBL >2X ULN 
▪ ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, 
right-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%). 
Refer to Section 10.1.8 for discontinuation of specific sites or of the study as a whole. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study  
 at any time at his or her own request  
 at the request of his or her designee (for example, parents or legal guardian) 
 at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
 if the participant becomes pregnant during the study  
 if enrollment in any other clinical study involving an investigational product 
or enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study, and 
 if the participant, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of the 
new agent. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. The 
participant will be permanently discontinued both from the study intervention and from the study 
at that time. 
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 or she may request destruction of any samples taken and not tested, 
and the investigator must document this in the site study records.  
7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. Site personnel or designee are 
expected to make diligent attempts to contact participants who fail to return for a scheduled visit 
or were otherwise unable to be followed up by the site.  
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8. 
Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA.  
 Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention. 
 Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will 
maintain a screening log to record details of all participants screened and to 
confirm eligibility or record reasons for screening failure, as applicable.  
8.1. 
Efficacy Assessments 
Primary: 
The primary efficacy measure is body weight. Body weight measurements will be collected at 
specific clinic visits as summarized in the SoA. Methods for measuring body weight are 
described in Section 10.8. 
Secondary: 
The following secondary efficacy measures will be collected at the times shown in the SoA. 
 BMI (derived using body weight in kilograms divided by the square of height in meters), 
and 
 waist circumference (see Section 10.8). 
Exploratory: 
The following exploratory efficacy measures will be collected at the times shown in the SoA: 
 blood pressure (see Section 4.1.2.3) 
 heart rate measured by ABPM (see Section 4.1.2.3) 
 lipid parameters 
 glycemic control 
 mechanistic biomarkers related to insulin sensitivity, pancreatic beta cell function, 
glucagon receptor target engagement, fatty acid oxidation, lipolysis, purine metabolism, 
cardiovascular risk, and inflammation (see table in Appendix 10 [Section 10.10]), and 
 patient-reported outcomes (see Section 10.11 [Appendix 11]). 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
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8.2.1. 
Physical Examinations 
For each participant, measurements including height, weight, and waist circumference should be 
conducted according to SoA, and following the study-specific recommendations included in 
Section 10.8 (Appendix 8). 
A complete physical examination will include, at a minimum, assessments of 
• skin, including feet 
• cardiovascular 
• respiratory 
• GI 
• neurological systems, and 
• thyroid exam. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.2. 
Vital Signs 
For each participant, vital sign measurements should be conducted according to the SoA and 
following the study-specific recommendations included in Section 10.8 (Appendix 8). 
Any clinically significant findings from vital sign measurement that result in a diagnosis and that 
occur after the participant receives the first dose of study intervention should be reported to Lilly 
or its designee as an AE via eCRF. 
8.2.3. 
Electrocardiograms 
For each participant, a 12-lead ECG should be collected according to Section 1.3 (for details, 
please see Section 10.8). Electrocardiograms will initially be interpreted by a qualified physician, 
the investigator, or qualified designee at the site as soon after the time of ECG collection as 
possible, and ideally while the participant is still present, for immediate participant management, 
should any clinically relevant findings be identified. Any clinically significant findings from 
ECGs that result in a diagnosis and that occur after the participant receives the first dose of the 
investigational treatment should be reported to Lilly or its designee as an AE via the eCRF. In 
addition, tracings collected at the baseline, 24, and 48 weeks will be assessed qualitatively by a 
blinded cardiologist. 
8.2.4. 
Clinical Safety Laboratory Assessments 
 See Section 10.2 (Appendix 2) for the list of clinical laboratory tests to be 
performed and to the SoA for the timing and frequency. 
 The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. 
The laboratory results must be retained with source documents unless a 
Source Document Agreement or comparable document cites an electronic 
location that accommodates the expected retention duration. Clinically 
significant abnormal laboratory findings are those which are not associated 
with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
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hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional Hepatic Data Collection (Hepatic Safety CRF) in Study Participants Who Have 
Abnormal Liver Tests during the Study  
Additional hepatic safety data collection in hepatic safety 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)  
 In participants with baseline ALT ≥1.5X ULN, the threshold is ALT ≥3X baseline on 
2 or more consecutive tests  
2. Elevated TBL to ≥2X ULN (if baseline TBL <1.5X ULN) (except for cases of known 
Gilbert’s syndrome)  
 In participants with baseline TBL ≥1.5X ULN, the threshold should be 
TBL ≥2X baseline  
3. Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests (if baseline 
ALP <1.5X ULN)  
 In participants with baseline ALP ≥1.5X ULN, the threshold is ALP ≥2X baseline on 
2 or more consecutive blood tests  
4. Hepatic event considered to be an SAE  
5. Discontinuation of study drug due to a hepatic event  
Note: The interval between the 2 consecutive blood tests should be at least 2 days.  
8.2.6. 
Suicidal Ideation and Behavior Risk Monitoring 
Participants who have obesity or are overweight are at increased risk for depression (Luppino et 
al. 2010). Depression can increase the risk for suicidal ideation and behavior. Therefore, study 
participants will be screened at trial entry and monitored during the study for depression, suicidal 
ideation, and behavior. 
Participants should be monitored appropriately for suicidal ideation and behavior or any other 
unusual changes in behavior, especially at the beginning and end of the course of treatment, or at 
the time of dose changes, either increases or decreases. Consideration should be given to 
discontinuing the study medication in participants who experience signs of suicidal ideation or 
behavior, following a risk assessment.  
Columbia Suicide-Severity Rating Scale (C-SSRS) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and behavior during the assessment period via a 
questionnaire. The scale was developed by the National Institute of Mental Health (NIMH) trial 
group (TASA) for the purpose of being counterpart to the Columbia Classification Algorithm of 
Suicide Assessment (C-CASA) categorization of suicidal events. 
 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for 
Reporting to 
Sponsor or 
Designee 
Mechanism 
for 
Reporting 
Back-Up 
Method of 
Reporting 
PC (after 
participant’s 
study 
participation 
has ended 
and the 
investigator 
becomes 
aware)  
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
Product 
complaint 
form 
N/A 
Abbreviations: AE = adverse event; eCRF = electronic case report form; N/A = not applicable; PC = product 
complaint; SAE = serious adverse events. 
*Serious adverse events, including death, caused by disease progression should not be reported unless the 
investigator deems them to be possibly related to study treatment. 
8.3.1.1. 
Adverse Event Monitoring with a Systematic Questionnaire 
Nonleading AE collection should occur prior to the collection of the C-SSRS. 
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. 
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
8.3.2. Adverse Events of Special Interest 
The following are adverse events of special interest and will be adjudicated by an independent 
clinical endpoint committee (CEC): 
 pancreatitis 
 major adverse cardiovascular events, and 
 deaths. 
The following are additional adverse events of special interest for this program that will not be 
adjudicated by an external committee: 
 hypoglycemia (Level 2 and 3) 
 thyroid malignancies and C-cell hyperplasia 
 supraventricular arrhythmias and cardiac conductive disorders 
 hypersensitivity events 
 injection site reactions 
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 hepatobiliary disorders 
 severe GI AEs 
 antidrug antibodies 
 acute renal events, and 
 depression, suicidal ideation or behavior monitoring. 
Sites should collect additional details and data regarding these safety topics, as instructed on the 
applicable eCRFs, and detailed below. 
8.3.2.1. 
Hypoglycemia  
Upon ICF signing, all participants will be educated about signs and symptoms of hypoglycemia 
and how to treat hypoglycemia. Participants will be asked to contact site personnel if they 
experience any of these symptoms. 
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood glucose (BG) 
samples collected during study visits. 
All participants who develop incident diabetes during the study will be provided with 
glucometers. Participants without diabetes may, at the investigator’s discretion, be given 
glucometers to assist in the evaluation of reported symptoms consistent with hypoglycemia. 
Participants receiving glucometers will be provided a diary to record relevant information (for 
example, glucose values and symptoms). 
Participants who develop incident diabetes during the study may be started on allowed glucose-
lowering medications (Section 6.5.2). In the event that participants subsequently develop 
persistent or recurrent unexplained hypoglycemia during the treatment period, participants will 
be asked to reduce the dose or discontinue any concomitant glucose-lowering medication 
commonly associated with hypoglycemia (for example, sulfonylurea or insulin). 
All hypoglycemic episodes will be recorded on a specific eCRF and should not be recorded as 
AEs unless the event meets serious criteria. If a hypoglycemic event meets severe criteria (see 
definition below), it should be recorded as serious on the AE and SAE eCRFs, and reported to 
Lilly as an SAE. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the 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). Level 2 and Level 3 
hypoglycemia events are considered as adverse events of special interest: 
Level 1 hypoglycemia:  
Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L): Level 1 hypoglycemia can 
alert a person to take action such as treatment with fast-acting carbohydrates. Providers should 
continue to counsel participants to treat hypoglycemia at this glucose alert value. 
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Level 2 hypoglycemia: 
Glucose <54 mg/dL (3.0 mmol/L): This is also referred to as documented or BG-confirmed 
hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is clinically 
relevant regardless of the presence of absence of symptoms of hypoglycemia.  
Level 3 hypoglycemia: 
Severe hypoglycemia (in adults): A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia. For example, participants 
had altered mental status and could not assist in their own care, or were semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another 
person was needed to actively administer carbohydrate, glucagon, or other resuscitative 
actions. Glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of glucose concentration to normal is considered 
sufficient evidence that the event was induced by a low glucose concentration. 
 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance. 
 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep. 
To avoid duplicate reporting, all consecutive BG values <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). 
8.3.2.2. 
Pancreatitis  
Diagnosis of Acute Pancreatitis 
Acute pancreatitis is an AE of interest in all studies with LY3437943, including this study. The 
diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks and Freeman 2006, 
Koizumi 2006):  
 abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating 
to the back, often associated with nausea and vomiting) 
 serum amylase (total, pancreatic, or both) and/or lipase ≥3X ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
If acute pancreatitis is suspected, the investigator should ensure that the following steps are 
taken: 
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 obtain appropriate laboratory tests, including pancreatic amylase (p-amylase) and 
lipase, and 
 perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal MRI. 
Note: Abdominal ultrasound may be used as an alternative method only if CT and 
MRI cannot be performed. 
 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications. 
Discontinuation for Acute Pancreatitis 
If acute pancreatitis is suspected by the investigator, the participant must temporarily discontinue 
use of the study drug. Afterwards, if the case is confirmed as acute pancreatitis by the 
adjudication committee, study drug must be permanently discontinued; the participant may 
continue in the study. If the case is not confirmed, then the participant can restart study drug, if 
the investigator deems as clinically appropriate, as described in the Section 6.6. 
Case Adjudication and Data Entry 
An independent CEC will adjudicate all suspected cases of acute pancreatitis. Relevant data from 
participants with acute pancreatitis will be entered into a specifically designed eCRF page. The 
adjudication committee representative will enter the results of adjudication in a corresponding 
eCRF page. 
Asymptomatic Elevation of Pancreatic Amylase and/or Lipase 
Serial measures 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). Therefore, further diagnostic follow-up of cases of asymptomatic elevation of pancreatic 
enzymes (lipase and/or p-amylase ≥3X ULN) is not mandated but may be performed based on 
the investigator’s clinical judgment and assessment of the participant’s overall clinical condition. 
8.3.2.3. 
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, papillary carcinoma, and others) and measurements of calcitonin. 
These data will be captured in specific eCRFs. The purpose of calcitonin measurements is to 
assess the potential of LY3437943 to affect thyroid C-cell function, which may indicate 
development of C-cell hyperplasia and neoplasms.  
8.3.2.3.1. 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. 
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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/1.73 m2 is defined 
below. If a participant’s laboratory results meet these criteria, these clinically significant 
laboratory results should be recorded as an AE. 
 Serum calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the screening 
value. These participants will be asked to repeat the measurement within 1 month. If this 
repeat value is increasing (≥10% increase), the study drug should be stopped, and the 
participants encouraged to undergo additional endocrine assessment and longer-term 
follow-up by an endocrinologist to exclude any serious adverse effects on the thyroid. 
 Serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. In these 
participants, study drug should be stopped, and the participants 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 serum 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 
participants recommended to immediately undergo additional endocrine assessments and longer-
term follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid. 
8.3.2.4. 
Major Adverse Cardiovascular Events  
Nonfatal cardiovascular AEs will be adjudicated by a committee of physicians external to Lilly 
with cardiology expertise. This committee will be blinded to treatment assignment. The nonfatal 
cardiovascular AEs to be adjudicated include 
 myocardial infarction  
 hospitalization for unstable angina 
 hospitalization for heart failure 
 coronary interventions (such as coronary artery bypass graft or percutaneous coronary 
intervention), and  
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack. 
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8.3.2.5. 
Deaths 
All deaths will be adjudicated by a committee of physicians external to Lilly. This committee 
will be blinded to treatment assignment. 
8.3.2.6. 
Supraventricular Arrhythmias and Cardiac Conduction Disorders  
Treatment-emergent cardiac conduction disorders will be further evaluated. Participants who 
develop any event from these groups of disorders should undergo an ECG, which should be 
submitted to the central reading center. 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 10.4 (Appendix 4) must be reported 
as SAEs.  
8.3.2.7. 
Hypersensitivity Reactions  
Many drugs, but particularly biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data describing each symptom should be provided 
to the sponsor in the eCRF. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study drug. It is recommended that participants 
who experience a systemic hypersensitivity reaction be treated per national and international 
guidelines. 
In the case of generalized urticaria or anaphylaxis, additional blood and urine samples should be 
collected as described in Section 10.3 (Appendix 3). Laboratory results are provided to the 
sponsor via the central laboratory. 
8.3.2.8. 
Injection Site Reactions 
Symptoms of a local injection site reaction may include erythema, induration, pain, pruritus, and 
edema. If an injection site event is reported, the AE will be recorded, and additional data will be 
provided to the sponsor in the eCRF. At the time of AE occurrence of severe or serious types, 
samples will be collected for measurement of LY3437943 antidrug antibodies (ADAs) and 
LY3437943 concentration. 
8.3.2.9. 
Antidrug Antibodies 
The occurrence of ADA formation will be assessed as outlined in Section 8.9. 
8.3.2.10. Hepatobiliary Disorders 
All events of treatment-emergent (TE) 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 laboratory tests, hepatic monitoring should be initiated as 
outlined in Section 8.2.5.1. 
8.3.2.11. Severe Gastrointestinal Adverse Events  
LY3437943 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 
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and Concomitant Medications forms, respectively. For detailed information concerning the 
management of GI AEs, please refer to Section 6.5.1. 
8.3.2.12. Acute Renal Events 
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute renal failure or worsening of preexisting chronic renal 
failure. Gastrointestinal AEs have been reported with LY3437943, including nausea, diarrhea, 
and vomiting. This is consistent with other GLP-1R agonists (Aroda and Ratner 2011). These 
events may lead to dehydration, which could cause a deterioration in renal function, including 
acute renal failure. Participants should be advised to notify investigators in case of severe nausea, 
frequent vomiting, or symptoms of dehydration. 
8.3.2.13. Depression, Suicidal Ideation, or Behavior Monitoring 
Participants will be monitored for depression and suicidal ideation or behavior through AE 
collection and by using the C-SSRS and the PHQ-9 questionnaires. Scores of the questionnaires 
must be reviewed by the investigator at the time of each visit and appropriate actions as 
described below should be taken. 
Columbia Suicide-Severity Rating Scale (C-SSRS) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and behavior during the assessment period via a 
questionnaire. The scale was developed by the National Institute of Mental Health (NIMH) trial 
group (TASA) for the purpose of being counterpart to the Columbia Classification Algorithm of 
Suicide Assessment (C-CASA) categorization of suicidal events. For this study, the C-SSRS is 
adapted for the assessment of the ideation and behavior categories only. The Intensity of Ideation 
and Lethality of Behavior sections are removed. 
The PHQ9 questionnaire is a validated, participant-completed 9-item depression module of the 
Patient Health Questionnaire, which is used as a diagnostic instrument for common mental 
disorders. The PHQ-9 consists of 9 items each scored on a scale of 0 = “not at all” to 3 = “nearly 
every day” with a recall period of “the last 2 weeks.” Major depression is diagnosed if 5 or more 
of the 9 depressive symptom criteria have been present at least “more than half the days” in the 
past 2 weeks, and 1 of the symptoms is depressed mood or anhedonia. As a severity measure, a 
higher score indicates greater severity.  
Participants will be referred to a MHP if in the opinion of the investigator it is necessary for the 
safety of the participant or if the participant had any of the following: 
 a PHQ-9 score ≥15 
 C-SSRS responses of 
o A “yes” answer to Question 4 (Active Suicidal Ideation with Some Intent to Act, 
Without Specific Plan) on the “Suicidal Ideation” portion of the C-SSRS  
or  
o A “yes” answer to Question 5 (Active Suicidal Ideation with Specific Plan and 
Intent) on the “Suicidal Ideation” portion of the C-SSRS  
or  
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o A “yes” answer to any of the suicide-related behaviors (actual attempt, interrupted 
attempt, aborted attempt, preparatory act, or behavior) on the “Suicidal Behavior” 
portion of the C-SSRS 
8.4. 
Treatment of Overdose 
For this study, any total dose of study drug within a 48-hour time period greater than the dose 
prescribed by IWRS for that participant will be considered an overdose and should be reported as 
per criteria described in Section 10.4 (Appendix 4). 
In the event of an overdose, the investigator should 
1. contact the Medical Monitor immediately 
2. closely monitor the participant for any AE/SAE and laboratory abnormalities until study drug 
can no longer be detected systemically (at least 30 days). Refer to Section 8.3 for reporting 
details, and 
3. obtain a plasma sample for PK analysis within 5 days from the date of the last dose of study 
drug if requested by the Medical Monitor (determined on a case-by-case basis). 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. In the 
event of overdose, refer to the LY3437943 IB.  
8.5. 
Pharmacokinetics 
Blood samples for PK analyses will be collected from all randomized participants at the specified 
visits in accordance with SoA. Efforts should be taken to align clinical visits with PK sampling 
windows specified in the Pharmacokinetic Schedule of Events (Section 1.3). Otherwise, 
participants may need to return to the clinical site for additional PK-specific visits to provide PK 
samples. Only samples from participants assigned to treatment with LY3437943 will be analyzed 
for drug concentration. 
Date and time of each sample and the most recent LY3437943 dose prior to PK blood draw must 
be recorded. Drug concentration information that would unblind the study will not be reported to 
study sites or blinded personnel while the study is blinded.  
8.5.1. 
Bioanalysis 
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of LY3437943 will be assayed using a validated liquid chromatography mass 
spectrometry method. Analyses of samples collected from participants who received placebo are 
not planned.  
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 1 year following last participant visit for the study. During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses, such as 
metabolism, protein binding, and/or bioanalytical cross-validation. 
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8.6. 
Pharmacodynamics 
Pharmacodynamics assessments for LY3437943 are included as part of the efficacy measures 
listed in Section 8.1 and will be collected in accordance with the SoA. 
8.7. 
Genetics 
A whole blood sample will be collected to enable exploratory pharmacogenetic analyses as 
specified in the SoA (Section 1.3), where local regulations allow (see Section 10.6). 
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future. Samples may be used to investigate variable exposure or response to 
LY3437943 and to investigate genetic variants thought to play a role in obesity, diabetes 
mellitus, and related clinical traits or complications, including nonalcoholic steatohepatitis. 
Assessment of variable response may include evaluation of AEs or differences in 
pharmacodynamic, mechanistic, safety, or efficacy measures.  
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 investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and/or the ethical review board impose shorter time limits, for 
the study at a facility selected by Lilly or its designee. 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 LY3437943 or after LY3437943 is 
commercially available.  
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, multiplex assays, and candidate gene studies. 
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
8.8. 
Biomarkers 
Biomarker research is performed on stored samples to address questions of relevance to drug 
disposition, target engagement, PD, 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 
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular 
elements (see Section 10.10).  
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. 
Samples will be used for research on the drug targets, disease process, variable response to 
LY3437943, pathways associated with obesity, diabetes mellitus, and related clinical traits or 
complications, including nonalcoholic steatohepatitis, mechanism of action of LY3437943, 
and/or research method, or for validating diagnostic tools or assay(s) related to obesity, diabetes 
mellitus, or related clinical traits or complications. 
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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 investigative site personnel. 
Samples will be retained for a maximum of 15 years after the last participant visit, or for a 
shorter period if local regulations and/or ERBs/Institutional Review Boards impose shorter time 
limits, at a facility selected by Lilly or its designee. 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 LY3437943, or after LY3437943 is 
commercially available. 
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 LY3437943. Antibodies may be further characterized 
for cross-reactive binding to endogenous counterparts (native GIP, GLP-1, and glucagon), and 
their ability to neutralize the activity of LY3437943 and endogenous counterparts. To interpret 
the results of immunogenicity, a venous blood sample will be collected at the same time points to 
determine the concentrations of LY3437943. All samples for immunogenicity should be taken 
predose when applicable and possible. 
Treatment-emergent ADAs are defined in Section 9.4.4.4. If the immunogenicity sample at the 
last scheduled assessment or discontinuation visit is TE-ADA positive, additional samples may 
be taken until the ADA signal returns to baseline (that is, no longer indicates TE-ADA) or up to 
1 year after last dose. A PK sample may be collected at each time point at the investigator’s 
discretion.  
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 the LY3437943. 
Any samples remaining after 15 years will be destroyed.  
8.10. 
Health Economics  
This section is not applicable for this study. 
 
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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The primary hypothesis that is being tested in this study is that LY3437943 1, 4, 8, or 12 mg 
administered SC QW is superior to placebo with regard to percent change in body weight from 
baseline to Week 24, in participants without T2D who have obesity or are overweight with 
weight-related comorbidities. 
9.2. 
Sample Size Determination 
Approximately 300 participants will be randomly assigned to LY3437943 1 mg, LY3437943 4 
mg (a), LY3437943 4 mg (b), LY3437943 8 mg (a), LY3437943 8 mg (b), LY3437943 12 mg or 
placebo with a 2:1:1:1:1:2:2 ratio. Assuming a 20% dropout rate, approximately 48 participants 
will complete each LY3437943 dose and placebo. An upper limit of 60% enrollment of women 
will be used to ensure a sufficiently large sample of men. 
Sample size selection is guided by the objective of establishing superiority of each LY3437943 
dose to placebo relative to the percent change in body weight from baseline to Week 24. The 
evaluation of superiority to placebo will be conducted for each of the 4 LY3437943 doses at 2-
sided significance level of 0.05 using 2-sample t-test. Assuming a standard deviation (SD) of 
10%, the LY3437943 group mean percent change in body weight at Week 24 from baseline 
compared to placebo is assumed to be -8%. The chosen sample size provides at least 97% power 
to establish superiority of LY3437943 1 mg, LY3437943 4 mg, LY3437943 8 mg, or 
LY3437943 12 mg compared to placebo. No adjustment for multiplicity will be performed.  
In addition, this sample size provides approximately 83% power to show that at least 1 
LY3437943 dose has superior effects of reducing waist circumference compared with placebo at 
Week 24. This assumes a reduction of 5.8 cm in waist circumference compared with placebo at 
Week 24 and a SD of 9.6 cm. 
9.3. 
Populations for Analyses 
For purposes of analysis, the following analysis sets are defined: 
Analysis Set 
Description 
Entered 
All participants who sign the ICF. 
Randomized 
All participants who are randomly assigned to a treatment arm. 
Efficacy analysis set 
 
Data obtained during treatment period from all randomly 
assigned participants who take at least 1 dose of double-blind 
study treatment. Excludes data after discontinuation of study 
drug. Participants will be analyzed according to the treatment 
group to which they were randomly assigned. 
Full analysis set 
 
Data obtained during treatment period from all randomly 
assigned participants who take at least 1 dose of double-blind 
study treatment, regardless of adherence to study drug. 
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Analysis Set 
Description 
Participants will be analyzed according to the treatment group to 
which they were randomly assigned.  
Safety analysis set 
 
Data obtained during treatment period plus safety follow-up 
period from all randomly assigned participants who take at least 
1 dose of double-blind study treatment, regardless of adherence 
to study drug. Participants will be analyzed according to the 
treatment group to which they were randomly assigned.  
 
9.4. Statistical Analyses 
9.4.1. General Considerations 
Statistical analysis of this study will be the responsibility of Sponsor or its designee. 
Any change to the data analysis methods described in the protocol will require an amendment 
only if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) and the CSR. Additional exploratory analyses of the data 
will be conducted as deemed appropriate. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 0.05, unless otherwise 
stated, and all confidence intervals (CIs) will be given at a 2-sided 95% level. In statistical 
summaries and analyses, participants will be analyzed as randomized. 
The primary estimand of interest in comparing efficacy of LY3437943 doses with placebo for 
this study is the “efficacy” estimand, which represents the efficacy prior to discontinuation of 
study drug. The primary efficacy assessment, guided by the “efficacy” estimand, will be 
conducted using the efficacy analysis set. The “treatment-regimen” estimand, which represents 
the efficacy irrespective of adherence to study drug, may also be used to compare the primary 
efficacy of LY3437943 doses with placebo. The analysis guided by the “treatment-regimen” 
estimand will use the full analysis set. Additional exploratory analyses for participants who can 
comply with treatment of LY3437943 based on principal stratification may be performed. 
Details will be provided in the SAP. 
The summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum. The analysis model to make comparisons among treatment groups 
relative to continuous measurements assessed over time (in addition to the baseline and end of 
treatment measurements) will be a mixed model for repeated measures (MMRM). Analysis of 
covariance (ANCOVA) may be used to make comparisons among treatment groups for 
continuous measurements with only 1 post-baseline assessment. 
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages. Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes. Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes. The negative binomial regression model may 
be used for the treatment comparison of discrete count measures if deemed appropriate. 
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Participant-specific random effects may be added to the logistic and the negative binomial 
regression models if longitudinal measurements are available. 
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP. 
9.4.2. 
Treatment Group Comparability 
9.4.2.1. 
Participant Disposition 
Frequency counts and percentages of all participants screened, randomized, and receiving at least 
1 dose of study drug will be presented by treatment groups and dose escalation subgroups. A 
listing of randomized participants not receiving study drug will be provided. All participants who 
discontinue the study will be identified, and the extent of their participation in the study will be 
reported. If known, a reason for their discontinuation will be given. The primary reasons for 
discontinuation will be listed and will be summarized by treatment. The percentage of 
participants discontinuing from each treatment will be compared using the Fisher’s exact test. 
Kaplan–Meier analyses of time from randomization to premature discontinuation from study and 
premature discontinuation from study drug by treatment group will be provided. 
9.4.2.2. 
Participant Characteristics 
Demographics, baseline characteristics, medical history, and concomitant illness will be 
summarized by treatment group using the full analysis set.  
9.4.2.3. 
Concomitant Therapy  
Concomitant medications will be summarized by drug class and treatment group using the full 
analysis set.  
9.4.2.4. 
Treatment Compliance 
Treatment compliance is defined as taking at least 75% of required injections of study drug 
during the treatment period while on study drug. Frequency counts and percentages of 
participants compliant to study drug will be summarized by treatment group and dose escalation 
subgroup using the full analysis set.  
9.4.3. 
Primary Endpoint(s) 
The efficacy analyses for the primary endpoint will be conducted to establish superiority of 
LY3437943 1 mg, LY3437943 4 mg, LY3437943 8 mg, or LY3437943 12 mg to placebo with 
regard to mean percent change of body weight from randomization (Week 0) to Week 24.  
The primary efficacy analysis will be guided by the “efficacy” estimand and conducted using the 
efficacy analysis set. The primary analyses model will be a MMRM with treatment, visit, and 
treatment-by-visit interaction as fixed effects, baseline body weight at randomization (Week 0) 
and sex as covariates, and participant as a random effect. Additional covariates may be added 
and will be detailed in the SAP. 
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9.4.4. 
Secondary Endpoint(s) 
9.4.4.1. 
Efficacy Analyses 
The following secondary endpoints will be analyzed on the efficacy analysis set: 
 mean percent change of body weight from randomization (Week 0) to Week 48 
 percentage of study participants who achieve the following criteria from randomization 
(Week 0) at Weeks 24 and 48: 
o ≥5% body weight reduction  
o ≥10% body weight reduction, and  
o ≥15% body weight reduction  
 mean change in body weight (kg) from randomization (Week 0) at Weeks 24 and 48 
 mean change in BMI (kg/m2) from randomization (Week 0) at Weeks 24 and 48, and 
 mean change in waist circumference (cm) from randomization (Week 0) at Weeks 24 and 
48. 
Analyses of continuous endpoints, including change in body weight (kg), BMI (kg/m2), and 
waist circumference (cm), will be conducted in a manner similar to the primary efficacy analyses 
discussed in Section 9.4.2. 
Analyses for percentages of participants reaching ≥5% body weight reduction, ≥10% body 
weight reduction, and ≥15% body weight reduction from baseline at Weeks 24 and 48 will be 
conducted using a longitudinal logistic regression model with treatment, visit, and treatment-by-
visit interaction as fixed effects, baseline values at randomization (Week 0) and sex as 
covariates, and participant as a random effect. Missing body weight data at Weeks 24 and 48 
may be imputed first before conducting the analyses. Additional secondary efficacy analyses 
may be performed, if deemed necessary. The details will be provided in the SAP. 
9.4.4.2. 
Safety Analyses 
Unless specified otherwise, safety assessments will be guided by an estimand comparing safety 
of LY3437943 doses with placebo irrespective of adherence to study drug. Thus, safety analyses 
will be conducted using the full analysis set. 
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class. Summary 
statistics will be provided for incidence of TEAEs, SAEs, study discontinuation due to AEs, 
study drug discontinuation due to AEs, deaths, and other CV endpoints. Counts and proportions 
of participants experiencing AEs will be reported for each treatment group and each dose 
escalation subgroup, and Fisher’s exact test will be used to compare the LY dose groups with 
placebo. 
9.4.4.3. 
Central Laboratory Measures, Vital Signs, and Electrocardiograms 
Values and change from baseline to postbaseline values of central laboratory measures, vital 
signs, and selected ECG parameters will be summarized for each treatment group at each 
scheduled visit. The details will be provided in the SAP. 
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9.4.4.4. 
Evaluation of Immunogenicity  
The frequency and percentage of participants with preexisting ADA and with treatment-
emergent ADA+ to LY3437943 may be tabulated. Treatment-emergent ADA are defined as 
those with a titer 2-fold (1 dilution) greater than the minimum required dilution if no ADAs were 
detected at baseline (treatment-induced ADA) or those with a 4-fold (2 dilutions) increase in titer 
compared to baseline if ADAs were detected at baseline (treatment-boosted ADA). For the 
treatment-emergent ADA+ participants, the distribution of maximum titers may be described. 
The frequency of neutralizing antibodies against LY3437943, if performed, may be tabulated in 
treatment-emergent ADA+ participants. If cross-reactivity to native GLP-1, GIP, and glucagon 
or neutralizing antibodies against native GLP-1, GIP, and glucagon assays are performed, the 
frequency of each may be reported. 
The relationship between the presence of antibodies and the PK parameters and PD response 
including safety and efficacy to LY3437943 may be assessed. 
9.4.5. 
Exploratory Endpoints 
Details will be provided in the SAP. 
9.4.6. 
Other Safety Analyses 
Other safety analyses may be conducted, if deemed necessary. Details will be provided in the 
SAP. 
9.4.7. 
Other Analyses  
9.4.7.1. 
Analysis of PHQ-9 Data 
Specific diagnostic symptoms that determine the presence of a clinical depressive disorder per 
the Diagnosis and Statistical Manual for Mental Disorders will be summarized based on 
responses to the PHQ-9 questionnaire (Kroenke et al. 2001, Moriarty et al. 2015). Details will be 
provided in SAP.  
9.4.7.2. 
Analysis of C-SSRS Data 
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide (C-SSRS 
WWW). Details will be provided in SAP. 
9.4.8. 
Pharmacokinetic/Pharmacodynamic Analyses 
LY3437943 concentration data will be summarized and analyzed using a population PK 
approach via nonlinear mixed-effects modeling. The relationships between LY3437943 dose 
and/or concentration and selected efficacy, tolerability, and safety endpoints may be 
characterized. Additionally, the impact of intrinsic and extrinsic factors, such as age, weight, 
gender, and renal function on PK and/or PD parameters, may be examined as needed. If ADA 
titers are detected from immunogenicity testing, then the impact of immunogenicity titers on 
LY3437943 PK or any relevant PD parameters may also be examined. Additional analyses may 
be conducted if they are deemed appropriate. Further details on PK and PK/PD analyses will be 
provided in the PK/PD analysis plan. 
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9.5. Interim Analyses  
No interim analyses are planned for this study. Unplanned interim analyses may be performed as 
necessary if a safety concern is identified from review of blinded data. In the event an interim 
analysis is conducted, both efficacy and safety data will be reviewed to assess the balance of 
benefit and risk.  
If there are unplanned interim analyses, an assessment committee (AC) will be formed to review 
the interim analyses in an unblinded manner. The details regarding number of participants and 
type of analysis will be provided in the AC charter. Study team members who have potential 
contact with the sites will remain blinded throughout the study. Information that may unblind the 
study during the analyses will not be reported to study sites or blinded study team members 
before the study has been unblinded. Study sites will receive information about interim results 
only if deemed necessary for the safety of the participants. 
The primary database lock and primary data analysis for Study GZBF may occur when all 
participants have completed 24 weeks of treatment. The final database lock and final analyses for 
this study will be performed after all randomized participants have completed 48 weeks of 
treatment and the 4-week follow-up period. Unblinded data and results will not be shared with 
the study sites in order to maintain blinding at the sites while the study is still ongoing. Details 
will be specified in the blinding/unblinding plan and in the AC charter. 
The addition of an interim analysis can be determined at any time during the study and will not 
result in a protocol amendment. 
9.6. Data Monitoring Committee (DMC)  
Not applicable. 
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10. Supporting Documentation and Operational Considerations 
10.1.  Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
● This study will be conducted in accordance with the protocol and with the 
following: 
○ Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines 
○ Applicable International Council for Harmonization (ICH) Good Clinical 
Practice (GCP) Guidelines 
○ Applicable laws and regulations 
● The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (for example, advertisements) must be submitted to an 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
● The investigator will be responsible for the following: 
○ Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
○ Providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
● Investigator sites are compensated for participation in the study as detailed in the 
clinical trial agreement. 
10.1.2 Informed Consent Process 
● The investigator or his or her representative will explain the nature of the study, 
including the risks and benefits, to the participant or his or her legally authorized 
representative and answer all questions regarding the study. 
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● 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, Health Insurance Portability and Accountability Act (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 and receive a new identification 
number. 
10.1.3 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 his or her 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 or her data to be used as described in the informed consent.  
● The participant must be informed that his or her 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. 
10.1.4 Committees Structure 
An independent CEC will be formed to adjudicate major adverse cardiovascular events, deaths, 
and pancreatitis AEs, as specified in Section 8.3.2.  
10.1.5 Dissemination of Clinical Study Data 
Required clinical trial registries (for example, ClinicalTrials.gov) will be updated with the results 
from registered clinical trials regardless of the research outcome in accordance with local laws 
and regulations.  
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All CSRs, amendments, and addenda will be submitted to external regulatory authorities, 
external partners (as applicable) and sites.  
The publication policy for Study GZBF is outlined in Section 10.1.9 and further described in the 
Clinical Trial Agreement (CTA). 
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). 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 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the CTA 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
● In addition, Sponsor or its representatives will periodically check a sample of the 
participant data recorded against source documents at the study site. The study 
may be audited by Sponsor or its representatives, and/or regulatory agencies at 
any time. Investigators will be given notice before an audit occurs. 
 
 
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Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Additionally, clinical outcome assessment data (participant/clinician-focused outcome 
instrument) will be collected by the participant/authorized study personnel, via a paper source 
document and will be transcribed by the authorized study personnel into the EDC system. 
Data collected via the sponsor-provided data capture system will be stored at third party. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system. 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 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 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 study training material.  
10.1.8 Study and Site Start and Closure 
10.1.8.1 
Discontinuation of the Study 
The sponsor designee reserves the right to terminate the study at any time for any reason at the 
sole discretion of the sponsor. The study will be discontinued if Lilly or its designee judges it 
necessary for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and GCP. 
 
 
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Medical Oversight and Safety Review  
Ongoing safety review(s) by designated sponsor personnel will occur and be documented. Such 
reviews will include  
 
monitoring and assessing the safety information collected during the trial both in real 
time and periodically 
 
reviewing safety data for trends that need action, and  
 
detecting adverse drug/device effects.  
A safety investigation will be triggered to determine if the study should be terminated early 
based on the following criteria 
 
two study participants develop the same TEAE or SAE considered possibly or probably 
related to study drug that is severe or medically significant but not immediately life-
threatening; or where hospitalization or prolongation of hospitalization is indicated; or 
is disabling; or limits self-care activities of daily living 
 
one study participant develops any TEAE or SAE regardless of attribution to study drug 
that has life-threatening consequences or requires urgent intervention  
 
death of any study participant at any time, and 
 
any other clinically significant safety signal. 
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. 
10.1.8.2 
Discontinuation of Study Sites 
The sponsor designee reserves the right to close the study site 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, and 
● discontinuation of further study intervention development. 
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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 Investigator Information 
Health care professionals with experience in managing participants who have obesity will serve 
as investigators. Each site must have a physician designated either as a principal investigator or a 
sub-investigator to provide necessary medical oversight of participant care. 
 
 
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Abbreviations: ADA = antidrug antibody; IgE = immunoglobulin E; IL = interleukin; PK = pharmacokinetic.
   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, and IL‐10) 
Assayed by Lilly-designated laboratory. Results will not be provided to the 
investigative sites. 
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 
combined contraceptive vaginal ring, or  
 
intrauterine devices. 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges, and 
 
barrier method with use of a spermicide 
o condom with spermicide 
o  diaphragm with spermicide, or 
o female condom with spermicide. 
 
Note: The barrier method must include use of a 
spermicide (that is, condom with spermicide, 
diaphragm with spermicide, female condom with 
spermicide) to be considered effective. 
Ineffective forms of contraception 
 
spermicide alone  
 
immunocontraceptives 
 
periodic abstinence 
 
fertility awareness (calendar method, 
temperature method, combination of 
above 2, cervical mucus, symptothermal) 
 
withdrawal 
 
post coital douche, and 
 
lactational amenorrhea. 
Collection of Pregnancy Information 
Male Participants with Partners Who Become Pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to randomized male participants who receive study 
drug. 
● After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and 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.  
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● The participant will be followed up 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 post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol. 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. If the participant is discontinued from the study drug, 
follow the standard discontinuation process for each study period. 
 
 
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10.6. Appendix 6: Genetics 
Use/Analysis of DNA 
● Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease. Variable response to 
study intervention 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 may be used for research related to LY3437943 or obesity, diabetes 
mellitus, and related clinical traits or complications, including nonalcoholic 
steatohepatitis and related diseases. They may also be used to develop 
tests/assays, including diagnostic tests related to LY3437943, study interventions 
related to this drug class, or obesity, diabetes mellitus, and related clinical traits or 
complications, including nonalcoholic steatohepatitis. Genetic research may 
consist of the analysis of 1 or more candidate genes, the analysis of genetic 
markers throughout the genome, or analysis of the entire genome. 
● The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to LY3437943 or study interventions related to 
this class to understand 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 LY3437943 or obesity, diabetes 
mellitus, and related clinical traits or complications, including nonalcoholic 
steatohepatitis, continues but no longer than 15 years or other period as per local 
requirements.  
 
 
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10.7. Appendix 7: Diet and Physical Activity Counseling  
10.7.1 Diet 
For this study, counseling on a healthy diet will be based on the Dietary Guidelines for 
Americans 2020-2025 published by the U.S. Department of Agriculture and the U.S. Department 
of Health and Human Services (USDA and HHS 2020). The following principles form the basis 
of these guidelines. 
 “Customize and enjoy nutrient-dense food and beverage choices to reflect personal 
preferences, cultural traditions, and budgetary considerations. 
o A healthy dietary pattern can benefit all individuals regardless of age, race, or 
ethnicity, or current health status. The Dietary Guidelines provides a framework 
intended to be customized to individual needs and preferences, as well as the 
foodways of the diverse cultures in the United States.” 
 “Focus on meeting food group needs with nutrient-dense foods and beverages, and stay 
within calorie limits. 
o An underlying premise of the Dietary Guidelines is that nutritional needs should 
be met primarily from foods and beverages—specifically, nutrient-dense foods 
and beverages. Nutrient-dense foods provide vitamins, minerals, and other health-
promoting components and have no or little added sugars, saturated fat, and 
sodium. A healthy dietary pattern consists of nutrient-dense forms of foods and 
beverages across all food groups, in recommended amounts, and within calorie 
limits. 
o The core elements that make up a healthy dietary pattern include: 
▪ Vegetables of all types—dark green; red and orange; beans, peas, and 
lentils; starchy; and other vegetables 
▪ Fruits, especially whole fruit 
▪ Grains, at least half of which are whole grain 
▪ Dairy, including fat-free or low-fat milk, yogurt, and cheese, and/or 
lactose-free versions and fortified soy beverages and yogurt as alternatives 
▪ Protein foods, including lean meats, poultry, and eggs; seafood; beans, 
peas, and lentils; and nuts, seeds, and soy products 
▪ Oils, including vegetable oils and oils in food, such as seafood and nuts” 
 “Limit foods and beverages higher in added sugars, saturated fat, and sodium, and limit 
alcoholic beverages.” 
o “Meeting food group recommendations—even with nutrient-dense choices—
requires most of a person’s daily calorie needs and sodium limits. A healthy 
dietary pattern doesn’t have much room for extra added sugars, saturated fat, or 
sodium—or for alcoholic beverages. A small amount of added sugars, saturated 
fat, or sodium can be added to nutrient-dense foods and beverages to help meet 
food group recommendations, but foods and beverages high in these components 
should be limited. Limits are:” 
▪ Added sugars—Less than 10 percent of calories per day  
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▪ Saturated fat—Less than 10 percent of calories per day 
▪ Sodium—Less than 2,300 milligrams per day 
▪ “Alcoholic beverages—Adults of legal drinking age can choose not to 
drink, or to drink in moderation by limiting intake to 2 drinks or less in a 
day for men and 1 drink or less in a day for women, when alcohol is 
consumed. Drinking less is better for health than drinking more. There are 
some adults who should not drink alcohol, such as women who are 
pregnant.” 
10.7.2 Physical Activity 
To safely engage in physical activity, types of physical activity appropriate for the participant’s 
current fitness should be chosen. Furthermore, the amount and duration of physical activity 
should be gradually increased over time. Participants with chronic conditions and symptoms 
should be under the care of a health care provider who can advise about the types and amounts of 
physical activity that are appropriate for the participant. 
For this study, counseling on physical activity will be based on the Physical Activity Guidelines 
for Americans, 2nd Edition published by the U.S. Department of Health and Human Services 
(HHS 2018). The following principles form the basis of these guidelines. 
 Key Guidelines for Adults (age <65 years) 
o “Adults should move more and sit less throughout the day. Some physical activity 
is better than none. Adults who sit less and do any amount of moderate-to-
vigorous physical activity gain some health benefits. 
o For substantial health benefits, adults should do at least 150 minutes (2 hours and 
30 minutes) to 300 minutes (5 hours) a week of moderate-intensity, or 75 minutes 
(1 hour and 15 minutes) to 150 minutes (2 hours and 30 minutes) a week of 
vigorous-intensity aerobic physical activity, or an equivalent combination of 
moderate- and vigorous-intensity aerobic activity. Preferably, aerobic activity 
should be spread throughout the week. 
o Additional health benefits are gained by engaging in physical activity beyond the 
equivalent of 300 minutes (5 hours) of moderate-intensity physical activity a 
week. 
o Adults should also do muscle-strengthening activities of moderate or greater 
intensity and that involve all major muscle groups on 2 or more days a week, as 
these activities provide additional health benefits.” 
 Key Guidelines for Older Adults (age ≥ 65 years) 
o “The key guidelines for adults also apply to older adults. In addition, the 
following key guidelines are just for older adults: 
▪ As part of their weekly physical activity, older adults should do 
multicomponent physical activity that includes balance training as well as 
aerobic and muscle-strengthening activities.  
▪ Older adults should determine their level of effort for physical activity 
relative to their level of fitness.  
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▪ Older adults with chronic conditions should understand whether and how 
their conditions affect their ability to do regular physical activity safely.  
▪ When older adults cannot do 150 minutes of moderate-intensity aerobic 
activity a week because of chronic conditions, they should be as physically 
active as their abilities and conditions allow.”  
 Key Guidelines for Adults With Chronic Health Conditions and Adults With Disabilities 
o “Adults with chronic conditions or disabilities, who are able, should do at least 
150 minutes (2 hours and 30 minutes) to 300 minutes (5 hours) a week of 
moderate-intensity, or 75 minutes (1 hour and 15 minutes) to 150 minutes (2 
hours and 30 minutes) a week of vigorous-intensity aerobic physical activity, or 
an equivalent combination of moderate- and vigorous-intensity aerobic activity. 
Preferably, aerobic activity should be spread throughout the week.  
o Adults with chronic conditions or disabilities, who are able, should also do 
muscle-strengthening activities of moderate or greater intensity and that involve 
all major muscle groups on 2 or more days a week, as these activities provide 
additional health benefits.  
o When adults with chronic conditions or disabilities are not able to meet the above 
key guidelines, they should engage in regular physical activity according to their 
abilities and should avoid inactivity.  
o Adults with chronic conditions or symptoms should be under the care of a health 
care provider. People with chronic conditions can consult a health care 
professional or physical activity specialist about the types and amounts of activity 
appropriate for their abilities and chronic conditions.” 
 
 
 
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10.8. Appendix 8: Protocol GZBF Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, and Vital Signs  
The following information has been adapted from standardized physical measurement protocols 
for the World Health Organization’s STEPwise approach to Surveillance (STEPS) (WHO 2017).  
Measuring Height 
Step 1. Ask the participant to remove their footwear and any headgear (light headgear worn for 
religious reasons can remain, but this should be worn by the participant at every clinic visit when 
their height is measured). 
Step 2. Ask the participant to stand on the calibrated height-measuring board (stadiometer) or 
against a wall with their feet together and their knees straight with their heels against the 
backboard, the stadiometer, or the wall. 
Step 3. Ask the participant to look straight ahead without tilting their head up. 
Step 4. Ask the participant to breathe in and stand tall. Measure and record the participant’s 
height in centimeters to 1 decimal place.  
Measuring Weight 
 
Body weight measurements should be done in a consistent manner using a calibrated 
electronic scale that measures in kg to 1 decimal place, with a capacity to 
accommodate participants with overweight/obesity. 
 
All weights for a given participant should be measured using the same scale, whenever 
possible, at approximately the same time in the morning after evacuation of bladder 
contents.  
 
Body weight must be measured in fasting state. If the participant is not fasting, the 
participant should be called in for a new visit within the visit window to have the 
fasting body weight measured. 
Step 1. Ask the participant to empty their pockets, remove their footwear, outerwear (coat, 
jacket, etc.), and any headgear (light headgear worn for religious reasons can remain, but this 
should be worn by the participant at every clinic visit when weight is measured). 
Step 2. Make sure the scale is placed on a firm, flat, even surface (not on carpet, on a sloping 
surface, or a rough, uneven surface). 
Step 3. Ask the participant to step onto the scale with 1 foot on each side of the scale. 
Step 4. Ask the participant to stand still with arms by sides and then record weight in kilograms 
to the nearest one-tenth kg. 
Measuring Waist Circumference 
 
Waist circumference should be measured in the horizontal plane and at the midpoint 
between the lower margin of the last palpable rib and the top of the iliac crest. 
 
Measurements should be taken at the end of a normal expiration using a nonstretchable 
measuring tape. The tape should lie flat against the skin without compressing the soft 
tissue. 
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 
The waist circumference should be measured twice, rounded to the nearest 0.5 cm. 
The measuring tape should be removed between the 2 measurements. Both 
measurements will be recorded in the eCRF. If the difference between the 2 
measurements exceeds 1 cm, this set of measurements should be discarded and the 2 
measurements repeated. 
Step 1: Ask the participant to wear little clothing (if available, patient gowns could also be used). 
Step 2: Ask the participant to stand with their feet close together, arms at their side, body weight 
evenly distributed. 
Step 3: Ask the participant to relax and measure the participant’s waist circumference. 
Sitting Vital Sign Measurements 
 
Vital sign measurements (BP and HR, measured by pulse) should be taken 
before obtaining an ECG tracing and before collection of blood samples for 
laboratory testing. 
 
The participant should sit quietly for 5 minutes before vital sign 
measurements are taken. 
 
For each parameter, 3 measurements will be taken using the same arm, 
preferably the nondominant arm. 
 
The recordings should be taken at least 1 minute apart. Each measurement of 
sitting pulse and BP needs to be recorded in the eCRF. 
 
Blood pressure must be taken with an automated BP instrument with full 
range of cuff sizes up to extra-large. 
 
If BP and pulse measurements are taken separately, pulse should be taken 
prior to BP.  
Note: In the event pulse measurement cannot be taken via an automated BP instrument, the 
preferred location for measurement of pulse is the radial artery.  
Orthostatic Vital Sign Measurements 
 
Orthostatic vital sign measurements (BP and HR, measured by pulse) should 
be taken before obtaining an ECG tracing and before collection of blood 
samples for laboratory testing. They should be done after completing the 
triplicate measures in the sitting position. 
 
The participant should lie quietly for 5 minutes before vital sign 
measurements are taken. 
 
The participant should be comfortably lying flat without legs crossed, in a 
calm, quiet area for 5 minutes before vital sign measurements are taken. 
 
For measurement of vital signs in the supine position, the arm should be 
supported by a pillow so that it is at the level of the right atrium 
(approximately halfway between the bed and the level of the sternum). 
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o Incorrect arm positioning results in erroneous BP values. 
o Upper arm below the level of the right atrium (for example, arm 
hanging down) results in readings that are too high. 
o Upper arm above the heart level results in readings that are too low. 
 
Measure BP and pulse rate once in the supine position. 
 
After the BP and pulse rate are determined in the supine position, the 
participant should immediately move to the standing position, bend the arm 
used for BP determination at the elbow, and rest the arm on an adjustable 
table or stand so that the upper arm is supported at the heart level. 
 
Determine the standing BP and pulse rate in the supported arm immediately 
after standing for 3 minutes. Only 1 measurement is needed. 
 
Record all symptoms (AEs) that the participant may experience, such as 
lightheadedness, syncope, or dizziness as AEs. 
Electrocardiogram 
 
12-lead ECGs should be obtained after the participant has rested in a supine position 
for at least 5 minutes. 
 
Electrocardiograms should be collected at least 30 minutes prior to collection of 
blood samples for laboratory testing, including PK samples. 
All digital ECGs will be obtained using centrally provided ECG machines and will be 
electronically transmitted to a designated central ECG laboratory. The central ECG laboratory 
will perform a basic quality control check (for example, demographics and study details) and 
then store the ECGs in a database. In addition, tracings collected at the baseline, 24 weeks, and 
48 weeks will be assessed qualitatively by a blinded cardiologist. At a future time, the remaining 
visits may be overread by a cardiologist at the central ECG laboratory for further evaluation of 
machine-read measurements or to meet regulatory requirements at timepoints as per the SoA. 
The machine-read ECG intervals and HR may be used for data analysis and report-writing 
purposes, unless a cardiology overreading of the ECGs is conducted prior to completion of the 
final study report (in which case, the overread data would be used). 
 
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    HBV DNAa 
Anti-smooth muscle antibody (ASMA)b 
Hepatis C Virus (HCV) Testing: 
Anti-actin antibodyc 
    HCV antibody 
Epstein-Barr Virus (EBV) Testing: 
    HCV RNAa 
    EBV antibody 
Hepatitis D Virus (HDV) Testing: 
    EBV DNAa 
    HDV antibody 
Cytomegalovirus (CMV) Testing: 
Hepatitis E Virus (HEV) Testing: 
    CMV antibody 
    HEV IgG antibody 
    CMV DNAa 
    HEV IgM antibody 
Herpes Simplex Virus (HSV) Testing: 
    HEV RNAa 
    HSV (Type 1 and 2) antibody 
Microbiologyd 
    HSV (Type 1 and 2) DNAa 
Culture: 
Liver Kidney Microsomal Type 1 (LKM-1) Antibody 
    Blood 
 
    Urine 
 
Abbreviations: EBV = Epstein-Barr Virus; Ig = immunoglobulin; INR = international normalized ratio. 
a Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
b This is not required if anti-actin antibody is tested. 
c This is not required if anti-smooth muscle antibody is tested. 
d Assayed by investigator-designated local laboratory ONLY. No central testing available. 
 
 
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10.11. Appendix 11: Patient-Reported Outcomes 
When feasible, the self-administered questionnaires will be translated into the native language of 
participants, linguistically validated and administered according to the SoA (Section 1.3). The 
language of the signed ICF will be considered the participant’s native language. If a translation is 
not available in the native language of a participant at baseline, the questionnaire(s) will not be 
administered for that participant for the duration of the trial. If PRO questionnaires are not 
collected due to a translation not being available, this will not be considered a protocol deviation.  
When the PROs are collected as per the SOA, 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, if the participant is not adversely affected by their fasting condition. 
 Patient Global Impression of Status for Physical Activity  
Study participants will be asked to complete a Patient Global Impression of Status 
(PGIs) for Physical Activity item specifically developed for this study. This is a 
participant-rated assessment of current limitation on physical activity due to health and 
is rated on a 5-point scale ranging from “1 - not at all limited” to “5 - extremely 
limited.” 
 Short Form-36 version 2 Health Survey acute form, 1-week recall version 
The SF-36v2 acute form, 1-week recall version is a 36-item generic, 
participant-administered measure designed to assess the following 8 domains: 
o Physical Functioning  
o Role-Physical 
o Bodily Pain 
o General Health 
o Vitality 
o Social Functioning  
o Role-Emotional, and  
o Mental Health.  
The Physical Functioning domain assesses limitations due to health “now” while the 
remaining domains assess functioning “in the past week.” Each domain is scored 
individually and information from these 8 domains are further aggregated into 2 health 
component summary scores: Physical Component Summary and Mental Component 
Summary. Items are answered on Likert scales of varying lengths (3-point, 5-point, or 6-
point scales). Scoring of each domain and both summary scores are norm-based and 
presented in the form of T-scores, with a mean of 50 and SD of 10; higher scores 
indicate better levels of function and/or better health (Maruish 2011). 
 Eating Inventory 
The Eating Inventory is a 51-item, participant-administered measure designed to assess 
3 aspects of eating behavior (Stunkard and Messick 1985) 
o dietary restraint (21 items) 
o disinhibition (16 items), and  
o perceived hunger (14 items). 
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Thirty-six items are rated in true/false format, 14 items are rated on a 4-point scale, and 
1 item is rated on a 6-point scale. Dietary restraint refers to both cognitive and 
behavioral dietary restraint, disinhibition measures the tendency to overeat in response 
to external cues, and perceived hunger measures susceptibility to feelings of hunger. 
Higher domain scores denote higher levels of restrained eating, disinhibited eating, and 
predisposition to hunger, respectively. 
 
 
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10.12. Appendix 12: Provisions for Changes in Study Conduct during 
Exceptional Circumstances 
Implementation of this appendix 
The changes to procedures described in this appendix are temporary measures intended to be 
used only during specific time periods as directed by the sponsor in partnership with the 
investigator. 
Exceptional circumstances 
Exceptional circumstances are rare events that may cause disruptions to the conduct of the study. 
Examples include pandemics or natural disasters. These disruptions may limit the ability of the 
investigators, participants, or both to attend on-site visits or to conduct planned study procedures. 
Implementing changes under exceptional circumstances 
In an exceptional circumstance, after receiving the sponsor’s written approval, sites may 
implement changes if permitted by local regulations.  
After approval by local Ethical Review Boards, regulatory bodies, and any other relevant local 
authorities, implementation of these exceptional circumstance changes will not typically require 
additional notification to these groups, unless they have specific requirements in which 
notification is required (for example, upon implementation and suspension of changes). All 
approvals and notifications must be retained in the study records. 
If the sponsor grants written approval for changes in study conduct, the sponsor will also provide 
additional written guidance, if needed. 
Considerations for making a change 
The prevailing consideration for making a change is ensuring the safety of study participants. 
Additional important considerations for making a change are compliance with Good Clinical 
Practice, enabling participants to continue safely in the study and maintaining the integrity of the 
study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for: 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study drug during an extended treatment period  
 alternate delivery of study drug and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
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Remote visits 
Types of remote visits 
Remote visits may apply to Visits 6, 7, 8, 9, 10, and 14.  
Any procedures that cannot be accomplished at a remote visit should be conducted at the next 
on-site visit and captured as a protocol deviation related to the exceptional circumstances. Of 
note, procedures from the missed visit that were not collected and are the same as ones at the 
next site visit do not need to be duplicated. ABPM scheduled for Visit 14 (Week 36) should be 
collected as close to the schedule as possible and before Visit 17 (Week 48). Electrocardiograms 
may be collected at alternate locations and reviewed by the investigator for participant safety; 
however, if collection of centralized ECGs is not feasible with a remote visit, they should be 
collected per the SoA at the next in-office visit. 
Telemedicine:  
Telephone or technology-assisted virtual visits, or both, are acceptable to complete 
appropriate assessments. Assessments to be completed in this manner include, but are not 
limited to  
 AEs 
 product complaints 
 concomitant medications 
 diet and physical activity counseling 
 review of study participant diary (including study drug compliance), and 
 mental health questionnaires (for example, C-SSRS, PHQ-9). 
Mobile healthcare:  
Healthcare visits may be performed by a mobile healthcare provider at locations other 
than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor. Procedures performed at 
such visits include, but are not limited to 
 weight and waist measurements 
 brief physical assessments or general wellness check 
 vital signs 
 collection of blood and urine samples, and 
 collection of health information. 
Other alternative locations:  
During exceptional circumstances, laboratory samples, and ECGs may be collected 
locally, if needed outside of mobile healthcare visits.  
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and product complaints remain unchanged.  
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Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. However, central 
laboratory testing must be retained for: PK, immunogenicity, and biomarkers. The local 
laboratory must be qualified in accordance with applicable local regulations. 
Study drug and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include  
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit  
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
These requirements must be met before action is taken 
 Alternate delivery of study drug should be performed in a manner that does not 
compromise treatment blinding and ensures product integrity. The existing protocol 
requirements for product accountability remain unchanged, including verification of 
participant’s receipt of study supplies. 
 When delivering supplies to a location other than the study site (for example, 
participant’s home), the investigator, sponsor, or both should ensure oversight of the 
shipping process to ensure accountability and product quality (that is, storage 
conditions maintained and intact packaging upon receipt). 
 Instructions may be provided to the participant or designee on the final disposition of 
any unused or completed study supplies. 
Screening period guidance  
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at the screening visit (Visit 1) are valid for a maximum of 70 days prior to the randomization 
visit (Visit 4). The following rules will be applied for active, nonrandomized participants whose 
participation in the study must be paused due to exceptional circumstances: 
 If screening period is paused for less than 50 days from screening (Visit 1) to Visit 3 
(or Visit 2 for participants identified with increased probability of liver fat ≥10% by 
the liver fat algorithm), the participant will proceed to the next study visit per the 
usual SoA, provided that the randomization visit (Visit 4) must be conducted within 
70 days from first screening (Visit 1).  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay.  
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o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening period is paused for more than 50 days from screening (Visit 1) to Visit 3 
(or Visit 2 for participants identified with increased probability of liver fat ≥10% by 
the liver fat algorithm), the participant must be discontinued because of screening 
interruption due to an exceptional circumstance. This is documented as a screen fail 
in the CRF. This screen fail is allowed in addition to the main protocol screen fail. 
The participant can reconsent and be rescreened as a new participant. The screening 
procedures per the usual SoA should be followed, starting at the screening visit (Visit 
1) to ensure participant eligibility by the randomization visit (Visit 4). 
Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
 
This table describes the allowed adjustments to visit windows after randomization (Visit 4). 
 
Visit Number Tolerance 
Visit 5  
Within 3 days before the intended date, or up to 3 days after 
the intended date 
Visit 6 
through Visit 
8 
Within 7 days before the intended date, or up to 7 days after 
the intended date 
Visit 9 
through Visit 
17 and Visit 
99 
Within 14 days from the intended date, or up to 14 days 
after the intended date (can be up to 28 days after the 
intended date for Visits 11, 17, and 99) 
Visit 801 
Within 14 days from the intended date, or up to 14 days 
after the intended date 
For participants whose visits have extended windows, additional study drug may need to be 
provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
Changes to study conduct will be documented: 
 Sites will identify and document the details of how participants, visits types, and 
conducted activities were affected by exceptional circumstances. 
Dispensing/shipment records of study drug and relevant communications, including 
delegation, should be filed with site study records. 
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Source documents at alternate locations 
 Source documents generated at a location other than the study site should be part of 
the investigator’s source documentation and should be transferred to the site in a 
secure and timely manner.  
 
 
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10.13. Appendix 13: Abbreviations 
Term 
Definition 
ABMP 
ambulatory blood pressure monitoring 
AC 
assessment committee 
ADAs 
antidrug antibodies 
AE 
adverse event: any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BG 
blood glucose 
blinding/masking 
a double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received. 
BMI 
body mass index 
BP 
blood pressure 
C-CASA 
Columbia Classification Algorithm of Suicide Assessment 
CEC 
clinical endpoint committee 
CFR 
Code of Federal Regulations 
CHF 
congestive heart failure 
CKD-EPI 
Chronic Kidney Disease Epidemiology 
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, and applicable regulatory 
requirements 
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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CRS 
clinical research scientist 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
DIO 
diet-induced obese 
DMC 
data monitoring committee 
DNA 
deoxyribonucleic acid 
DPP-4 
dipeptidyl peptidase-4 
ECG 
electrocardiogram 
EDC 
electronic data capture 
eCRF 
electronic case report form 
ED 
early discontinuation of treatment 
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. 
FBG 
fasting blood glucose 
Gcg 
glucagon 
GcgR 
glucagon receptor 
GCP 
good clinical practice 
GI 
gastrointestinal 
GIP 
glucose-dependent insulinotropic polypeptide 
GIPR 
glucose-dependent insulinotropic polypeptide receptor 
GLP-1 
glucagon-like peptide-1 
GLP-1RA 
glucagon-like peptide-1 receptor agonist 
HbA1c 
hemoglobin A1c 
HDL 
high-density lipoprotein 
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hERG 
HR 
Human ether-a-go-go-related gene 
heart rate 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committees 
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. 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked. 
investigational 
product 
a pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IWRS 
interactive web-response system 
LDL 
low-density lipoprotein 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 
multiple endocrine neoplasia 
MMRM 
mixed-model for repeated measures 
MRI 
magnetic resonance imaging 
MRI-PDFF 
magnetic resonance imaging-derived proton density fat fraction 
MTC 
medullary thyroid carcinoma 
NAFLD 
non-alcoholic fatty liver disease 
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 
PHQ-9 
Patient Health Questionnaire-9 
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PK/PD 
pharmacokinetics/pharmacodynamics 
PR 
pulse rate 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
QW 
once weekly 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
screen 
the act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical study.  
SF-36 v2 
Short-Form-36 Health Survey (SF-36), version 2 
SMBG 
self-monitored blood glucose 
SUSARs 
suspected unexpected serious adverse reactions 
T1D 
Type 1 diabetes  
T2D 
Type 2 diabetes 
TBL 
total bilirubin level 
TE 
treatment emergent 
TEAE 
treatment-emergent adverse event: an untoward medical occurrence that emerges during 
a defined treatment period, having been absent pretreatment, or worsens relative to the 
pretreatment state, and does not necessarily have to have a causal relationship with this 
treatment. 
ULN 
upper limit of normal 
WOCBP 
women of childbearing potential 
WNOCBP 
women not of childbearing potential 
 
 
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10.14. Appendix 14: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment a: 21-May-2021 
Overall Rationale for the Amendment: 
The overall changes and rationale for the changes made to this protocol are described in the 
following table. Note that minor edits have been made throughout the protocol, which are not 
captured in the table below. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities 
Added the following note to 
Patient-Reported Outcomes 
(PROs), “If a PRO questionnaire 
is not available in the native 
language of a participant at 
baseline, that questionnaire will 
not be administered for that 
participant for the duration of 
the trial (Appendix 10.10)”  
If a PRO questionnaire is not 
available in the native language, 
then there is no scientific value 
in collecting these data as 
participants would not be able to 
meaningfully understand and 
provide appropriate responses to 
the questions 
Removed Predose 
Pharmacokinetic (PK) sample 
collection at Visit 801 
Correction in timepoint for PK 
sample collection at Visit 801 
Updated the general notes to 
include information on 
ambulatory blood pressure 
modeling (ABPM) 
If the ABPM needs to be 
repeated at Visit 3, then the 
screening period may exceed 6 
weeks and this will not be 
considered a protocol deviation 
Section 4.1.1  
Overview of Study 
Periods 
Addition of “when collected” for 
PROs at Visit 4, during 
maintenance period (Visit 11 
and Visit 17), and during early 
discontinuation of treatment visit 
To be aligned with PROs in 
Schedule of Events 
Section 5.2 Exclusion 
Criteria 
Addition of history of 
symptomatic gallbladder disease 
To address Food and Drug 
Administration (FDA) feedback 
Addition of history of 
documented human 
immunodeficiency virus 
infection 
Medications used to treat HIV 
infection may affect body fat 
distribution 
Revised language for 
implantable or injectable 
contraceptives 
Clarified that intrauterine 
devices are allowed if the 
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Section # and Name 
Description of Change 
Brief Rationale 
participant has been using the 
device for at least 3 months 
Clarified language for 
participants who have previously 
received LY3437943 
Minor edit to clarify language 
Inclusion and Exclusion Criteria 
1–51 and 58–59 can be referred 
to in the current protocol 
 
For inclusion and Exclusion 
Criteria 52–57, refer to J1I-MC-
GZBF Addendum (1)  
The inclusion and exclusion 
criteria numbered from 52 to 57 
are part of J1I-MC-GZBF 
Addendum (1). So, in the current 
protocol, the exclusion criteria 
continue with the next available 
number in the sequence from the 
last number in the protocol 
addendum (58–59) 
Section 8.3.1 Timing 
and Mechanism for 
Collecting Events 
Change of “Pregnancy eCRF” to 
“SAE eCRF” 
Correction in mechanism for 
reporting 
Section 10.2 Appendix 
2: Clinical Laboratory 
Tests 
Removed uric acid from clinical 
chemistry tests 
To maintain internal document 
consistency. It is presented in 
Appendix 10 as biomarker of 
purine metabolism 
Added LTS P800 to exploratory 
samples 
Addition of plasma metabolic 
marker 
Section 10.8 Appendix 
8: Protocol GZBF 
Standardized Protocols 
for the Measurement of 
Height, Weight, Waist 
Circumference, and 
Vital Signs 
Updated electrocardiogram 
tracings to be assessed 
qualitatively by a blinded 
cardiologist 
To maintain consistency with 
Section 8.2.3 
(Electrocardiograms) 
Section 10.11 Appendix 
11: Patient-Reported 
Outcomes 
Added information to clarify that 
PRO questionnaires will be 
translated into the native 
language of participants if 
feasible. If a translation is not 
available in the native language 
of a participant, then that PRO 
questionnaire will not be 
administered for that participant 
for the duration of the trial 
If a PRO questionnaire is not 
available in the native language, 
then there is no scientific value 
in collecting the data as 
participants would not be able to 
meaningfully understand and 
provide appropriate responses to 
the questions  
 
 
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11. References 
[ADA] American Diabetes Association. 6. Glycemic targets: standards of medical care in 
diabetes-2020. Diabetes Care. 2020;43(suppl 1):S66-S76. https://doi.org/10.2337/dc20-S006 
[AMA] American Medical Association. American Medical Association House of Delegates 
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