A Phase 2 Study of Once-Weekly LY3437943 Compared With Placebo and Dulaglutide in Participants With Type 2 Diabetes
Phase: PHASE2
Conditions: Type 2 Diabetes
Sponsor: Eli Lilly and Company

 
 
 
Protocol: J1I-MC-GZBD(c) 
 
 
A Phase 2 Study of Once-Weekly LY3437943 Compared with Placebo and 
Dulaglutide in Participants with Type 2 Diabetes 
 
 
NCT04867785 
 
 
Approval Date: 29-Aug-2022 

CONFIDENTIAL 
J1I-MC-GZBD(c) 
 
1 
Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of 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 and 
Dulaglutide in Participants with Type 2 Diabetes  
Protocol Number: J1I-MC-GZBD 
Amendment Number: c 
Compound: LY3437943 
Study Phase: Phase 2 
Short Title: Effect of LY3437943 Versus Placebo and Dulaglutide in Participants with Type 2 
Diabetes  
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number(s) 
IND: 145825 
Approval Date: Protocol Amendment (c) Electronically Signed and Approved by Lilly on date 
provided below.  
Document ID: VV-CLIN-072318 
 
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 J1I-MC-GZBD(c)  
 
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Medical Monitor Name and Contact Information will be provided separately. 
 
 
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 J1I-MC-GZBD(c)  
 
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Protocol Amendment Summary of Changes Table 
 
DOCUMENT HISTORY 
Document 
Date 
Amendment b 
10-May-2021 
Amendment a 
1-Mar-2021 
Original Protocol 
19-Feb-2021 
Amendment [c]  
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 13 from Predose to 
Postdose 
Dosing does not occur at Visit 
13 (Week 36); therefore, time 
point is now described as 
approximately 1 week post the 
last dose (Week 35). 
Pharmacokinetic Schedule of 
Events table 
Sample #11 row: Updated 
collection time point from 
“Predose (up to 8 hours)” to 
“Postdose (approximately 1 
week)” 
Dosing does not occur on 
Week 36. This sample collection 
time point is approximately 1 
week following the last dose.  
Pharmacokinetic Schedule of 
Events table 
Sample #12 row: Updated 
collection time point from “4 
weeks post last dose” to “5 
weeks post last dose” 
Since last dose is on Week 35, 
the Sample #12 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. 
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 ..........................................................................................................7 
1.1. 
Synopsis ............................................................................................................................7 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities (SoA) ..........................................................................................11 
2. 
Introduction ...................................................................................................................18 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................18 
2.3. 
Benefit/Risk Assessment ................................................................................................20 
2.3.1. 
Risk Assessment .............................................................................................................20 
2.3.2. 
Benefit Assessment .........................................................................................................20 
2.3.3. 
Overall Benefit: Risk Conclusion ...................................................................................20 
3. 
Objectives and Endpoints ............................................................................................21 
4. 
Study Design ..................................................................................................................23 
4.1. 
Overall Design ................................................................................................................23 
4.1.1. 
Overview of Study Periods .............................................................................................24 
4.2. 
Scientific Rationale for Study Design ............................................................................26 
4.3. 
Justification for Dose ......................................................................................................27 
4.4. 
End of Study Definition ..................................................................................................27 
5. 
Study Population ...........................................................................................................28 
5.1. 
Inclusion Criteria ............................................................................................................28 
5.2. 
Exclusion Criteria ...........................................................................................................29 
5.3. 
Lifestyle Considerations .................................................................................................32 
5.3.1. 
Meals and Dietary Restrictions .......................................................................................32 
5.3.2. 
Activity and Physical Exercise .......................................................................................32 
5.4. 
Screen Failures ................................................................................................................32 
6. 
Study Intervention ........................................................................................................34 
6.1. 
Study Intervention(s) Administered................................................................................34 
6.1.1. 
Medical Devices..............................................................................................................37 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................37 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................37 
6.4. 
Study Intervention Compliance ......................................................................................38 
6.5. 
Concomitant Therapy .....................................................................................................39 
6.5.1. 
Glucose-lowering Agents................................................................................................40 
6.5.2. 
Other Concomitant Medications .....................................................................................41 
6.5.3. 
Management of Participants with Gastrointestinal Symptoms .......................................41 
6.6. 
Dose Modification ..........................................................................................................42 
6.6.1. 
Temporary Interruption of Study Drug ...........................................................................42 
6.6.2. 
Dose Reductions Indicated to Ensure Participant Safety ................................................44 
6.7. 
Intervention after the End of the Study ...........................................................................45 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................46 
7.1. 
Discontinuation of Study Intervention ............................................................................46 
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7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................47 
7.3. 
Lost to Follow-Up ...........................................................................................................48 
8. 
Study Assessments and Procedures.............................................................................49 
8.1. 
Efficacy Assessments .....................................................................................................49 
8.2. 
Safety Assessments .........................................................................................................50 
8.2.1. 
Physical Examinations ....................................................................................................50 
8.2.2. 
Vital Signs .......................................................................................................................50 
8.2.3. 
Electrocardiograms .........................................................................................................50 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................50 
8.2.5. 
Safety Monitoring ...........................................................................................................51 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................54 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................54 
8.3.2. 
Adverse Events of Special Interest .................................................................................56 
8.4. 
Treatment of Overdose ...................................................................................................62 
8.5. 
Pharmacokinetics ............................................................................................................62 
8.5.1. 
Bioanalysis ......................................................................................................................62 
8.6. 
Pharmacodynamics .........................................................................................................63 
8.7. 
Genetics ..........................................................................................................................63 
8.8. 
Biomarkers ......................................................................................................................63 
8.9. 
Immunogenicity Assessments.........................................................................................64 
8.10. 
Health Economics ...........................................................................................................64 
9. 
Statistical Considerations .............................................................................................65 
9.1. 
Statistical Hypotheses .....................................................................................................65 
9.2. 
Sample Size Determination ............................................................................................65 
9.3. 
Populations for Analyses ................................................................................................65 
9.4. 
Statistical Analyses .........................................................................................................66 
9.4.1. 
General Considerations ...................................................................................................66 
9.4.2. 
Treatment Group Comparability .....................................................................................67 
9.4.3. 
Efficacy Analyses ...........................................................................................................67 
9.4.4. 
Safety Analyses ...............................................................................................................68 
9.4.5. 
Pharmacokinetic/Pharmacodynamic Analyses ...............................................................69 
9.4.6. 
Evaluation of Immunogenicity .......................................................................................69 
9.4.7. 
Subgroup Analyses .........................................................................................................69 
9.5. 
Interim Analyses .............................................................................................................69 
9.6. 
Data Monitoring Committee (DMC) ..............................................................................70 
10. 
Supporting Documentation and Operational Considerations ..................................71 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................71 
10.1.1. Regulatory and Ethical Considerations ...........................................................................71 
10.1.2. Informed Consent Process ..............................................................................................72 
10.1.3. Data Protection................................................................................................................72 
10.1.4. Committees Structure......................................................................................................72 
10.1.5. Dissemination of Clinical Study Data.............................................................................73 
10.1.6. Data Quality Assurance ..................................................................................................73 
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10.1.7. Source Documents ..........................................................................................................74 
10.1.8. Study and Site Start and Closure ....................................................................................75 
10.1.9. Publication Policy ...........................................................................................................76 
10.1.10. Investigator Information .................................................................................................76 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................77 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting ........................................................82 
10.3.1. Definition of AE .............................................................................................................82 
10.3.2. Definition of SAE ...........................................................................................................83 
10.3.3. Definition of Product Complaints ...................................................................................84 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................85 
10.3.5. Reporting of SAEs ..........................................................................................................87 
10.3.6. Regulatory Reporting Requirements ...............................................................................87 
10.4. 
Appendix 4: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................89 
10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments ....................................................................................................................94 
10.6. 
Appendix 6: Genetics......................................................................................................96 
10.7. 
Appendix 7: World Health Organization Classification of 
Diabetes and Diagnostic Criteria ....................................................................................97 
10.8. 
Appendix 8: New York Heart Association Functional 
Classification IV CHF ....................................................................................................98 
10.9. 
Appendix 9: Protocol GZBD Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital 
Signs, ECG, SMBG and MNSI ......................................................................................99 
10.10. 
Appendix 10: Patient-Reported Outcomes ...................................................................104 
10.11. 
Appendix 11: Metabolic Mechanistic Biomarkers .......................................................106 
10.12. 
Appendix 12: Provisions for Changes in Study Conduct during 
Exceptional Circumstances ...........................................................................................108 
10.13. 
Appendix 13: Abbreviations .........................................................................................112 
10.14. 
Appendix 14: Protocol Amendment History ................................................................117 
11. 
References ....................................................................................................................119 
 
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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 2 Study of Once-Weekly LY3437943 Compared with Placebo and 
Dulaglutide in Participants with Type 2 Diabetes  
Short Title: Effect of LY3437943 Versus Placebo and Dulaglutide in Participants with Type 2 
Diabetes  
Rationale: 
Epidemiological studies have shown that type 2 diabetes (T2D) and obesity are tightly associated 
(Verma and Hussain 2017; Marreno 2009). The ongoing global obesity epidemic increases the 
incidence of T2D and other comorbidities, including hyperlipidemia and hypertension resulting 
in an increased incidence of micro- and macrovascular complications (Garber 2012; Neeland et 
al. 2019; Dwivedi et al. 2020). In addition, obesity complicates treatment of T2D by worsening 
insulin resistance, preventing many patients from achieving their treatment goals (Kahn et al. 
2006; Scheen and Van Gaal 2014; Barazzoni et al. 2018). Glucose-lowering therapeutic 
interventions that encompass weight loss may have a potential to slow the progression of T2D 
and reduce the risk of chronic complications (Lau and Teoh 2015; Aroda 2018; Pereira and 
Eriksson 2019; Chun and Butts 2020). Treatments that simultaneously target T2D and obesity 
are considered an important unmet medical need. 
LY3437943 is a novel synthetic long-acting 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 equal or  greater activity in glucose-dependent insulin 
secretion compared with an existing GLP-1 receptor agonist (GLP-1 RA), as demonstrated by 
intravenous glucose tolerance test in lean rat. In addition, LY3437943 demonstrated greater 
weight loss in diet-induced obese (DIO) mice compared with an existing GLP-1 receptor agonist 
(GLP-1 RA). 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. 
Pharmacokinetic data from Phase 1 clinical studies support once-weekly administration of 
LY3437943. In these trials, LY3437943 was found to be safe and well tolerated, thereby 
justifying further investigation in a Phase 2 study. 
Study J1I-MC-GZBD (GZBD) is a Phase 2, multicenter, randomized, double-blind, parallel, 
placebo- and active comparator-controlled 36-week study, with the primary outcome at 24 
weeks, that will investigate glucose-lowering and body weight-lowering efficacy, as well as 
tolerability and safety of LY3437943 in participants with T2D who failed to achieve adequate 
glycemic control on diet and exercise alone or on a stable dose of metformin (1000 mg/day for 
at least 3 months prior to Visit 1). The primary objective will be to assess the effect on 
hemoglobin A1c (HbA1c) after 24 weeks of treatment. Participants will be studied for a total of 
36 weeks of treatment to provide sufficient follow-up time to obtain additional weight loss 
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8 
efficacy data over a longer time period. This study is designed to support dose selection for 
Phase 3. 
Objectives and Endpoints 
Objectives 
Estimands/Endpoints 
Primary 
 
To demonstrate superiority of QW LY3437943 (0.5, 
4.0, 8.0, or 12.0 mg) in change from baseline for 
HbA1c relative to placebo, in participants with T2D 
inadequately controlled with diet and exercise with or 
without a stable dose of metformin 
Change in HbA1c (%) from baseline to 24 weeks 
Secondary 
 
To compare the effect of QW LY3437943 versus 
placebo and versus dulaglutide on: 
 
Glucose control  
 
 
 
Change in HbA1c from baseline to 24 
(dulaglutide comparison only) and 36 weeks 
 
Percentage of participants reaching HbA1c 
<7.0% at 24 and 36 weeks 
 
 
 
Change in FBG from baseline to 24 and 36 
weeks (mg/dL, mmol/L) 
 
 
Body weight control 
 
Change in body weight (kg) from baseline to 24 and 36 
weeks 
To assess safety and tolerability of study interventions 
 
 
Adverse events overall  
 
Adverse events of special interest 
 
Laboratory parameters 
 
Electrocardiogram 
 
Vital signs 
 
 
Number of participants testing positive for 
anti-LY3437943 antibodies 
 
To assess PK of LY3437943 and potential participant 
factors that may influence its PK  
 
 
LY3437943 plasma concentration 
Abbreviations: FBG = fasting blood glucose; HbA1c = hemoglobin A1c; PK = pharmacokinetics; QW = once-
weekly; T2D = type 2 diabetes.  
 
 
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Overall Design 
Study GZBD is a Phase 2, multicenter, randomized, double-blind, parallel, placebo- and active 
comparator-controlled 36-week study, with the primary outcome at 24 weeks, to investigate the 
safety and efficacy of LY3437943 in participants with T2D who failed to achieve adequate 
glycemic control on diet and exercise alone or on a stable dose of metformin (1000 mg/day for 
at least 3 months prior to Visit 1). 
Disclosure Statement: This is a parallel group treatment study that is participant and 
investigator blinded. 
Number of Participants: 
A total of approximately 300 participants will be randomized in a 2:2:2:1:1:1:1:2 ratio to either 
placebo, dulaglutide 1.5 mg, LY3437943 0.5 mg, LY3437943 4 mg (with starting dose at 2 mg; 
slow escalation), LY3437943 4 mg (with starting dose at 4 mg; no escalation), LY3437943 8 mg 
(with starting dose at 2 mg; slow escalation), LY3437943 8 mg (with starting dose at 4 mg; rapid 
escalation) or LY3437943 12 mg (starting dose at 2 mg; slow escalation).  
Intervention Groups and Duration: 
There are 6 treatment arms, including placebo, 4 maintenance dose levels of LY3437943, and 
dulaglutide 1.5 mg. The maintenance doses in the 4-, 8-, and 12-mg dose range groups will be 
achieved using dose-escalation schemes, which will reduce the risk of tolerability issues and will 
occur in some LY3437943 treatment arms up to Week 12 by increasing the volume of 
administered study drug (or matched placebo). Participants will be blinded as to whether she or 
he is receiving either  
 LY3437943 and dulaglutide placebo (single-dose pen; SDP) or 
 Dulaglutide (SDP) and LY3437943 placebo or  
 LY3437943 placebo and dulaglutide placebo.  
 
Data Monitoring Committee: No
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1.2. Schema    
 
 
Abbreviations: Dula = dulaglutide; LY = LY3437943; PBO = Placebo. 
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11 
1.3. 
Schedule of Activities (SoA) 
The Schedule of Activities described below should be followed for all participants enrolled in Study GZBD. However, for those 
participants whose participation in this study is affected by exceptional circumstances (such as pandemics or natural disasters), please 
refer to Section 10.12, Appendix 12 for additional guidance. 
 
 
Study Period 
I 
Screening/ 
Lead-in 
Study Period II 
Treatment 
 
Study Period III 
Post-
Treatment 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
ED 
801 
Week Relative to Randomization 
-3 
-2 
0 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
- 
4 Wks post 
end of TXP 
Allowable Interval Tolerance 
(days) 
±5 
±5 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Fasting Visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Administrative 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
review  
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preexisting conditions and 
medical history, including 
relevant surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history includes assessment of relevant preexisting conditions (for example, history of 
gallbladder disease, cardiovascular disease, medullary thyroid carcinoma, and pancreatitis). 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events and product 
complaints 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Evaluation 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body weight must be measured in the fasting state. If the participant is not fasting, the participant 
should return at a later date within the visit window to have the fasting body weight measured. 
Waist circumference 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
X 
 
Vital signs (3 sitting BP and PR 
measurements) 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
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Study Period 
I 
Screening/ 
Lead-in 
Study Period II 
Treatment 
 
Study Period III 
Post-
Treatment 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
ED 
801 
Week Relative to Randomization 
-3 
-2 
0 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
- 
4 Wks post 
end of TXP 
Allowable Interval Tolerance 
(days) 
±5 
±5 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Fasting Visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital sign measurements should be taken before obtaining an ECG tracing and before collection of 
blood samples for laboratory testing (See Section 10.9). 
Supine and standing BP 
(orthostatic vital signs) 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Referral to Section 10.9 for description of the orthostatic vital sign measurements. 
Physical examination 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
Visit 1 should be a complete physical while other visits should be “targeted” exams based on the 
physician’s judgment. 
12-Lead electrocardiogram 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Singlet-electrocardiograms should be obtained prior to collection of blood samples for laboratory 
testing, including PK samples (see Section 10.9 Appendix 9). 
Participant Education and Supplies 
Blood glucose (BG) meter 
instructions 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense BG meter/supplies (if 
needed) 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Diabetes education 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diabetes education to be performed by personnel who are qualified to educate participants on 
symptoms and management of hyperglycemia and hypoglycemia, SMBG, self-injection, and diabetes 
management. All trainings should be repeated as needed to ensure participant compliance. 
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Study Period 
I 
Screening/ 
Lead-in 
Study Period II 
Treatment 
 
Study Period III 
Post-
Treatment 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
ED 
801 
Week Relative to Randomization 
-3 
-2 
0 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
- 
4 Wks post 
end of TXP 
Allowable Interval Tolerance 
(days) 
±5 
±5 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Fasting Visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Glucose Monitoring 
Remind participants about 7-
point SMBG 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
7-point SMBG 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
Review SMBG and hypoglycemic 
events in the diary for diabetes 
management 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Participant Diary (paper) 
Participant diary dispensed 
 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Diary compliance check 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diary return 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Patient-Reported Outcomes (paper) 
SF-36v2 acute form 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Eating Inventory 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
Appetite Visual Analog Scale 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
  
If a translation is not available in the native language of a participant at baseline, the PRO 
questionnaire(s) will not be administered for that participant for the duration of the trial (Appendix 
10.10). 
Laboratory Tests and Sample Collections 
Hematology 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Hemoglobin A1c (HbA1c) 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Clinical chemistry 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
X 
X 
Glucose 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
Lipid panel 
X 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Urinalysis 
X 
 
 
 
 
X 
 
X 
 
 
X 
 
X 
X 
 
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14 
 
Study Period 
I 
Screening/ 
Lead-in 
Study Period II 
Treatment 
 
Study Period III 
Post-
Treatment 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
ED 
801 
Week Relative to Randomization 
-3 
-2 
0 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
- 
4 Wks post 
end of TXP 
Allowable Interval Tolerance 
(days) 
±5 
±5 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Fasting Visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For women of childbearing potential only 
Urine pregnancy (local) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
A urine pregnancy test must be performed at Visit 3 with the result available prior to first injection of 
study intervention(s) for women of childbearing potential only. Additional pregnancy tests (beyond 
those required per the SoA) should be performed at any time during the trial if a menstrual period is 
missed, there is clinical suspicion of pregnancy, or as required by local law or regulation. If the urine pregnancy 
test is inconclusive at Visit 3, the recommendation would be to collect an additional serum pregnancy test.  
Follicle stimulating hormone 
(FSH) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only for postmenopausal women at least 40 years of age with an intact uterus, not on hormone 
therapy, and who have had spontaneous amenorrhea for more than 1 year without an alternative 
medical cause. 
Insulin 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Glucagon 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
C-peptide 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Intact proinsulin 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Calcitonin 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
X 
Pancreatic amylase, lipase 
X 
 
X 
 
 
 
 
X 
 
 
X 
 
X 
X 
X 
Longitudinal biomarkers 
 
 
X 
 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
See Section 10.11 for list of biomarkers  
Endpoint biomarkers 
 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
See Section 10.11 for list of biomarkers 
eGFR (CKD-EPI) 
X 
 
X 
 
 
 
 
X 
X 
 
X 
 
X 
X 
 
Urinary albumin/creatinine ratio 
(UACR) 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
X 
 
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15 
 
Study Period 
I 
Screening/ 
Lead-in 
Study Period II 
Treatment 
 
Study Period III 
Post-
Treatment 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
ED 
801 
Week Relative to Randomization 
-3 
-2 
0 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
- 
4 Wks post 
end of TXP 
Allowable Interval Tolerance 
(days) 
±5 
±5 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Fasting Visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacokinetic 
(PK) sample 
 
Predose 
 
 
X 
X 
 
X 
 
X 
 
 
X 
X 
 
 
 
Postdose 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
X 
X 
X 
 
Efforts should be taken to align clinical visit scheduling with PK sampling windows specified in the 
Pharmacokinetic Schedule of Events table below; otherwise, participants may need to return to the 
clinical site for additional PK-specific visits to provide PK samples.  
Immunogenicity (ADA) samples 
 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
X 
Stored Samples 
Genetic sample 
(pharmacogenetic stored sample) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory stored samples 
(nonpharmacogenetic stored 
samples) 
 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Randomization and Dosing 
IWRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Observe participant administer 
study intervention 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Participants should administer their first dose of study drug at the end of Visit 3, after other study 
procedures and randomization have been completed. Further observation and information on self-injection can 
be reviewed as necessary throughout the study. 
Dispense study intervention and 
injection supplies 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Review injection technique 
 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
Drug accountability 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Participant returns unused study 
intervention and injection 
supplies 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Study Period 
I 
Screening/ 
Lead-in 
Study Period II 
Treatment 
 
Study Period III 
Post-
Treatment 
Safety Follow-
Up 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
ED 
801 
Week Relative to Randomization 
-3 
-2 
0 
1 
2 
4 
8 
12 
16 
20 
24 
30 
36 
- 
4 Wks post 
end of TXP 
Allowable Interval Tolerance 
(days) 
±5 
±5 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±3 
Fasting Visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess drug compliance 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ADA = anti-drug antibody; BG = blood glucose; BP = blood pressure; CKD-EPI = chronic kidney disease-epidemiology; 
ECG = electrocardiogram; ED = early discontinuation; eGFR=estimated glomerular filtration rate; HbA1c = hemoglobin A1c; IWRS = Interactive Web 
Response Systems; PK = pharmacokinetics; PR = pulse rate; SF-36v2 acute form = Short Form-36 Version 2 Health Survey acute form; SMBG = 
self-monitoring of blood glucose; TXP = treatment period; wks = weeks.  
Notes: 
 
Visit 3 baseline assessments must be completed before processing the randomization in the IWRS. 
 
The visit date is determined in relation to the date of Visit 3 (randomization). 
 
Participants who are unable or unwilling to continue the study treatment 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 801 (safety follow-up visit) should be performed 4 weeks after the last treatment period visit.  
 
For fasting office visits, remind participants to report to the site before taking study drug(s) in a fasting condition, after a period of at least 8 hours 
without eating, drinking (except water), or any significant physical activity. Since some screening procedures need to be completed in the fasting state, 
Visit 1 may be conducted over more than 1 day to ensure necessary conditions are met. The participant should not take any antihyperglycemic 
medications prior to the fasting visit. 
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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 
Predose (up to -8 hours) 
3 
2 
1 to 24 hours postdose 
4 
4 
Predose (up to -8 hours)* 
5 
8 
24 to 72 hours postdose 
6 
12 
Predose (up to -8 hours)* 
7 
16 
72 to 168 hours postdose  
8 
20 
Any time during this week 
9 
24 
Predose (up to -8 hours)* 
10 
30 
Predose (up to -8 hours) 
11 
36 
Postdose (approximately 1 week)* 
12 
Safety follow-up  
5 weeks post last dose* 
13 
Early discontinuation 
Any time* 
 * Immunogenicity (ADA) samples collected with PK at these visits.
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2. 
Introduction 
2.1. 
Study Rationale 
Epidemiological studies have shown that T2D and obesity are tightly associated (Marrero 2009; 
Verma and Hussain 2017). The ongoing global obesity epidemic increases the incidence of T2D 
and other comorbidities, including hyperlipidemia and hypertension resulting in an increased 
incidence of chronic micro- and macrovascular complications (Garber 2012; Neeland et al. 2019; 
Dwivedi et al. 2020). In addition, obesity complicates treatment of T2D by worsening insulin 
resistance, preventing many patients from achieving their treatment goals (Kahn et al. 2006; 
Scheen and Van Gaal 2014; Barazzoni et al. 2018). Glucose-lowering therapeutic interventions 
that encompass weight loss may have a potential to slow the progression of T2D and reduce the 
risk of chronic complications (Lau and Teoh 2015; Aroda 2018; Pereira and Eriksson 2019; 
Chun and Butts 2020). Treatments that simultaneously target T2D and obesity are considered an 
important unmet medical need.  
Glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1, and glucagon 
(Gcg) have a role in the regulation of carbohydrate, protein and lipid metabolism, and energy 
balance. While some of their actions are similar, each hormone also has unique metabolic 
regulatory actions, providing an opportunity to combine their respective actions in a single 
molecule to develop a pharmacological agent with improved efficacy and safety profile for the 
treatment of a range of metabolic conditions compared with existing therapies.  
LY3437943 is a novel synthetic single peptide with triple receptor activity in GIP, GLP-1, and 
Gcg receptors (GIPR, GLP-1R, and GcgR, respectively). 
In Phase 1 studies, LY3437943 was found to be safe and well tolerated, thereby justifying further 
investigation in Phase 2 study. Pharmacokinetic data support once-weekly administration of 
LY3437943. 
Study GZBD is a 36-week Phase 2 study, with the primary outcome at 24 weeks, designed to 
examine the safety and efficacy of 4 dose levels of QW, subcutaneously administered 
LY3437943 compared with QW, subcutaneously administered placebo and QW dulaglutide 
1.5 mg. The study objectives will be evaluated in participants with T2D who have inadequate 
glycemic control with diet and exercise with or without a stable dose of metformin. The primary 
objective at Week 24 will be to assess superiority of QW LY3437943 (0.5, 4, 8, or 12 mg) in 
change from baseline for HbA1c (%) relative to placebo. Participants will be studied for a total 
of 36 weeks of treatment to provide sufficient follow-up time to obtain additional weight loss 
information. This trial is designed to support dose selection for Phase 3 development. 
2.2. 
Background 
Type 2 diabetes is characterized by impaired glycemic control due to resistance in the peripheral 
tissues to insulin actions and inadequate insulin secretion caused by -cell failure (Zheng et al. 
2018). Type 2 diabetes is commonly associated with comorbidities such as obesity, hypertension, 
and dyslipidemia resulting in increased risk of chronic diabetic complications.  
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Structure of LY3437943 
LY3437943 is a novel long-acting synthetic peptide containing 39 amino acids and a fatty acyl 
side chain to allow QW dosing, which shows potent agonist action at GIP, GLP-1, and Gcg 
receptors (GIPR, GLP-1R, and GcgR, respectively).  
Nonclinical data with efficacy and toxicology 
In nonclinical pharmacology models, LY3437943 demonstrated equal or greater effect on 
glucose-dependent insulin secretion compared with an existing GLP-1 RA, as demonstrated by 
intravenous glucose tolerance test in lean rats and with greater weight loss in DIO mice. The 
body weight reduction in DIO mice was primarily due to loss of fat mass. 
 
 
 
 
 
 
 
 
 
 
 
Summary of clinical studies 
Study J1I-MC-GZBA (GZBA) was a first-in-human, single-ascending dose (SAD) study 
investigating the safety, tolerability, and PK/PD of LY3437943 (dose ranging from 0.1 to 6 mg) 
administered as a SC injection in 45 healthy participants. 
The most common treatment emergent adverse events (TEAEs) were gastrointestinal (GI) 
events, including vomiting, 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 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 an ongoing Phase 1, randomized, investigator- and 
participant-blind 12-week study that assesses the safety, tolerability, and PK/PD effects of 
multiple doses of LY3437943 when administered QW in participants with T2D. Trulicity® 
(dulaglutide) 1.5 mg is used as an active comparator. Participants in Cohorts 1 to 3 are receiving 
fixed doses of LY3437943 (0.5, 1.5, or 3 mg QW) or placebo for 12 weeks. Participants in 
Cohorts 4 and 5 are receiving escalated doses starting from 3 mg to 12 mg, respectively, over the 
12-week treatment period. 
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Based on preliminary data from this study, 72 participants in all treatment arms received study 
treatment, and 43 completed the study to date. Gastrointestinal 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 
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 adverse events 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 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. 
More detailed information about the known and expected benefits and risks of dulaglutide may 
be found in the USPI or SmPC (Trulicity USPI, 2020; Trulicity SmPC, 2020). 
2.3.1. Risk Assessment 
Most common AEs seen in clinical trials of LY3437943 have been those related to the GI organ 
system. The GI AEs, as well as those related to pancreatic safety, hypoglycemia, vital signs, 
allergic and hypersensitivity reactions, and thyroid C-cell effects are safety topics of special 
interest in incretin development programs and will, therefore, be assessed in this study, too. Most 
of these AEs have not been observed with LY3437943 in the completed or ongoing phase trials. 
Please refer to the IB Section 6 for more details. 
2.3.2. Benefit Assessment 
LY3437943 is a tri-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 initial efficacy assessment in participants with T2D, 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-1 RAs. 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 can be assumed since LY3437943 is in the early phase of clinical development. All 
participants taking part in this study will receive diet and physical activity counseling according 
to site programs. 
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3. 
Objectives and Endpoints 
Objectives 
Estimands/Endpoints 
Primary 
 
To demonstrate superiority of QW LY3437943 (0.5, 
4.0, 8.0, or 12.0 mg) in change from baseline for 
HbA1c relative to placebo, in participants with T2D 
inadequately controlled with diet and exercise with 
or without a stable dose of metformin 
Change in HbA1c (%) from baseline to 24 weeks  
Secondary 
 
To compare the effect of QW LY3437943 versus 
placebo and versus dulaglutide on: 
 
Glucose control 
 
 
 
 
Change in HbA1c (%) from baseline to 24 
(for dulaglutide comparison only) and 36 
weeks 
 
Percentage of participants reaching HbA1c of 
<7.0% at 24 and/or 36 weeks 
 
 
 
Change in FBG from baseline to 24 and 36 
weeks (mg/dL, mmol/L) 
 
 
Body weight control 
 
 
Change in body weight (kg) from baseline to 
24 and 36 weeks 
 
To assess safety and tolerability of study intervention  
 
Adverse events overall 
 
Adverse events of special interest 
 
Laboratory parameters 
 
Electrocardiogram 
 
Vital signs  
 
 
Number of participants testing positive for 
anti-LY3437943 antibodies 
To assess the PK of LY3437943 and potential 
participant factors that may influence its PK  
 
LY3437943 plasma concentrations 
Tertiary/Exploratory 
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 
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Objectives 
Estimands/Endpoints 
To compare the effect of QW LY3437943 versus 
placebo and versus dulaglutide on: 
 
Glucose control 
 
 
 
 
Change in SMBG profile from baseline to 24 
and 36 weeks 
 
 
Percentage of participants reaching HbA1c of 
<5.7%, <6.5%, and <7.0% at 24 and/or 36 
weeks 
Dose–response including placebo   
 
Body weight control 
 
Percentage of participants with 5%, 10%, 
15%, or greater body weight loss from 
baseline to 24 and 36 weeks 
 
Dose–response including placebo  
 
 
Appetite VAS 
 
Change from baseline to 4, 8, 12, 16, 24, and 
36 weeks 
 
 
Lipids 
 
Change from baseline to 16, 24, and 36 weeks 
for total cholesterol, triglycerides, HDL 
cholesterol, LDL cholesterol, and VLDL 
cholesterol 
 
 
Biomarkers 
 
Change from baseline to Week 16, 24, and 36 
weeks for mechanistic biomarkers (see 
detailed list of parameters in Section 10.11) 
 
 
Patient-reported outcomes 
 
Mean change from baseline to Weeks 16, 24, 
and 36 for:  
SF-36v2 acute form domain scores 
Eating Inventory domain scores  
Abbreviations: FBG = fasting blood glucose; HbA1c = hemoglobin A1c; HDL = high-density lipoprotein; LDL = 
low-density lipoprotein; PK = pharmacokinetics; QW = once-weekly; SF-36v2 = Short Form-36 version 2 Health 
Survey; SMBG = self-monitoring of blood glucose; T2D = type 2 diabetes; VAS = Visual Analog Scale; VLDL = 
very low-density lipoprotein. 
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4. 
Study Design 
4.1. 
Overall Design 
Study GZBD is a Phase 2, multicenter, randomized, double-blinded, parallel, placebo- and active 
comparator-controlled 36-week study, with the primary outcome at 24 weeks, to investigate the 
safety and efficacy of LY3437943 in participants with T2D who failed to achieve adequate 
glycemic control on diet and exercise alone or on a stable dose of metformin (1000 mg/day for 
at least 3 months prior to Visit 1) (see Section 1.2). 
Four maintenance doses of LY3437943 will be evaluated in the trial, 0.5, 4, 8, and 12 mg. Dose 
escalation to reduce the risk of tolerability issues 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 as appropriate and as described in Section 4.1.1. Study participants will be 
randomized in a 2:2:2:1:1:1:1:2 ratio to either placebo, dulaglutide 1.5 mg, LY3437943 0.5 mg, 
LY3437943 4 mg (with starting dose at 2 mg; slow escalation), LY3437943 4 mg (with starting 
dose at 4 mg; no escalation), LY3437943 8 mg (with starting dose at 2 mg; slow escalation), 
LY3437943 8 mg (with starting dose at 4 mg; rapid escalation), or LY3437943 12 mg (with 
starting dose at 2 mg; slow escalation). 
All participants will undergo a 3-week screening period, a 36-week treatment period, followed 
by a 4-week safety follow-up period.  
During the 36-week treatment period, each participant will receive one injection of LY3437943 
or placebo (PBO) administered with a syringe and one injection of dulaglutide or PBO 
administered with an SDP (see Section 6 for more details). The table below specifies the number 
of injections per treatment arm. 
 
Number of Injections Per Treatment Arm 
Randomization 
LY3437943 
PBO 
LY3437943 
Dulaglutide 
1.5 mg SDP 
PBO 
Dulaglutide 
SDP 
Total 
LY 0.5 mg 
1 
0 
0 
1 
2 
LY 4 mg 
1 
0 
0 
1 
2 
LY 8 mg 
1 
0 
0 
1 
2 
LY 12 mg 
1 
0 
0 
1 
2 
Dulaglutide 1.5 mg 
0 
1 
1 
0 
2 
PBO 
0 
1 
0 
1 
2 
Abbreviations: LY = LY3437943; PBO = placebo; SDP = single-dose pen. 
 
During the trial, an unblinded internal assessment committee (AC) will review safety, 
tolerability, and efficacy data in study participants according to a prespecified schedule in order 
to assure the safety of randomized participants (see Section 9.5). 
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4.1.1. 
Overview of Study Periods 
 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. Screening procedures will be performed according to the SoA (Section 1.3).  
Visit 2  
At Visit 2, the screening laboratory results will be reviewed to confirm eligibility.  
 
Participants will be provided paper diaries and will be trained how to record key study 
information, as appropriate. Participants will start recording their self-monitoring of blood 
glucose (SMBG) values and hypoglycemic events immediately after Visit 2 and will perform 
these procedures until the last study visit. See Section 10.9 for details about glucose self-
monitoring. 
Diabetes education will be performed by the personnel qualified to educate participants on 
symptoms and management of hyperglycemia and hypoglycemia, self-monitored BG, self-
injection, and diabetes management according to American Diabetes Association Standards of 
Medical Care in Diabetes (ADA 2020) or local standards. Participants will be trained on how to 
utilize BG meters and how to collect SMBG, including 7-point measurements as appropriate. 
Blood glucose meters or supplies will be provided to measure SMBG values (see Section 10.9).  
Visit 3 Randomization 
At Visit 3, eligible participants, those who meet all applicable inclusion criteria and none of the 
applicable exclusion criteria, will perform all required study procedures prior to randomization. 
When collected, patient-reported outcomes questionnaires should be administered as early as 
possible during the visit. Preferred administration order of these questionnaires throughout the 
trial is 
1. SF-36v2 acute form 
2. Eating Inventory, and 
3. Appetite Visual Analog Scale. 
Following randomization, study site personnel will train participants on how to use the syringe 
and vial, and single-dose pen and observe the study participant inject the first dose of study 
drugs. The date, time, and location of the first dose of study drugs will be recorded on the 
electronic case report form (eCRF). Beginning at randomization, all participants will receive 
study drugs according to the randomized treatment arm for the duration of the 36-week treatment 
period as per the SoA (Section 1.3).  
 
 
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Treatment Period  
During the Treatment Period, study drugs and injection supplies will be returned per the SoA 
(Section 1.3) and according to local requirements. New supplies will be dispensed as needed. 
Participants should be instructed to contact the investigative site for assistance as soon as 
possible if they experience any difficulties administering their study drugs.  
Participants should also be advised about the appropriate course of action if study drugs are not 
taken at the required time (late/missing doses) (see Section 6.6.1). 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.  
Dose-Escalation Period (Visits 4-8) 
For maintenance doses of LY3437943 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. Study site 
personnel will continue to train participants on how to use the syringe and vial at each dose 
titration visit during dose escalation and as needed during the trial. The dose will be increased at 
4-week increments until the maintenance dose is achieved (see Section 6.1 for dosing details), as 
follows: 
 Maintenance dose of 0.5 mg: no dose escalation 
 Maintenance dose of 4 mg will be randomized 1:1 into 2 subsets:  
o 2 mg  4 mg (slow escalation) 
o 4 mg (no dose escalation) 
 Maintenance dose of 8 mg will be randomized 1:1 into 2 subsets:  
o 2 mg  4 mg  8 mg (slow escalation) 
o 4 mg  8 mg (rapid escalation) 
 Maintenance dose of 12 mg:  
o 2 mg  4 mg  8 mg  12 mg (slow escalation). 
The maintenance doses of LY3437943 or dulaglutide 1.5 mg will be continued for the remainder 
of the study. In participants who experience intolerable GI symptoms or may need dose 
adjustment for other reasons, the dose can be changed as described in Section 6.5.1.  
Maintenance Period (Visits 9-13) 
During the maintenance period, visits will occur every 4 weeks until 24 weeks and then every 6 
weeks from Weeks 24 to 36. Visit procedures should be conducted according to the SoA 
(Section 1.3). At Visits 10 and 12, when collected, patient-reported outcomes questionnaires 
should be administered as early as possible in the visit and in the preferred administration order 
(Section 1.3). 
Early Discontinuation Visit 
Participants unable or unwilling to continue the study for any reason will perform an early 
discontinuation (ED) of treatment visit (Section 7.1). If the participant is discontinuing during an 
unscheduled visit or a scheduled visit, that visit should be performed as an ED visit. Procedures 
should be completed according to the SoA (Section 1.3). Participants who discontinue from the 
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26 
study early and perform ED visit should also perform Visit 801 (see below) approximately 4 
weeks after ED visit. 
Safety Follow-up Period 
Visit 801 
A safety follow-up visit will occur approximately 4 weeks following the last treatment period 
visit. All participants are required to complete a safety follow-up visit (Visit 801), according to 
the SoA (Section 1.3). Participants discontinuing the study early and performing an ED visit will 
also be asked to perform the safety follow-up visit.  
Participants are also required to return any remaining study diaries to the study site at the end of 
this period. 
4.2. 
Scientific Rationale for Study Design 
Study GZBD is a Phase 2 study designed to examine the glucose and body weight-lowering 
efficacy and safety of LY3437943 QW (dose ranging from 0.5 to 12 mg) compared with placebo 
and dulaglutide 1.5 mg during the 36-week treatment period in participants with T2D who have 
inadequate glycemic control with diet and exercise alone or in combination with a stable dose of 
metformin. 
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 are designed to provide information on optimal dose escalation schemes for 
Phase 3 clinical development.  
The placebo comparison will provide efficacy and safety data to characterize the effects 
attributable to LY3437943. Inclusion of an active comparator (dulaglutide 1.5 mg) will allow for 
a direct comparison of QW LY3437943 to an injectable GLP-1 RA for preliminary assessment 
of potential additional benefits of LY3437943 on glucose control and body weight versus a 
selective GLP-1 RA commonly used in treatment of T2D patients in the clinical setting.  
The primary efficacy measure, HbA1c, is a generally accepted surrogate of chronic glycemic 
exposure and has been shown to predict long-term outcome of diabetes. In addition, the protocol 
includes other parameters relevant to the assessment of the effects on treatment interventions of 
glucose control, body weight control, safety, and mechanism of action.  
The primary objective will be tested at 24 weeks since this period is considered as adequate for 
evaluation of glucose-lowering efficacy in a Phase 2 trial. The full planned duration of 36 weeks 
will allow for an initial comparison of the body weight effects of the study drugs. The putative 
mechanism of action of LY3437943 suggests that treatment with LY3437943 may result in 
continued weight loss over this treatment period. The data from this trial will form the primary 
basis to assess dose–response/exposure–response of LY3437943 efficacy for selection of doses 
to be included in Phase 3 testing. In addition, safety and tolerability over a wide dose range of 
LY3437943 versus placebo and dulaglutide 1.5 mg will be assessed to enable robust benefit–risk 
characterizations in treatment of T2D. 
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The current study will enroll participants with inadequate glycemic control based on HbA1c 
values ranging from 7.0% to 10.5%, inclusive. The study population, as defined by inclusion and 
exclusion criteria, is expected to include participants with modestly advanced T2D and partially 
preserved pancreatic  cell function, the key prerequisite for glucose-lowering efficacy of 
incretins. Stable metformin treatment for at least 3 months is required to minimize glucose 
variability prior to study entry. 
To minimize the potential confounding effect of changes in 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. 
4.3. 
Justification for Dose 
LY3437943 maintenance doses of 0.5, 4, 8, and 12 mg, administered subcutaneously QW, were 
selected based on 
 Safety and tolerability of LY3437943 in healthy subjects and T2D patients in the Phase 1 
studies GZBA (0.1 to 6 mg) and GZBB (0.5 to 12 mg), respectively. 
 PK/PD modeling based on 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 dose of 0.5 mg is being investigated in this study to enable full 
characterization of the exposure–response relationships. This dose is predicted to achieve 
LY3437943 concentration levels that will demonstrate greater HbA1c lowering compared 
with placebo, but less than that of 1.5 mg dulaglutide.  
 Maintenance doses of 4, 8, and 12 mg are expected to provide clinically relevant HbA1c 
reductions relative to placebo with increasing HbA1c lowering 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 
(Section 1.3). 
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 of the following criteria are met: 
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 been diagnosed with T2D based on the World Health Organization (WHO) 
classification (see Section 10.7) or other locally applicable diagnostic standards 
3. Have an HbA1c value at screening of 7.0% and 10.5% and treated with diet and 
exercise alone or with a stable dose of metformin (either immediate release or extended 
release, 1000 mg/day and not more than the locally approved dose) for at least 3 months 
prior to screening/Visit 1  
4. Have had a stable body weight for the 3 months prior to randomization (5 kg body weight 
gain and/or loss) 
5. Have not modified diet or adopted any nutritional lifestyle modification within 3 months 
prior to randomization 
6. Have a body mass index (BMI) of 25-50 kg/m2 at Visit 1 
 
Sex 
7. Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
Men, women of childbearing potential, and women not of childbearing potential (for 
definitions, see Section 10.4) can participate in this study considering the following: 
 males agree to refrain from sperm donation and to use contraceptive methods 
as described in Section 10.4 throughout the study and for 5 half-lives of study 
drugs plus 90 days, corresponding to 4 months after the last injection.  
 women of childbearing potential agree to use contraceptive methods as 
described in Section 10.4 throughout the study and for 5 half-lives of study 
drugs plus 30 days, corresponding to 2 months after the last injection. Female 
participants should not be breastfeeding. 
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Note: Hormone replacement therapy in post-menopausal women and contraceptives 
containing an estrogen and a progestin (oral or transdermal system) in pre-
menopausal women are allowed but women must be on stable therapy for 3 months 
prior to screening/Visit 1. 
8. In the investigator’s opinion, are well motivated, capable, and willing to 
 perform finger-stick BG monitoring, including scheduled BG profiles with up 
to 7 measurements in 1 day 
 learn how to self-inject study drugs (LY3437943/placebo and 
dulaglutide/placebo), 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 drugs; persons with physical 
limitations who are not able to perform the injections must have the assistance 
of an individual trained to inject the study drugs)  
 inject study intervention QW, and 
 maintain study diaries, as required for this protocol. 
Informed Consent 
9. Capable of giving signed informed consent as described in Section 10.1.2, 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 applies: 
Medical Conditions 
10. Have type 1 diabetes mellitus (T1DM)  
11. Have history of ketoacidosis or hyperosmolar state/coma  
12. Have a history of proliferative diabetic retinopathy, diabetic maculopathy, or severe 
nonproliferative diabetic retinopathy that requires immediate treatment intervention 
13. Have a history of severe hypoglycemia and/or hypoglycemia unawareness within the 6 
months prior to Visit 1 
14. Have a history of acute or chronic pancreatitis or have signs and symptoms of acute 
pancreatitis at screening  
15. Have a known clinically significant gastric emptying abnormality (for example, severe 
diabetic gastroparesis or gastric outlet obstruction), have undergone gastric bypass 
(bariatric) surgery or restrictive bariatric surgery (for example, Lap-Band®), or chronically 
take medications that directly affect GI motility 
16. Have obesity induced by other endocrine disorders (such as Cushing’s syndrome or 
Prader-Willi syndrome) 
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17. Have uncontrolled hypertension (systolic blood pressure above or equal to 160 mmHg 
and/or diastolic blood pressure above or equal to 100 mmHg). For participants with 
uncontrolled hypertension at the screening visit, antihypertensive medication may be 
started. Blood pressure must meet the protocol criterion for hypertension control by Visit 
3 
18. Have an elevated resting pulse rate (>100 bpm) at baseline 
19. 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). 
20. Have an ECG considered by the investigator indicative of active cardiac disease or with 
abnormalities that may have interfered with the interpretation of changes in ECG intervals 
at screening 
 
21. Have a history of New York Heart Association Functional Classification III or IV CHF 
(see Section 10.8) 
22. Have acute or chronic hepatitis, signs, and symptoms of any liver disease other 
than nonalcoholic fatty liver disease (NAFLD), or alanine aminotransferase (ALT) 
level >3.0 times the upper limit of normal (ULN) for the reference range, as 
determined by the central laboratory at study entry. Participants with NAFLD are 
eligible to participate in this trial if their ALT level is ≤3.0 times the ULN for the 
reference range 
23. Have an estimated glomerular filtration rate <45 mL/min/1.73 m2 (or lower than 
the country-specific threshold for discontinuing metformin therapy per local label), 
calculated by Chronic Kidney Disease-Epidemiology as determined by central 
laboratory at Visit 1)  
24. Have family or personal history of medullary thyroid carcinoma (MTC) or 
multiple endocrine neoplasia syndrome type 2 (MEN2)  
25. Have evidence of a significant, uncontrolled endocrine abnormality (for example, 
hypothyroidism, thyrotoxicosis, or adrenal crises), in the opinion of the 
investigator 
26. Have a serum calcitonin level 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 
27. Have known or suspected hypersensitivity to trial product(s), to selective GLP-1 
RAs or GIP/GLP-1 or GLP-1/Gcg dual receptor agonists 
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28. Have evidence of a significant, active autoimmune abnormality (for example, 
lupus or rheumatoid arthritis) that, in the opinion of the investigator, is likely to 
require concurrent treatment with systemic glucocorticoids in the next 12 months 
29. Have had a transplanted organ (only corneal transplants [keratoplasty] allowed) or 
awaiting an organ transplant 
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 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 (for example, hemolytic anemia or 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 measurements 
32. Have a history of any other condition (such as known drug, alcohol abuse, or 
psychiatric disorder) that, in the opinion of the investigator, may preclude the 
participant from following and completing the protocol 
Prior/Concomitant Therapy 
33. Any glucose-lowering medications other than metformin within 3 months prior to 
screening  
34. Have been treated or plan to be treated with prescription or over-the-counter 
(OTC) medications that promote weight loss within 3 months prior to screening 
For example  
 Saxenda® [liraglutide 3.0 mg]  
 Xenical® [orlistat]  
 Meridia® [sibutramine]  
 Acutrim® [phenylpropanolamine]  
 Sanorex® [mazindol]  
 Adipex® [phentermine]  
 BELVIQ® [lorcaserin]  
 Qsymia™ [phentermine/topiramate combination]  
 Contrave® [naltrexone/bupropion], or  
 other similar body weight loss medication, including OTC medications, for 
example, allī®. 
 
35. Have received chronic (>2 weeks or 14 days) systemic glucocorticoid therapy (excluding 
topical, intraocular, intranasal, intra-articular, or inhaled preparations) within 1 month 
prior to screening  
Prior/Concurrent Clinical Study Experience 
36. Are currently enrolled in a clinical study involving an IP or any other type of medical 
research judged not to be scientifically or medically compatible with this study 
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37. Have participated, within the past 30 days of screening, in a clinical study 
involving an IP; at least 5 half-lives or 30 days (whichever is longer) should have 
passed  
38. Have previously completed or withdrawn from this study or any other study 
investigating LY3437943 
Other Exclusions 
39. 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 
40. Are Eli Lilly and Company employees or are employees of any third party 
involved in study who require exclusion of their employees 
41. Are, in the opinion of the investigator or sponsor, unsuitable for inclusion in the 
study 
5.3. 
Lifestyle Considerations 
Per the SoA (Section 1.3), qualified medical staff will provide diabetes management counseling, 
which will include instructions on diet and exercise and education about the signs, symptoms, 
and treatment of hypoglycemia and hyperglycemia, should it occur. Throughout the study, 
participants may undergo medical assessments and review of compliance with requirements 
before continuing in the study. 
Study participants should be instructed not to donate blood or blood products during the study. 
5.3.1. 
Meals and Dietary Restrictions 
Participants should continue their usual meal plan (with consistent meal size and time of day) 
throughout the course of the study, as agreed with the investigator or his or her designee. Per 
Inclusion Criterion 5 (Section 5.1), participants should not initiate a structured diet and/or 
exercise program for weight reduction during the study other than the lifestyle and dietary 
measures for diabetes treatment.  
For certain assessments, the participants will be required to come to the site in a fasting state, 
after an overnight fast (except for water) of at least 8 hours when clinical laboratory assessments 
and/or weight measures are performed as specified in the SoA (Section 1.3).  
5.3.2. 
Activity and Physical Exercise 
Participants will be advised to maintain their regular levels of physical activity/exercise during 
the study; strenuous exercise within 24 hours prior to all visits should be avoided.  
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 serious adverse event (SAE).  
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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 as outlined in 
Section 10.12. 
 
  
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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be 
administered to/used by a study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
The following study interventions will be administered: 
 LY3437943 vial containing 12 mg/2 mL of solution or 
 Placebo to match LY3437943 vial containing 2 mL of solution  
and 
 Dulaglutide 1.5 mg/0.5 mL single-dose pen or 
 Placebo to match Dulaglutide in a 0.5 mL single-dose pen 
Treatment Arm 
Escalation Period Dose 
Maintenance Period Dose 
LY weekly 
dose/ 
Administered 
as 
12-Week Escalation Period 
24-Week Dosing 
Week 0 to Week 3 
Week 4 to Week 7 
Week 8 to Week 11 
Week 12 through Week 35 
0.5 mg LY3437943a/1.5 
mg dulaglutide (dula) 
PBO 
LY weekly dose 
(no escalation) 
0.5 mg LY QW 
0.5 mg LY QW 
0.5 mg LY QW 
0.5 mg LY QW 
Administered as 
 
1 dose 0.5 mg LY  
1 dose 1.5 mg dula 
PBO  
1 dose 0.5 mg LY 
1 dose 1.5 mg dula 
PBO  
1 dose 0.5 mg LY 
1 dose 1.5 mg dula 
PBO  
1 dose 0.5 mg LY  
1 dose 1.5 mg dula PBO  
4 mg LY3437943/1.5 mg 
dulaglutide (dula) PBO 
 
LY weekly dose 
(slow escalation) 
2 mg LY QW 
4 mg LY QW 
4 mg LY QW 
4 mg LY QW 
Administered as 
1 dose 2 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY 
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY 
1 dose 1.5 mg dula PBO 
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LY weekly dose 
(no escalation) 
4 mg LY QW 
4 mg LY QW 
4 mg LY QW 
4 mg LY QW 
Administered as 
1 dose 4 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY 
1 dose 1.5 mg dula PBO 
8 mg LY3437943/1.5 mg 
dulaglutide (dula) PBO 
 
LY weekly dose 
(slow escalation) 
2 mg LY QW 
4 mg LY QW 
8 mg LY QW 
8 mg LY QW 
Administered as 
1 dose 2 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 8 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 8 mg LY  
1 dose 1.5 mg dula PBO 
LY weekly dose 
(rapid 
escalation) 
4 mg LY QW 
8 mg LY QW 
8 mg LY QW 
8 mg LY QW 
Administered as 
1 dose 4 mg LY 
1 dose 1.5 mg dula 
PBO 
1 dose 8 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 8 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 8 mg LY  
1 dose 1.5 mg dula PBO 
12 mg LY3437943/1.5 
mg dulaglutide (dula) 
PBO 
LY weekly dose 
(slow escalation) 
2 mg LY QW 
4 mg LY QW 
8 mg LY QW 
12 mg LY QW 
Administered as 
1 dose 2 mg LY 
1 dose 1.5 mg dula 
PBO 
1 dose 4 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 8 mg LY  
1 dose 1.5 mg dula 
PBO 
1 dose 12 mg LY 
1 dose 1.5 mg dula PBO 
1.5 mg 
Dulaglutideb/LY3437943 
PBO 
Dula weekly 
dose 
1.5 mg dula QW 
1.5 mg dula QW 
1.5 mg dula QW 
1.5 mg dula QW 
Administered as 
1 dose 1.5 mg dula 
1 dose LY PBOc 
1 dose 1.5 mg dula 
1 dose LY PBOc 
1 dose 1.5 mg dula 
1 dose LY PBOc 
1 dose 1.5 mg dula 
1 dose LY PBOc 
PBO weekly 
dose 
PBO 
PBO 
PBO 
PBO 
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Placebo (LY3437943 
PBO/1.5 mg dulaglutide 
PBO) 
Administered as 
1 dose LY PBOc 
1 dose 1.5 mg dula 
PBO 
1 dose LY PBOc 
1 dose 1.5 mg dula 
PBO 
1 dose LY PBOc 
1 dose 1.5 mg dula 
PBO 
1 dose LY PBOc  
1 dose 1.5 mg dula PBO 
Abbreviations: dula = dulaglutide; LY = LY3437943; PBO = placebo; QW = once-weekly. 
a LY3437943 QW will be administered by syringe from a 12 mg/2 mL vial. 
b Dulaglutide QW will be administered using a single-dose pen.  
c LY3437943 PBO will be randomly assigned to follow the injection dose schedule for one active LY arm.
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The first injections of study drugs should occur at Visit 3 immediately after randomization. 
Subsequently, administrations should be scheduled on the same day of the week and 
approximately the same time of the day. If a dose of study drug(s) is missed on the regularly 
scheduled day, the participant should administer it as soon as possible, unless less than 72 hours 
remains until the next scheduled dose. If less than 72 hours remains, that dose should be skipped, 
and the next dose should be taken at the scheduled day and time. All participants will inject study 
interventions SC into the abdominal wall, using 2 different abdominal quadrants each week for 
the 2 injections. The injection quadrant will be changed each week for each study drug injection 
using the clockwise rotation rule. A caregiver may administer the injection after appropriate 
training. A new syringe or disposable single-use pen will be used for each injection. The actual 
date, time, and injection-site location of all dose administrations will be recorded in the diary by 
the participant. 
6.1.1. 
Medical Devices 
The combination products provided for use in the study are marketed prefilled single-use pens 
for dulaglutide and prefilled single-dose placebo pens for dulaglutide placebo. Any medical-
device incidents, including those resulting from malfunctions of the device, must be detected, 
documented, and reported by the investigator throughout the study (see Section 10.3.3). 
6.2. 
Preparation/Handling/Storage/Accountability 
 
The investigator or designee must confirm appropriate storage conditions have been 
maintained during transit for all study intervention received and any discrepancies 
are reported and resolved before use of the study intervention. 
 
Only participants enrolled in the study may receive study intervention. Only study 
personnel may supply, prepare, or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized study personnel. 
 
The investigator-authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, 
reconciliation, and final disposition records). 
 
Further guidance and information for the final disposition of unused study 
interventions are provided in the study training materials.  
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
At Visit 3, participants who meet all criteria for enrollment will be randomized to 1 of the 6 
study treatment groups and 2 different starting dose subgroups within the 4 and 8 mg 
LY3437943 treatment groups. Assignment to treatment groups and starting dose subgroups will 
be determined by a computer-generated random sequence using an interactive web-response 
system (IWRS) with the following stratification variables: baseline HbA1c (<8.5%, 8.5%) and 
BMI (<30, 30). Study participants will be randomized in a 2:2:2:1:1:1:1:2 ratio to either 
placebo, dulaglutide 1.5 mg, LY3437943 0.5 mg, LY3437943 4 mg (with starting dose at 2 mg), 
LY3437943 4 mg (with starting dose at 4 mg), LY3437943 8 mg (with starting dose at 2 mg), 
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LY3437943 8 mg (with starting dose at 4 mg), or LY3437943 12 mg (with starting dose at 2 
mg). 
This is a double-blind study. All participants will administer 2 weekly injections (syringe 
containing LY3437943 or PBO, single-use pen containing dulaglutide 1.5 mg or PBO) matching 
their treatment allocation, as described in Section 6.1. Therefore, each participant will be 
administering one of the following study drug combinations in a blinded fashion: 
 LY3437943 and dulaglutide placebo (SDP)  
 Dulaglutide (SDP) and LY3437943 placebo, and  
 LY3437943 placebo and dulaglutide placebo.  
Where required, dose escalation of LY3437943 (or matched placebo) will be done by increasing 
the volume of administered study drug. 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 
clinical research physician (CRP) 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 interventions will be assessed at each visit. Compliance will 
be assessed by direct questioning and counting of unused study interventions and/or empty 
cartons returned. Study intervention compliance will be determined by the following:  
 Study intervention administration data will be recorded in the diary by the 
participant and reviewed by the investigator at each study visit. 
 The participants will be instructed to return any unused study drugs and/or empty 
cartons at the next visit to the study site for the purpose of performing study drug 
accountability. 
Treatment compliance will be assessed every 4 weeks, or every 6 weeks after Visit 11, since the 
schedule of visits after this visit would NOT allow more frequent assessments. Treatment 
compliance for each 4- to 6-week interval is defined as taking at least 75% of the required SC 
doses of study drugs.  
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In addition to the assessment of a participant’s compliance with administration of study drugs, 
other aspects of compliance with the study treatments will be assessed at each visit based on the 
participant’s adherence to the visit schedule, completion of study diaries, and any other 
parameters the investigator considers necessary. 
Participants considered to be poorly compliant with their medication and/or the study procedures 
will receive additional training and instruction, as required, and will be reminded of the 
importance of complying with the protocol. 
6.5. 
Concomitant Therapy 
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications that may interfere with the assessment of efficacy and safety of the 
study treatments. The table below provides a summary of criteria for use of concomitant 
medications that may interfere with planned assessments during the study. 
 
 Criteria for Use of Concomitant Medications that May Interfere with Efficacy and Safety 
Assessments in Study GZBD 
Abbreviations: DPP-4 = dipeptidyl peptidase-4; GLP-1 RA = glucagon-like peptide-1 receptor agonist; N = no; N/A 
= not applicable; SGLT2 = sodium-glucose co-transporter 2; Y = yes. 
a Acute therapy = treatment for up to 14 days. 
b Rescue therapy is glucose-lowering intervention added to manage severe persistent hyperglycemia, as defined in 
Section 8.3.2.2 
c See Section 5.2  
d From 1 month prior to Visit 1 or between Visits 1 and 3; does not apply to topical, intraocular, intranasal, 
intra-articular, or inhaled preparations.  
e Switching metformin manufacturers is allowed as long as the dosage is the same.  
f For rescue therapy, metformin dose can be increased if the dose is below maximum approved dose per country-
specific label. 
 
Drug Class 
Use during 
Screening/Lead-In 
Conditions for Use after Randomization 
Acute 
Therapy
a 
Rescue 
Therapyb  
During Safety 
Follow-Up Period 
Drugs with approved weight loss 
indicationc 
Excluded 
N 
N/A 
Y 
Systemic glucocorticoid therapyd 
Excluded except for 
acute therapya 
Y 
N/A 
Y 
Antihyperglycemia medications 
Other GLP-1 RAs 
Excluded 
N 
N 
N 
DPP-4 inhibitors 
Excluded 
N 
N 
N 
SGLT2 inhibitors 
Excluded 
N 
Y 
Y 
Insulins and insulin mixtures 
Excluded except for 
acute therapya  
Y 
Y 
Y 
Meglitinides 
Excluded 
N 
Y 
Y 
Alpha-glucosidase inhibitors 
Excluded 
N 
Y 
Y 
Sulphonylureas 
Excluded 
N 
Y 
Y 
Thiazolidinediones 
Excluded 
N 
Y 
Y 
Metformine 
Optional 
N/A 
Yf 
Y 
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Investigative site staff will inform participants that they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the study. This 
may not be possible when initiated for treatment of medical emergencies, in which case, the 
participant will inform the investigator or a designated site staff member as soon as possible. 
Any additional medication initiated during the course of the study (including OTC drugs, such as 
paracetamol or aspirin) must be documented, and the name of the drug and the date(s) of 
administration must be recorded on the “Concomitant Medications” section of the eCRF. 
6.5.1. 
Glucose-lowering Agents 
The only concomitant antihyperglycemic medication permitted at baseline is metformin. 
Metformin dose must be stable for at least 3 months prior to screening.  
 Participants who enter the study on diet and exercise alone will not be allowed to initiate 
metformin therapy after study entry, unless if rescue therapy is required (for more details 
see below). 
 Participants who are being treated with metformin upon entering this study should remain 
on the same metformin dose throughout the course of the study. A change in dose is 
allowed only after randomization when needed to protect the participant’s safety (see 
below for further details). If needed between screening and randomization, that 
participant will be discontinued from the trial.  
 If a participant switches from the immediate-release formulation of metformin to the 
sustained-release formulation, the change will be on a milligram per milligram basis. 
 
After randomization, discontinuation of metformin or change in dosage and formulation is  
permitted in the following situations: 
 
In the event of a hypoglycemic episode(s) (clinical symptoms of hypoglycemia and/or 
BG-confirmed symptomatic BG hypoglycemia: glucose concentration <3.0 mmol/L [<54 
mg/dL]: participants may reduce/discontinue the dose of metformin. 
In certain situations that require short-term discontinuation in line with the product(s) 
labeling for each respective country (for example, severe dehydration, elective surgery, or 
need for radiologic examination involving IV iodinated contrast dye). Once the situation 
that led to temporary discontinuation of the drug is resolved, treatment should be 
restarted at investigator’s discretion. 
If a participant develops contraindications to metformin such that the use of the drug is 
contraindicated according to the country-specific label. 
If a participant meets the criteria for severe, persistent hyperglycemia or discontinues 
study drugs, then metformin may be added (for participants managed by diet/exercise 
alone) or the metformin dose may be increased according to country-specific label as 
long as that is not the sole intervention (see Section 8.3.2.2). 
 
A participant will be considered noncompliant with the protocol (protocol deviation) if he or she 
changes the dose or discontinues metformin for reasons other than those described here. Dose 
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reduction or discontinuation of metformin during the trial should be properly documented and 
recorded on the appropriate eCRF. 
 
Glucose-lowering medications other than study drugs and metformin are not allowed at any time 
during the study except for those participants who require permanent discontinuation of study 
drugs, but remain in the study, rescue therapy after randomization due to severe, persistent 
hyperglycemia (criteria provided in Section 8.3.2.2), or during the safety follow-up period as 
indicated in the table above (Section 6.5). Short-term insulin use for up to 14 days is allowed for 
certain clinical situations (for example, elective surgery, during hospitalization, and 
hyperosmolar states) and must be differentiated from insulin use as rescue therapy when reported 
in the eCRF. 
All nonstudy medications will be recorded in the eCRF at all visits. 
Nonstudy medications taken by participants who are screened but not randomly assigned to 
treatment will not be reported to Lilly unless an SAE or AE occurs that the investigator believes 
may have been caused by a study procedure. 
6.5.2. 
Other Concomitant Medications 
Treatment with medications that are excluded per entry criteria (Section 5.2, Exclusion Criteria) 
is not permitted during the trial. 
Doses of prescription medications for treatment of concurrent medical conditions should remain 
constant during the study unless an adjustment is medically indicated. When needed, the sponsor 
should be contacted to clarify if an individual medication is allowed in the study. If an additional 
concomitant medication is already started, the sponsor should be informed as soon as possible. 
Doses of antihypertensive and lipid-lowering therapies should not be changed and remain 
constant during the study unless an adjustment is medically indicated. For example, doses of 
antihypertensive medication may be reduced if the participant’s blood pressure declines 
significantly during the study resulting in symptoms of lightheadedness or may be increased 
during a hypertensive crisis. 
Nonsteroidal anti-inflammatory medications (including ibuprofen and aspirin), acetaminophen, 
cough suppressants, antihistamines, vitamin/mineral supplements, 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. Any additional medication used during the 
course of the study (including those not requiring sponsor notifications) must be documented on 
the appropriate eCRF. Specifically excluded concomitant medications are listed in Section 5.2. 
6.5.3. 
Management of Participants with Gastrointestinal Symptoms 
Consistent with other incretins, in Phase 1 studies, the most reported TEAEs for participants 
receiving LY3437943 or dulaglutide 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. 
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 If GI AEs occur, 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 drugs. The data related to temporary interruption of study 
treatment should be documented in source documents and entered on the eCRF (see 
Section 6.6.1). 
 After the symptoms have resolved, restart dosing as per the guidance provided in Section 
6.6. 
If intolerable GI symptoms or events persist despite the above measures, see Section 6.6.1 
6.6. 
Dose Modification 
Study drug administration should follow the schedule provided in Section 1.3 (SoA) and Section 
4.1.1 (Overview of Study Periods). Dose modification is not allowed, except for 
 temporary dose interruption to address tolerability or other clinically important safety 
issues, or 
 dose reductions, without dosing interruptions, when appropriate to ensure participant 
safety. 
Any changes in dosing will be documented in the participant diaries and eCRF. Dose reductions 
may occur at unscheduled visits. 
6.6.1. 
Temporary Interruption of Study Drug 
In certain situations, participants may need to temporarily interrupt study drug, for example due 
to 
 occurrence of intolerable GI AEs, and 
 other AEs deemed by the investigator severe enough to warrant dosing interruption. 
If the reason for temporary dosing interruption is related to poor participant tolerability, for 
example when protracted GI events of vomiting and/or diarrhea trigger a request from the 
participant and/or from the investigator for temporary discontinuation of dosing, 1 weekly dose 
of study drug can be omitted. A longer interruption must be approved by Lilly study physician 
upon review of the case with the primary investigator or designee. In other situations when 
participant safety is compromised, for example due to an SAE, more than 1 dose may need to be 
skipped. The decision to interrupt dosing in any of these situations will not be considered a 
protocol deviation. If the participant interrupts dosing for other reasons, that are not related to the 
tolerability or safety of the participant, dosing interruption will be considered a protocol 
deviation. Every effort should be made by the investigator to restart dosing as soon as it is safe to 
do so. A participant may experience multiple events that require dosing interruption; each event 
should be addressed individually per guidance provided in this section. Any other situation of 
study drug interruption that is not described in this section will be discussed between the primary 
investigator or designee and Lilly study physician to decide on an appropriate dosing plan for 
any participant with such events. 
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The following table provides detailed guidance on additional procedures to follow temporary 
interruption of study drugs in a blinded fashion.  
Reason for 
Interruptions 
Number of 
Doses Missed 
Actions at Dosing Re-Initiation 
Tolerability TEAEs 
related to study drug  
 
1 dose 
Dosing will be restarted with the same dose 
that was last administered prior to 
interruption for 1 week and will then follow 
the planned dosing schedule. 
 If the rechallenge with LY3437943 is 
not tolerated, the dose will be reduced 
to the previously tolerated dose and 
the participant will be kept on that 
dose until the end of the treatment 
period.  
If the starting LY3437943 dose of 0.5 mg or 
2 mg or maintenance dose of 4 mg or 
dulaglutide 1.5 mg dose is not tolerated on 
rechallenge, the participant will discontinue 
study drug.  
If the starting LY3437943 dose of 4 mg is not 
tolerated upon rechallenge, the participant 
will be switched to the 2 mg starting dose, per 
the alternate dose escalation scheme. 
 
 
 
2 or more 
consecutive 
doses 
For participants on LY3437943, dosing will 
be restarted on the previously tolerated, lower 
dose (that is, one dose level lower for that 
treatment arm than the dose that was not 
tolerated) for 2 weeks and then resume 
dosing per the planned dosing schedule. 
Participants in the dulaglutide group will be 
restarted on 1.5 mg dose. 
If the rechallenge with LY3437943 is not 
tolerated for a second time, the dose will be 
reduced to the previously tolerated dose and 
the participant will be kept on that dose until 
the end of the treatment period.  
If the starting LY3437943 dose of 0.5 mg or 
2 mg, or maintenance dose of 4 mg or 
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Reason for 
Interruptions 
Number of 
Doses Missed 
Actions at Dosing Re-Initiation 
dulaglutide 1.5 mg is not tolerated upon 
rechallenge, the participant will discontinue 
study drug.  
If the starting LY3437943 dose of 4 mg is not 
tolerated upon rechallenge, the participant 
should be switched to the 2 mg starting dose, 
per the alternate dose escalation scheme. 
Other TEAEs or 
reasons not related to 
TEAEs (that is, due to a 
protocol deviation) 
1 dose 
Dosing will be restarted with the same dose 
that was last administered prior to 
interruption for 1 week and then follow the 
planned dosing schedule. 
 
2 or more 
consecutive 
doses 
For participants on LY3437943, dosing will 
be restarted at one dose lower (for that 
treatment arm) than the last dose 
administered prior to interruption; continue 
this dose for 2 weeks and then resume the 
planned dosing schedule. If the dose prior to 
interruption is the lowest dose level, restart 
dosing on that dose. Participants in the 
dulaglutide group will be restarted on 1.5 mg 
dose. 
Investigators should inform the sponsor that study drug has been temporarily interrupted. The 
data related to temporary interruption of study treatment will be documented in source 
documents and entered on the eCRF.  
6.6.2. 
Dose Reductions Indicated to Ensure Participant Safety 
In addition to the dose modifications described in Section 6.6, there may be situations when dose 
interruptions occur, where only dose reduction (without interrupting dosing) would be 
appropriate (for example, clinically significant changes in vital signs accompanied by AEs or 
similar events when it is reasonable to assume causal relationship with active treatments 
[LY3437943, dulaglutide] in the trial).  
If a participant is experiencing any such safety issue, dose reduction to the next lower 
maintenance dose level or discontinuation of study drug, if the participant is already on the 
lowest dose level, should be considered. The decision to lower the dose or discontinue study 
drug in such situation should be approved by Lilly CRP. 
All dosing modifications described in this section and in Section 6.6 will be conducted in a 
blinded fashion, by modifying administration of both LY3437943 and dulaglutide as appropriate. 
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Participants will be blinded during dose modification. LY3437943 dose modification should 
occur together with temporary interruption of the dulaglutide SDP as described in Section 6.6.1.  
6.7. 
Intervention after the End of the Study 
LY3437943 will not be made available to participants after conclusion of the study. 
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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 interventions. If study interventions are definitively discontinued, the 
participant will remain in the study to be evaluated for all planned efficacy and safety measures. 
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
interventions and follow-up and for any further evaluations that need to be completed. The 
participants will receive additional glucose-lowering agents if needed based on the investigator’s 
judgment (see Section 6.5.1. for detailed guidance). 
Possible reasons leading to permanent discontinuation of study drug: 
participant decision 
the participant requests to discontinue study drug 
clinical considerations 
BMI ≤ 19 kg/m2 
initiation of prohibited concomitant medications (see Section 6.5) if participants will not or 
cannot discontinue them 
intolerable GI symptoms despite management as described in Section 6.5.3 
Note: The investigator should contact the Lilly CRP/Clinical research scientist 
(CRS) to discuss whether it is medically appropriate for the participant to 
continue study treatment.  
diagnosis of T1DM 
diagnosis of MTC or MEN2 after randomization 
significant elevation of calcitonin (serum calcitonin value ≥20 ng/L and <35 ng/L and ≥50% 
increase from the screening value; or serum calcitonin value ≥35 ng/L and ≥50% over the 
screening value) or diagnosis of C-cell hyperplasia 
diagnosis of acute or chronic pancreatitis  
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 
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 
onset of pregnancy in a female participant  
occurrence of any other TEAE, SAE, or clinically significant finding for which the investigator 
believes that permanent study drug discontinuation is the appropriate measure to be taken 
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 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 one of the following 
conditions after consultation with the Lilly-designated medical monitor: 
 ALT or aspartate aminotransferase (AST) >8X ULN 
 ALT >2X baseline value (for participants with elevated 
ALT levels at baseline) OR ≥300 U/N, whichever occurs 
first, if baseline ALT ≥2X ULN 
 ALT or AST >5X ULN for more than 2 weeks 
 ALT or AST >3X ULN and total bilirubin level (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%) 
 alkaline phosphatase (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%). 
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 
 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. 
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At the time of discontinuing from the study, if possible, an ED visit should be conducted. See 
SoA (Section 1.3) 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.  
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1 
Appendix 1. 
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8. 
Study Assessments and Procedures 
 Study procedures and their timing are summarized in the SoA.  
 Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue 
or discontinue study 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 change from baseline in HbA1c, as determined by the central 
laboratory.  
Secondary: 
The following secondary efficacy measures will be collected at the times shown in the SoA. 
 HbA1c as determined by the central laboratory 
 Fasting blood glucose (FBG) as determined by the central laboratory, and 
 Body weight (see Section 10.9 for measurement procedure). 
Exploratory: 
 Seven-point SMBG (see Section 10.9)  
Lipid profile, consisting of total cholesterol, low-density lipoprotein (LDL)-cholesterol, 
very low-density lipoprotein (VLDL)-cholesterol, high-density lipoprotein (HDL)-
cholesterol, and triglycerides 
Mechanistic biomarkers: to explore potential mechanism of action modifying glucose, 
lipid, or nutrient metabolism, markers will be assessed (see Section 10.11 for detailed list 
of biomarkers) related to 
insulin sensitivity 
pancreatic beta or alpha cell function  
glucagon receptor target engagement  
fatty acid oxidation 
lipolysis 
purine metabolism, and 
cardiovascular risk. 
Patient-reported outcomes (see Section 10.10)  
Short Form-36 version 2 Health Survey acute form, 1-week recall version 
Eating Inventory, and 
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Appetite Visual Analog Scale. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. 
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 10.9.  
A complete physical examination will include, at a minimum, assessments of 
skin, including feet 
cardiovascular (CV) 
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 SoA, and 
following the study-specific recommendations included in Section 10.9. 
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 single 12-lead ECG should be collected according to Section 1.3 (for 
details, please see Section 10.9. In addition, tracings collected at the baseline, 24 and 36 weeks 
will be assessed qualitatively by a blinded cardiologist. 
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. 
8.2.4. 
Clinical Safety Laboratory Assessments 
 
See Section 10.2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 
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The investigator must review the laboratory results, document this review, and 
report any clinically relevant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents unless a Source 
Document Agreement or comparable document cites an electronic location that 
accommodates the expected retention duration. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the 
participant’s condition. 
 All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 4 weeks after the last dose of study 
intervention should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or medical 
monitor. 
o If such values do not return to normal or baseline within a period of 
time judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified. 
o All protocol-required laboratory assessments, as defined in Appendix 
2, must be conducted in accordance with the SoA, standard collection 
requirements, and laboratory manual.  
 If laboratory values from non-protocol-specified laboratory assessments 
performed at an investigator-designated local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator (for example, SAE or AE or dose modification), then report the 
information as an AE.  
8.2.5. 
Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods. The study team will review safety reports in a blinded fashion (for applicable blinded 
study period) according to the schedule provided in the Trial-Level Safety Review plan. Lilly 
will also review SAEs within time frames mandated by company procedures. The Lilly CRP 
will, as appropriate, consult with the functionally independent Global Patient Safety (GPS) 
therapeutic area physician or clinical scientist. Safety monitoring will include review of hepatic, 
pancreatic, cardiovascular, thyroid c-cell function, and renal safety data. The hepatic safety 
monitoring plan is provided below; for additional information, please see also Section 8.3.2. 
8.2.5.1. 
Hepatic Safety Monitoring 
Close hepatic monitoring  
If any of the following abnormalities occurred, laboratory tests (Section 10.5), including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyltransferase, and creatine kinase, should be 
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repeated within 48 to 72 hours to confirm the abnormality and to determine if the values are 
increasing or decreasing:  
If a participant with baseline results 
of… 
develops the following elevations: 
ALT or AST <1.5X ULN  
ALT or AST ≥3X ULN 
ALP <1.5X ULN  
ALP ≥2X ULN  
TBL <1.5X ULN  
TBL ≥2X ULN (except for participants with 
Gilbert’s syndrome) 
ALT or AST ≥1.5X ULN 
ALT or AST ≥2X baseline  
ALP ≥1.5X ULN  
ALP ≥2X baseline  
TBL ≥1.5X ULN  
TBL ≥1.5X baseline (except for participants 
with Gilbert’s syndrome) 
If the abnormality persists or worsens, clinical and laboratory monitoring, and evaluation for 
possible causes of abnormal liver tests should be initiated by the investigator in consultation with 
the Lilly-designated medical monitor. At a minimum, this evaluation should include physical 
examination and a thorough medical history, including symptoms, recent illnesses (for example, 
heart failure, systemic infection, hypotension, or seizures), recent travel, history of concomitant 
medications (including OTC), herbal and dietary supplements, history of alcohol drinking, and 
other substance abuse.  
Initially, monitoring of symptoms and hepatic biochemical tests should be done at a frequency of 
1 to 3 times weekly, based on the participant’s clinical condition and hepatic biochemical tests. 
Subsequently, the frequency of monitoring may be reduced to once every 1 to 2 weeks, if the 
participant’s clinical condition and lab results stabilize. Monitoring of ALT, AST, ALP, and 
TBL should continue until levels normalize or return to approximate baseline levels. 
Comprehensive hepatic evaluation 
A comprehensive evaluation should be performed to search for possible causes of liver injury if 
1 or more of these conditions occur:  
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If a participant with baseline results of… 
develops the following elevations: 
ALT or AST <1.5X ULN  
ALT or AST ≥3X ULN with hepatic signs or 
symptoms*, or ALT or AST ≥5X ULN  
ALP <1.5X ULN  
ALP ≥3X ULN  
TBL <1.5X ULN  
TBL ≥2X ULN (except for participants with 
Gilbert’s syndrome)  
ALT or AST ≥1.5X ULN 
ALT or AST ≥2X baseline with hepatic signs or 
symptoms*, or ALT or AST ≥3X baseline  
ALP ≥1.5X ULN  
ALP ≥2X baseline  
TBL ≥1.5X ULN  
TBL ≥2X baseline (except for participants with 
Gilbert’s syndrome)  
* Hepatic signs or symptoms are severe fatigue, nausea, vomiting, jaundice, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%.  
At a minimum, this evaluation should include physical examination and a thorough medical 
history, as outlined above, as well as tests for prothrombin time (PT)-INR; tests for viral 
hepatitis A, B, C, or E; tests for autoimmune hepatitis; and an abdominal imaging study (for 
example, ultrasound or computed tomography [CT] scan).  
Based on the participant’s history and initial results, further testing should be considered in 
consultation with the Lilly-designated medical monitor, including tests for hepatitis D virus, 
cytomegalovirus, Epstein-Barr virus, acetaminophen levels, acetaminophen protein adducts, 
urine toxicology screen, Wilson’s disease, blood alcohol levels, urinary ethyl glucuronide, and 
blood phosphatidylethanol. Based on the circumstances and the investigator’s assessment of the 
participant’s clinical condition, the investigator should consider referring the participant for a 
hepatologist or gastroenterologist consultation, magnetic resonance cholangiopancreatography, 
endoscopic retrograde cholangiopancreatography, cardiac echocardiogram, or a liver biopsy. 
Additional hepatic data collection (hepatic safety CRF) in study participants who have 
abnormal liver tests during the study  
Additional hepatic safety data collection in hepatic safety 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  
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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.  
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints 
The definitions of the following events can be found in Section 10.3 Appendix 3.  
 AEs 
 SAEs, and 
 Product complaints (PCs). 
These events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet these definitions and remain responsible for following up events that 
are serious, considered related to the study intervention or study procedures, or that caused the 
participant to discontinue the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All SAEs, and AEs of special interest, will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up 
(as defined in Section 7.3). For PCs, the investigator is responsible for ensuring that follow-up 
includes any supplemental investigations as indicated to elucidate the nature and/or causality. 
Further information on follow-up procedures is provided in Appendix 10.3. 
8.3.1. 
Timing and Mechanism for Collecting Events 
The following table describes the timing, deadlines, and mechanism for collecting events. 
Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting to 
Sponsor or Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Adverse Event 
AE 
Signing of 
the ICF 
Participation 
in study has 
ended 
As soon as possible upon site 
awareness 
AE eCRF 
N/A 
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Event 
Collection 
Start 
Collection 
Stop 
Timing for Reporting to 
Sponsor or Designee 
Mechanism for 
Reporting 
Back-Up 
Method of 
Reporting 
Serious Adverse Event 
SAE and SAE 
updates – prior 
to start of study 
intervention 
and deemed 
reasonably 
possibly 
related with 
study 
procedures 
Signing of 
the ICF 
Start of 
intervention 
Within 24 hours of 
awareness 
SAE eCRF  
SAE paper 
form 
SAE* and SAE 
updates – after 
start of study 
intervention 
Start of 
intervention 
Participation 
in study has 
ended 
Within 24 hours of 
awareness 
SAE eCRF  
SAE paper 
form 
SAE* – after 
participant’s 
study 
participation 
has ended and 
the investigator 
becomes aware 
After 
participant’s 
study 
participation 
has ended 
N/A 
Promptly 
SAE paper form 
N/A 
Pregnancy 
Pregnancy in 
female 
participants 
and female 
partners of 
male 
participants 
After the 
start of study 
intervention 
35 days 
after the last 
dose  
Within 24 hours of learning 
of the pregnancy 
SAE eCRF  
SAE paper 
form 
PCs 
PC associated 
with an SAE or 
might have led 
to an SAE 
Start of 
study 
intervention 
End of 
study 
intervention 
Within 24 hours of 
awareness 
PC form 
N/A 
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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 not 
associated with 
an SAE 
Start of 
study 
intervention 
End of 
study 
intervention 
Within 1 business day of 
awareness 
PC form 
N/A 
Updated PC 
information 
— 
— 
As soon as possible upon site 
awareness 
Originally 
completed PC 
form with all 
changes signed 
and dated by the 
investigator 
N/A 
PC (if 
investigator 
becomes 
aware) 
Participation 
in study has 
ended 
N/A 
Promptly 
PC form 
 
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. 
8.3.2. Adverse Events of Special Interest  
The following are adverse events that will be adjudicated by an external adjudication committee: 
 pancreatitis (see Section 8.3.2.3) 
 major adverse cardiovascular events (see Section 8.3.2.5), and 
 deaths. 
The following are additional adverse events of special interest : 
 hypoglycemia (Level 2 and 3) 
 severe persistent hyperglycemia 
 thyroid malignancies and C-cell hyperplasia 
 CV safety 
 hypersensitivity events 
 injection site reactions 
 hepatobiliary disorders 
 severe GI AEs 
 antidrug antibodies, and 
 acute renal events. 
Sites should collect additional details and data regarding these adverse events, as instructed on 
the applicable eCRFs, and detailed below. 
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8.3.2.1. 
Hypoglycemia  
Upon ICF signing, all participants will be educated about signs and symptoms of hypoglycemia, 
how to treat hypoglycemia, and how to collect appropriate information for each episode of 
hypoglycemia. 
Participants who develop persistent or recurrent unexplained hypoglycemia during the treatment 
period will be asked to reduce the dose or discontinue any concomitant glucose-lowering agents 
other than study drug. Study drug discontinuation for recurrent hypoglycemia should be 
considered only if these events continue despite complete discontinuation of concomitant 
medications. 
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) as below. Level 2 and 
Level 3 hypoglycemia events are considered as safety topics 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. 
Level 2 hypoglycemia:  
Glucose <54 mg/dL (3.0 mmol/L): This is also referred to as documented or blood glucose 
confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose threshold is 
clinically relevant regardless of the presence 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. 
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 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep. 
8.3.2.2. 
Severe Persistent Hyperglycemia 
An additional glucose-lowering intervention should be considered by the investigator for 
participants with any persistent severe hyperglycemia, defined as meeting any of the following 
criteria during the treatment period:  
During the first 8 weeks postrandomization (between Visits 3 and 7): An average fasting blood 
glucose (FBG) above 255 mg/dL (14.1 mmol/L) over at least a 2-week period (at least 4 
values/week must be available) 
OR 
Between Weeks 8 and 16 (between Visits 7 and 9): An average FBG above 240 mg/dL (13.3 
mmol/L) over at least a 2-week period (at least 4 values/week must be available) 
OR 
Between Weeks 16 and 24 (between Visits 9 and 11): An average FBG above 200 mg/dL (11.1 
mmol/L) over at least a 2-week period (at least 4 values/week must be available 
OR 
Beginning at Week 24 (Visits 11 through 13): HbA1c above 8.0% (64.0 mmol/mol) which is not 
at least 0.3% lower than the HbA1c at the previous scheduled measurement. 
In considering whether initiation of rescue therapy is warranted, investigators should first 
confirm that the participant is fully compliant with the assigned therapeutic regimen and that he 
or she does not have an acute condition causing severe hyperglycemia. If these other reasons are 
excluded, the investigator will initiate an appropriate glucose-lowering intervention (rescue 
intervention) according to the guidance outlined in Section 6.5, and it will be recorded on the 
eCRF specified for collecting antihyperglycemic medications. Other GLP-1 RAs or DPP-4 
inhibitors must not be used as the rescue intervention. Participants who receive rescue 
intervention for hyperglycemia management should also continue administering study drug for 
the remaining period in the trial. 
8.3.2.3. 
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; 
Kouzumi 2006):  
 abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating to the 
back, often associated with nausea and vomiting) 
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 serum amylase (total, pancreatic, or both) and/or lipase ≥3X ULN, and 
 characteristic findings of acute pancreatitis on CT scan or magnetic resonance imaging 
(MRI). 
If acute pancreatitis is suspected, the investigator should 
 obtain appropriate laboratory tests, including pancreatic amylase and lipase 
 perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal MRI, and 
 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone or 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 IP. In this case, the participant needs to receive an appropriate alternative glucose 
lowering regimen. Afterwards, if pancreatitis is confirmed by the adjudication committee, the IP 
must be permanently discontinued and the participant needs to be followed throughout the 
duration of the study. If the case is not confirmed, then the participant can restart the IP if the 
investigator deems as clinically appropriate as described in Section 6.6 (Dose Modification). 
Case adjudication and data entry 
An independent clinical endpoint committee (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 pancreatic amylase ≥3X ULN) is not mandated but may be performed 
based on the investigator’s clinical judgment and assessment of the participant’s overall clinical 
condition.  
8.3.2.4. 
Thyroid Malignancies and C-Cell Hyperplasia  
Individuals with personal or family history of MTC and/or MEN2 will be excluded from the 
study. Participants who are diagnosed with MTC and/or MEN2 during the study will have study 
drug stopped and should continue follow-up with an endocrinologist. Additionally, participants 
who have a serum calcitonin level 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, will also be 
excluded. 
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
neoplasms (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. 
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If an increased calcitonin value (see definitions below) is observed in a participant who has been 
administered a medication that is known to increase serum calcitonin, then this medication 
should be stopped, and calcitonin levels should be measured after an appropriate washout period. 
For participants who require additional endocrine assessment because of increased calcitonin 
concentration as defined in this section, data from the follow-up assessment will be collected in 
the specific section of the eCRF. 
Calcitonin Measurements in Participants with eGFR ≥60 mL/min/1.73 m2  
A significant increase in calcitonin for participants with eGFR ≥60 mL/min/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 requested to repeat the measurement within 1 month. If 
this repeat value is increasing (≥10% increase), the study drug should be discontinued, 
and the participant should undergo additional endocrine assessment and longer term 
follow-up by an endocrinologist to exclude adverse effects on the thyroid gland. 
 Serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. In these 
participants, study drug should be discontinued, and the participant should be 
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, if the increased concentration of calcitonin is confirmed, the participant 
must be recommended to immediately undergo additional endocrine assessments and longer-
term follow-up by an endocrinologist to exclude adverse effects on the thyroid gland.  
8.3.2.5. 
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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8.3.2.6. 
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 10.3 must be reported as SAEs.  
8.3.2.7. 
Deaths 
All deaths will be adjudicated by a committee of physicians external to Lilly. This committee 
will be blinded to treatment assignment. 
8.3.2.8. 
Hypersensitivity Reactions  
Many drugs, 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 10.2. Laboratory results are provided to the sponsor via the 
central laboratory. 
8.3.2.9. 
Injection Site Reactions 
Symptoms of a local injection site reaction (ISR) 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 occurrence of severe or serious 
ISRs, samples will be collected for measurement of LY3437943 antidrug antibodies (ADAs) and 
LY3437943 concentration. 
8.3.2.10. Hepatobiliary Disorders 
All events of 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 markers, hepatic monitoring should be initiated as outlined in Section 8.2.5.1. 
8.3.2.11. Severe Gastrointestinal Adverse Events  
LY3437943 and dulaglutide may cause severe GI AEs, such as nausea, vomiting, and diarrhea. 
Information about severe GI AEs as well as antiemetic or antidiarrheal use will be collected in 
the AE and concomitant medications eCRFs, respectively. For detailed information concerning 
the management of GI AEs, please refer to Section 6.5.3. 
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 
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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). The 
events may lead to dehydration, which could cause a deterioration in renal function, including 
acute renal failure. Participants should be advised to notify investigators in case of severe nausea, 
frequent vomiting, or symptoms of dehydration. 
8.4. 
Treatment of Overdose 
For this study, any total dose of study intervention within a 48-hour time period greater than the 
dose assigned by IWRS for that participant will be considered an overdose and should be 
reported as per criteria described in Section 10.3. 
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 
intervention can no longer be detected systemically (at least 30 days). Refer to Section 
8.3 for reporting details. 
3. Obtain a plasma sample for PK analysis within 5 days from the date of the last dose of 
study intervention 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 Lilly CRP based on the clinical evaluation of the participant.  
In the event of overdose, refer to the IB for the study drug and/or product label for Trulicity 
(dulaglutide), as applicable. 
8.5. 
Pharmacokinetics 
Blood samples for PK analyses will be collected from all randomized participants in accordance 
with schedule provided in Section 1.3 and at ED. Efforts should be taken to align clinical visits 
with PK sampling windows specified in the Pharmacokinetic Schedule of Events table (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.  
Instructions for the collection and handling of blood samples will be provided by the sponsor.  
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 or dulaglutide are not planned. Bioanalytical samples 
collected to measure IP concentrations will be retained for a maximum of 1 year following the 
last participant visit for the study. During this time, samples remaining after the bioanalyses may 
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be used for exploratory analyses such as additional metabolism, protein binding, or exploratory 
analyses including bioanalytical assay validation or cross-validation exercises. 
8.6. 
Pharmacodynamics 
Pharmacodynamic assessments for LY3437943 are included as part of the efficacy and safety 
measures listed in Section 8.1 and will be collected according to the SoA (Section 1.3). 
8.7. 
Genetics  
A blood sample will be collected to enable exploratory pharmacogenetic analyses as specified in 
the SoA (Section 1.3), where local regulations allow. 
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 diabetes mellitus and 
related clinical traits or complications, including nonalcoholic steatohepatitis or obesity. 
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 (ERB) 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 
In addition to the planned biomarker research as indicated in the SoA and Section 10.11, 
biomarker research on stored nonpharmacogenetic samples may be performed to address 
questions of relevance to drug disposition, target engagement, pharmacodynamics, mechanism of 
action, variability of participant response (including safety), and clinical outcome. Sample 
collection is incorporated into clinical studies to enable examination of these questions through 
measurement of biomolecules, including DNA, RNA, proteins, lipids, and other cellular 
elements.  
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. 
 
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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 at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ERBs 
impose shorter time limits. This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in the development of LY3437943 or after LY3437943 becomes commercially available. 
8.9. 
Immunogenicity Assessments 
At the visits and times specified in the SoA (Section 1.3), 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 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 9.4.6. If the immunogenicity sample at the last 
scheduled assessment or discontinuation visit is TE-ADA positive, additional samples may be 
taken until the signal returns to baseline (in other words, no longer indicates TE-ADA) or for 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 Ethical Review Boards 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 0.5, 4, 8, or 12 mg 
administered SC QW is superior to placebo with regards to change in HbA1c from baseline to 
Week 24, in participants with T2D inadequately controlled with diet and exercise with or without 
a stable dose of metformin  
Secondary hypotheses are that at least one of LY3437943 doses is superior to placebo and 
dulaglutide 1.5 mg with regards to 
 change in HbA1c from baseline to 24 and 36 weeks except comparison with placebo at 
24 weeks (primary objective) 
 percentage of participants reaching HbA1c of <7.0% at 24 and/or 36 weeks 
 change in FBG from baseline to 24 and 36 weeks, and 
 change in body weight (kg) from baseline to 24 and 36 weeks. 
9.2. Sample Size Determination 
Approximately 300 participants will be randomized in a 2:2:2:1:1:1:1:2 ratio to either placebo, 
dulaglutide 1.5 mg, LY3437943 0.5 mg, LY3437943 4 mg (with starting dose at 2 mg), 
LY3437943 4 mg (with starting dose at 4 mg), LY3437943 8 mg (with starting dose at 2 mg), 
LY3437943 8 mg (with starting dose at 4 mg), or LY3437943 12 mg (with starting dose at 2 
mg). Assuming a 20% dropout rate, this results in approximately 40 completers per arm. Sample 
size selection is guided by the objective of establishing superiority of each LY3437943 
maintenance dose to placebo relative to the change in HbA1c from baseline to 24 weeks. The 
evaluation of superiority to placebo will be conducted for each of the 4 LY3437943 maintenance 
doses at 2-sided significance level of 0.05 using 2-sample t-test. The LY3437943 group mean 
reduction in HbA1c at Week 24 from baseline compared to placebo is assumed to be -2.1% 
assuming a common standard deviation (SD) of 1.1%. The chosen sample size provides at least 
99% power to establish superiority of LY3437943 0.5 mg, LY3437943 4 mg, LY3437943 8 mg, 
or LY3437943 12 mg compared to placebo. No adjustment for multiplicity will be performed. 
9.3. 
Populations for Analyses 
The following populations are defined for the purpose of analysis: 
Population 
Description 
Screened 
All participants who have signed informed consent. 
Randomized 
All participants who are randomly assigned to a treatment arm. 
Efficacy analysis set (EAS) 
All randomized participants who take at least 1 dose of double-blinded study 
treatment from randomization. Excludes data after discontinuation of study 
drug or initiation of rescue medication. Participants will be included in the 
treatment group to which they were randomized. 
Full analysis set (FAS) 
All randomized participants who take at least 1 dose of double-blinded study 
treatment, regardless of adherence to study drug or initiation of rescue 
medication. Participants will be included in the treatment group to which they 
were randomized.  
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9.4. 
Statistical Analyses 
9.4.1. General Considerations 
Statistical analyses of this study will be the responsibility of Lilly or its designee. 
Any change to the data analyses methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to data analyses 
methods described in the protocol, and the justification for making the change, will be described 
in the statistical analysis plan (SAP) or the clinical study report (CSR). Additional exploratory 
analyses of the data will be conducted as deemed appropriate. 
Unless otherwise noted, all tests of treatment effects will be conducted at a 2-sided alpha level of 
0.05, and the confidence interval (CI) will be calculated at 95%, 2-sided. In statistical summaries 
and analyses, participants will be analyzed as randomized. 
The baseline value used for the analyses will be the last scheduled baseline value obtained for 
each participant prior to randomization.  
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 without confounding effects of antihyperglycemic rescue therapy. The primary 
efficacy assessment, guided by the “efficacy estimand,” will be conducted using the EAS. The 
“treatment-regimen estimand,” using the FAS, which represents the efficacy irrespective of 
adherence to study drug or initiation of rescue antidiabetic drug, and the “principle-stratification 
estimand” that shows efficacy for those who would comply with the study treatment LY3437943 
(as defined in Section 9.4.2.4) will be estimated in the exploratory analyses. 
The summary statistics for continuous measures will include sample size, mean, SD, median, 
minimum, and maximum, and for categorical measures will include sample size, frequency, and 
percentage. 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) with terms:  
treatment 
visit  
treatment-by-visit interaction  
baseline HbA1c category [<8.5% or 8.5%]  
baseline BMI category [<30 or 30], and  
baseline measurement as a covariate. 
Summary statistics for categorical measures (including categorized continuous measures) will 
include sample size, frequency, and percentages. Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes. Logistic regression may be used to examine the 
treatment difference in binary efficacy outcomes. The negative binomial regression model will 
be used for the treatment comparison of discrete count measures if deemed appropriate.  
Other statistical methods may be used, as appropriate, and details will be documented in the 
SAP. 
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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. 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. A 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, medical history, and concomitant illness will be summarized by treatment group 
using the full FAS.  
9.4.2.3. 
Concomitant Therapy  
Concomitant medications, including previous therapy for diabetes, will be summarized by drug 
class and treatment group using the FAS. In particular, the incidence of rescue therapy for 
severe, persistent hyperglycemia will be analyzed as an exploratory safety endpoint.  
9.4.2.4. 
Treatment Compliance 
Treatment compliance for each 4- to 6-week interval is defined as taking at least 75% of the 
required SC doses of study drug. Frequency counts and percentages of participants compliant to 
study drug will be summarized by treatment arm using the FAS.  
9.4.3. 
Efficacy Analyses 
9.4.3.1. 
Primary Analyses 
The primary efficacy analyses will be conducted to establish superiority of LY3437943 0.5 mg, 
LY3437943 4 mg, LY3437943 8 mg, or LY3437943 12 mg to placebo with regards to change in 
HbA1c from baseline to 24 weeks. The primary analyses will be performed on EAS using 
MMRM with treatment, visit, and treatment-by-visit interaction as fixed effects, baseline HbA1c 
and stratification factors as covariates, and participant as a random effect. An unstructured 
variance-covariance matrix will be used to model the within-participant effects. Additional 
covariates may be added, and this MMRM analysis will be detailed in the SAP.  
9.4.3.2. 
Secondary Analyses 
In addition to the primary efficacy analysis of change in HbA1c in study population, the 
following secondary study objectives will be analyzed on the EAS: 
 change in HbA1c from baseline to 24 and 36 weeks 
 percentage of participants reaching HbA1c of <7.0% at 24 and/or 36 weeks 
 change in FBG from baseline to 24 and 36 weeks, and 
 change in body weight (kg) from baseline to 24 and 36 weeks. 
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Continuous endpoints, including change in HbA1c from baseline to 24 and 36 weeks, change in 
FBG from baseline to 24 and 36 weeks, change in body weight (kg) from baseline to 24 and 36 
weeks, will be conducted in a manner similar to the primary efficacy analyses discussed in 
Section 9.4.3.1. The details will be provided in SAP. 
9.4.3.3. 
Tertiary/Exploratory Analyses 
A Bayesian approach will be used as the dose–response model for change in HbA1c and body 
weight from baseline to the 24-week endpoint. The placebo group will be modeled with 
LY3437943 doses. Details of the prior distribution specifications along with other analyses with 
regards to the exploratory objectives will be provided in the SAP. 
9.4.4. 
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 or initiation of rescue 
therapy. Thus, safety analyses will be conducted using the FAS. Selected safety analyses may be 
conducted after excluding data on rescue therapy or data after starting another antihyperglycemic 
medication.  
Adverse events will be coded from the actual term using the Medical Dictionary for Regulatory 
Activities (MedDRA) and reported with preferred terms and system organ class. Selected notable 
AEs of interest may be reported using high-level terms or Standardized MedDRA Queries. 
Summary statistics will be provided for incidence of TEAEs, SAEs, study discontinuation due to 
AEs, study 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 
Fisher’s exact test will be used to compare the treatment groups. 
9.4.4.1. 
Hypoglycemia Events 
Hypoglycemic events will be analyzed. Incidence and rate of hypoglycemia will be reported. 
Some analyses may be conducted excluding data after introducing another antihyperglycemic 
therapy. 
9.4.4.2. 
Gastrointestinal Events 
Summaries and analyses for incidence and severity of nausea, vomiting, and diarrhea will be 
provided by each treatment. 
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 at each scheduled visit. The analysis 
model to make comparisons among treatment groups relative to continuous change from baseline 
values assessed over time will be an MMRM similar to the primary efficacy analysis and with 
baseline measurement as a covariate. An unstructured covariance structure will model 
relationship of within-participant errors.  
The percentages of participants with treatment-emergent (TE) abnormal, high, or low measures 
(including laboratory, vital, and ECG parameters) will be summarized and compared between 
treatment groups using Fisher’s exact test.  
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The analysis details will be provided in the SAP. 
9.4.5. 
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 antidrug 
antibody 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. 
9.4.6. 
Evaluation of Immunogenicity  
The frequency and percentage of participants with preexisting ADA and with treatment-
emergent ADA+ to LY3437943 may be tabulated. Treatment-emergent ADAs 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 GIP, GLP-1, and glucagon 
or neutralizing antibodies against native GIP, GLP-1, 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. 
9.4.7. 
Subgroup Analyses  
Subgroup analyses of important factors, including baseline BMI, baseline HbA1c, and other 
factors to be specified in the SAP, are planned for the key outcomes. The models used for these 
analyses will vary depending on the subgroups and the outcome. More details of the modeling 
will be provided in the SAP. Other exploratory subgroup analyses may be performed as deemed 
appropriate. 
9.5. 
Interim Analyses  
An interim efficacy and safety assessment after all participants complete Visit 9 (Week 16) of 
the treatment period will be conducted to provide initial guidance for the design of future clinical 
studies of LY3437943. An internal AC will be formed to review the interim analyses for the 
safety and efficacy reports in an unblinded manner. Additional interim analyses may be 
conducted to monitor safety of study participants. Details on the timing of the interim analyses, 
operational support, and unblinding will be specified in the AC charter and in the study 
unblinding plan. 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 
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unblinded until final data base lock. Study sites will receive information about interim results 
only if deemed necessary for the safety of the participants. The trial will not be stopped based on 
the superiority of LY3437943 versus placebo and dulaglutide 1.5 mg. Therefore, there will be no 
inflation of the type 1 error rate, and no need to employ an alpha spending function or 
multiplicity adjustment. 
The primary database lock and primary data analysis for Study GZBD will occur when all 
participants have completed 24 weeks of treatment. The final analyses for this study will be 
performed after all randomized participants have completed 36 weeks of treatment and the 4-
week follow-up period. Participants and investigators will remain blinded until the completion of 
the study.  
The cancellation or addition of an interim analysis can be determined at any time during the 
study and will not require 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 ICH Good Clinical Practice (GCP) Guidelines, and 
○ applicable laws and regulations. 
● The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (for example, advertisements) must be submitted to an 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) by the 
investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 
● Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 
 Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants.  
● The investigator will be responsible for the following: 
○ providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/IEC 
○ notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures, and 
○ providing oversight of study conduct for participants under their responsibility 
and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
● Investigator sites are compensated for participation in the study as detailed in the 
Clinical Trial Agreement (CTA). 
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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. 
● 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. 
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. Sections 8.3.2.3 and 8.3.2.5 outline additional information on pancreatic 
and cardiovascular adjudication committees, respectively. 
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An internal AC will be formed compromising individuals with expertise needed for the 
evaluation and interpretation of the results from the interim analyses. The AC for this study is 
comprised of 3 members: one clinical physician, one GPS physician, and one statistician, 
including a designated chairperson. The AC will include members from Lilly only.  
The primary responsibility of the AC is to review the efficacy and safety reports after all 
participants reach 16 weeks of treatment in an unblinded manner. The details regarding number 
of participants and analysis plan will be provided in the AC charter (see Section 9.5).  
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.  
All CSRs, amendments, and addenda will be submitted to external regulatory authorities, 
external partners (as applicable), and sites.  
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. 
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● Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for the time period outlined in the 
Clinical Trial Agreement (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. 
Data Capture System 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system (EDC) 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 PC 
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. 
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● 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. 
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. 
 
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. 
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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. 
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 
Physicians with experience in Phase II or Phase III diabetes clinical trials will participate as 
investigators in this clinical trial.  
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
● The tests detailed below will be performed by the central laboratory. 
● Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time. In circumstances where the 
sponsor approves local laboratory testing in lieu of central laboratory testing (in 
the table below), the local laboratory must be qualified in accordance with 
applicable local regulations. 
● Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol. 
● Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
● Pregnancy testing (please refer to Section 5.1 (Inclusion Criteria) for screening 
pregnancy criteria). 
Investigators must document their review of the laboratory safety results.  
Laboratory results that could unblind the study will not be reported to investigative sites or other 
blinded personnel and are denoted in the table below.  
 
Clinical Laboratory Tests  
Comments  
Hematology 
Assayed by Lilly-designated laboratory 
Hemoglobin 
Hematocrit 
Erythrocyte count (RBCs - red blood cells) 
Mean cell volume  
Mean cell hemoglobin 
Mean cell hemoglobin concentration  
Leukocytes (WBCs - white blood cells)  
Differential 
   Neutrophils, segmented 
   Lymphocytes 
   Monocytes 
   Eosinophils 
   Basophils 
Platelets 
Cell morphology (RBCs and WBCs) 
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Clinical Chemistry 
Assayed by Lilly-designated laboratory 
Sodium 
Potassium 
Chloride 
Bicarbonate 
 
Total bilirubin 
Direct bilirubin 
 
Alkaline phosphatase (ALP) 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Gamma-glutamyl transferase (GGT) 
Blood urea nitrogen (BUN) 
Creatinine  
Creatine kinase (CK) 
Total protein 
Albumin 
Calcium 
Phosphorus 
Glucose 
Lipid Panel  
Assayed by Lilly-designated laboratory 
High-density lipoprotein cholesterol (HDL-C) 
 
Low-density lipoprotein cholesterol (LDL-C) 
Very low-density lipoprotein cholesterol 
(VLDL-C) 
Total cholesterol  
Triglycerides 
 
Urinalysis 
Assayed by Lilly-designated laboratory 
Specific gravity 
pH 
Protein 
Glucose 
Ketones 
Bilirubin 
Urobilinogen 
Blood 
Nitrite 
Urine leukocyte esterase 
Microscopic examination of sediment 
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Hormones (female) 
 
Serum pregnancy  
Assayed by Lilly-designated laboratory  
Urine pregnancy 
Evaluated locally  
Follicle stimulating hormone (FSH)  
Assayed by Lilly-designated laboratory  
Urine Chemistry 
Assayed by Lilly-designated laboratory 
Albumin 
Creatinine 
Calculations 
Generated by Lilly-designated 
laboratory 
eGFR (CKD-EPI)  
Urinary albumin/creatinine ratio (UACR) 
Pharmacokinetic Samples – LY3437943 
concentration 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
Biomarkers 
Assayed by Lilly-designated laboratory  
HbA1c 
Calcitonin 
Pancreatic amylase 
Lipase 
Insulin 
Glucagon 
 
C-peptide 
 
Intact proinsulin 
 
Longitudinal biomarkers 
Assayed by Lilly-designated laboratory. 
Results in this group of biomarkers (see 
Section 10.11), which are not defined in 
this table, will not be provided to the 
sites. 
Endpoint biomarkers 
Assayed by Lilly-designated laboratory. 
Results in this group of biomarkers (see 
Section 10.11), which are not defined in 
this table, will not be provided to the 
sites. 
Genetic sample 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
Exploratory samples  
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
Exploratory storage samples:  
   Serum 
   Plasma (EDTA) 
 
   P800  
 
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   Whole blood (EDTA)  
 
Immunogenicity Samples 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
   Anti-LY3437943 antibodies  
 
   Anti-LY3437943 antibodies neutralization 
Hypersensitivity Tests 
 Laboratory assessments 
should be performed if the 
participant experiences 
generalized urticaria or if 
anaphylaxis is suspected. 
 Collect sample after the participant 
has been stabilized, and within 1 to 2 
hours of the event; however, 
samples may be obtained as late as 
12 hours after the event as analytes 
can remain altered for an extended 
period of time. Record the time at 
which the sample was collected. 
 Obtain a follow-up sample at 
the next regularly scheduled 
visit or after 4 weeks, 
whichever is later. 
  Anti-LY antibodies (immunogenicity/ADA) 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
   LY3437943 concentrations (PK) 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
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   Drug-specific IgE 
Will be performed if a validated assay 
is available. 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
   Basophil activation test 
Will be performed if a validated assay 
is available. 
Assayed by Lilly-designated 
laboratory. Results will not be 
provided to the investigative sites. 
Note: The basophil activation test is an 
in vitro cell-based assay that only 
requires a serum sample. It is a surrogate 
assay for drug-specific IgE, but is not 
specific for IgE. 
   Complement (C3, C3a, and C5a) 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
   Cytokine panel (IL‐6, IL‐1β, and IL‐10) 
Assayed by Lilly-designated laboratory. 
Results will not be provided to the 
investigative sites. 
 
 
 
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10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-Up, and Reporting 
 The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization (ISO) 14155. 
 Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
 The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. 
10.3.1. 
Definition of AE 
AE Definition 
 An AE is any untoward medical occurrence in a participant administered a 
pharmaceutical product and which does not necessarily have a causal relationship with 
the study intervention. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 An AE that can be attributed to a medical device or device constituent deficiency is 
referred to as ADE (adverse device effect). It is any untoward medical occurrence, 
unintended disease or injury, or untoward clinical signs (including abnormal laboratory 
finding) in study participants, users, or other persons, whether or not related to the 
investigational medical device. This definition includes events related to the 
investigational medical device or comparator and events related to the procedures 
involved except for events in users or other persons, which only include events related 
to investigational devices.  
 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (for example, ECG, radiological scans, and vital sign 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (that is, not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though they may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug–drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
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AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdose should be reported regardless of sequelae.  
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease or disorder being studied or expected progression, signs, or symptoms of 
the disease or disorder being studied, unless more severe than expected for the 
participant’s condition. 
 Medical or surgical procedure (for example, endoscopy and appendectomy): the 
condition that leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.  
10.3.2. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (for example, hospitalization for signs or symptoms of the disease under study, death due 
to progression of disease). An SAE that can be attributed to a medical device or device 
constituent is referred to as SADE (serious adverse device effect). An SAE that can be attributed 
to a not previously identified device risk is referred to as UADE (unanticipated adverse device 
effect). 
SAE is defined as any untoward medical occurrence that, at any dose: 
 
 Results in death 
 
 Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted to hospital 
for observation and/or treatment that would not have been appropriate in the 
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physician’s office or outpatient setting. Complications that occur during hospitalization 
are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE. 
 
 Results in persistent disability or incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (for example, sprained ankle), which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 
 Is a congenital anomaly or birth defect 
 
 Other situations 
 Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious. 
 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency or 
drug abuse. 
10.3.3. 
Definition of Product Complaints 
Product Complaint 
A PC is any written, electronic, or oral communication that alleges deficiencies related to the 
identity, quality, durability, reliability, safety, effectiveness, or performance of a study 
intervention. When the ability to use the study intervention safely is impacted, the following 
are also PCs: 
deficiencies in labeling information, and 
use errors for device or drug–device combination products due to ergonomic design elements 
of the product. 
Product complaints related to study interventions used in clinical trials are collected in order to 
ensure the safety of participants, monitor quality, and to facilitate process and product 
improvements. 
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Investigators will instruct participants to contact the site as soon as possible if he or she has a 
PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 
10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints 
 
 AE, SAE, and PC Recording 
 When an AE/SAE/PC occurs, it is the responsibility of the investigator to review all 
documentation (for example, hospital progress notes, laboratory reports, and 
diagnostics reports) related to the event. 
 The investigator will then record all relevant AE/SAE/PC information in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice. AE/SAE information is reported on the appropriate (e)CRF page and PC 
information is reported on the PC Form. 
Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor or designee in lieu of completion of the (e)CRF page for AE/SAE 
and the PC Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested 
by Sponsor or designee. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs or symptoms) will be documented as the AE/SAE.  
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories:  
 Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
 Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the research 
participant. 
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 Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention. 
An AE that is assessed as severe should not be confused with a SAE. Severe is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can be 
assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
 The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, for marketed products, in his or her assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he or she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Sponsor or designee. However, it 
is very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Sponsor or designee. 
 The investigator may change his or her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.  
 
Follow-Up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
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 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor or designee with a copy of any 
post-mortem findings, including histopathology.  
 
10.3.5. 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
 The primary mechanism for reporting an SAE will be the electronic data collection 
tool. 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.  
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the sponsor contact for SAE reporting by telephone. 
 Contacts for SAE reporting can be found in study training material.  
 
SAE Reporting via Paper CRF 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the sponsor contacts for SAE reporting. 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
Contacts for SAE reporting can be found in study training material.  
10.3.6. 
Regulatory Reporting Requirements 
SAE Regulatory Reporting 
 
Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation 
are met. 
● The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators. 
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● An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (for example, summary or listing of SAEs) 
from the sponsor will review and then file it along with the IB and will notify 
the IRB/IEC, if appropriate according to local requirements. 
 
 
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10.4. 
Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information 
Women of childbearing potential (WOCBP) and women not of childbearing potential 
(WNOCBP) may participate in this trial. WOCBP need to either remain abstinent (if this is their 
usual preferred lifestyle) or if they are in a same-sex relationship exclusively, they do not need to 
use contraception. If they are in a heterosexual relationship, they need to use contraception as 
described below throughout the study and for 5 half-lives of study drug plus 30 days, 
corresponding to 2 months after the last injection. 
 
Word/Phrase 
Definition 
Women of 
childbearing 
potential 
Females are considered a WOCBP if 
 
they have had at least one cycle of menses, or 
 
they have Tanner 4 breast development. 
 
Any amount of spotting should be considered menarche.  
Women not of 
childbearing 
potential 
Females are considered WNOCBP if 
 
they have a congenital anomaly such as Mullerian agenesis 
 
they are infertile due to surgical sterilization, or  
 
they are post-menopausal. 
 
Examples of surgical sterilization include hysterectomy, bilateral oophorectomy, 
and tubal ligation. 
Post-menopausal 
state 
The post-menopausal state should be defined as 
1. A woman at any age at least 6 weeks post-surgical bilateral oophorectomy 
with or without hysterectomy, confirmed by operative note; or  
2. A woman at least 40 years of age and up to 55 years old with an intact 
uterus, not on hormone therapy*, who has had cessation of menses for at 
least 12 consecutive months without an alternative medical cause, AND  
With a follicle-stimulating hormone >40 mIU/mL; or  
3. A woman 55 or older not on hormone therapy, who has had at least 12 
months of spontaneous amenorrhea, or 
4. A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy. 
*Women should not be taking medications during amenorrhea, such as oral 
contraceptives, hormones, gonadotropin-releasing hormone, anti-estrogens, 
selective estrogen receptor modulators, or chemotherapy that could induce 
transient amenorrhea. 
Reproductive 
toxicology 
studies 
Embryo-fetal studies are toxicity studies in pregnant animals designed to identify 
abnormalities in the development of fetuses, which could indicate potential for 
teratogenicity in humans. The relevant dosing period is during organogenesis. 
 
Please see guidance for specific participant populations below: 
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 
WOCBP who are completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle 
Must… 
Must not… 
agree to either remain abstinent, or 
 
use periodic abstinence methods 
calendar  
ovulation  
symptothermal, or 
post-ovulation  
 
declare abstinence just for the duration of 
a trial, or 
stay in a same-sex relationship without sexual 
relationships with males 
 
use the withdrawal method 
 
 
WOCBP who are NOT completely abstinent as their preferred and usual lifestyle, or in a same-sex 
relationship, as part of their preferred and usual lifestyle: 
Topic 
Condition 
Pregnancy testing 
Negative serum result at screening followed by a 
negative urine result within 24 hours prior to 
treatment exposure. 
Contraception 
Agree to use 2 forms of effective contraception, 
where at least one form must be highly effective 
(less than 1% failure rate). 
 
Examples of different forms of contraception:  
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 
mini-pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices. 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges 
 
barrier method with use of a spermicide 
o condom with spermicide 
o  diaphragm with spermicide, or 
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o female condom with spermicide. 
Note: The barrier method must include use of a 
spermicide (that is, condom with spermicide, 
diaphragm with spermicide, and 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, and 
symptothermal) 
 
withdrawal 
 
post coital douche, and 
 
lactational amenorrhea. 
 
 
Males  
Topic 
Guidance 
For all men  
 
should refrain from sperm donation for 
the duration of the study and for 5 
terminal half-lives of the study drug (30 
days) plus 90 days, corresponding to 4 
months after the last injection. 
Contraception for men with partners of 
childbearing potential  
 
either remain abstinent (if this is their 
preferred and usual lifestyle), or 
 
must use condoms plus 1 additional 
highly effective (less than 1% failure rate) 
method of contraception for the duration 
of the study, and for 5 terminal half-lives 
of the study drug (30 days) plus 90 days, 
corresponding to 4 months after the last 
injection. 
Contraception for men in exclusively same-sex 
relationships, as their preferred and usual lifestyle 
Are not required to use contraception. 
 
 Examples of highly effective, effective, and unacceptable methods of contraception can be found 
below. 
Methods 
Examples 
Highly effective contraception  
 
combination oral contraceptive pill and 
mini-pill 
 
implanted contraceptives 
 
injectable contraceptives 
 
contraceptive patch (only women <198 
pounds or 90 kg) 
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 
total abstinence 
 
vasectomy (if only sexual partner) 
 
fallopian tube implants (if confirmed by 
hysterosalpingogram) 
 
combined contraceptive vaginal ring, or  
 
intrauterine devices. 
Effective contraception  
 
male or female condoms with spermicide  
 
diaphragms with spermicide or cervical 
sponges, or 
 
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, and 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, and 
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 male participants who receive study 
intervention. 
● 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.  
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Female participants who become pregnant 
● The investigator will collect pregnancy information on any female participant 
who becomes pregnant while participating in this study. The initial information 
will be recorded on the appropriate form and submitted to the sponsor within 24 
hours of learning of a participant’s pregnancy.  
● The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate, 
and the information will be forwarded to the sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. 
Any termination of pregnancy will be reported, regardless of fetal status (presence 
or absence of anomalies) or indication for the procedure. 
● While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE.  
● A spontaneous abortion (occurring at <20 weeks gestational age) or still birth 
(occurring at ≥20 weeks gestational age) is always considered to be an SAE and 
will be reported as such.  
● Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
protocol Section 8.3.1. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
● Any female participant who becomes pregnant while participating in the study 
will discontinue study drug. If the participant is discontinued from the study drug, 
follow the standard discontinuation process for each study period. 
 
 
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10.5. 
Appendix 5: Liver Safety: Suggested Actions and Follow-Up 
Assessments 
For testing selected, analysis is required to be completed by the Lilly-designated central 
laboratory, except for microbiology. 
Local testing may be performed in addition to central testing when required for immediate 
participant management. 
Results will be reported if a validated test or calculation is available. 
 
Hematology 
Clinical Chemistry 
Hemoglobin 
Total bilirubin 
Hematocrit 
Direct bilirubin 
Erythrocytes (RBCs - red blood cells) 
Alkaline phosphatase (ALP) 
Leukocytes (WBCs - white blood cells) 
Alanine aminotransferase (ALT) 
Differential: 
Aspartate aminotransferase (AST) 
    Neutrophils, segmented 
Gamma-glutamyl transferase (GGT) 
    Lymphocytes 
Creatine kinase (CK) 
    Monocytes 
Other Chemistry 
    Basophils 
Acetaminophen 
    Eosinophils 
Acetaminophen protein adducts 
Platelets 
Alkaline phosphatase isoenzymes 
Cell morphology (RBC and WBC) 
Ceruloplasmin 
Coagulation 
Copper 
Ethyl alcohol (EtOH) 
Prothrombin time, INR (PT-INR) 
Haptoglobin 
Serology 
Immunoglobulin IgA (quantitative) 
Hepatitis A virus (HAV) testing: 
Immunoglobulin IgG (quantitative) 
    HAV total antibody 
Immunoglobulin IgM (quantitative) 
    HAV IgM antibody 
Phosphatidylethanol (PEth) 
Hepatis B virus (HBV) testing: 
Urine Chemistry 
    Hepatitis B surface antigen (HBsAg) 
Drug screen 
    Hepatitis B surface antibody (anti-HBs) 
Ethyl glucuronide (EtG) 
    Hepatitis B core total antibody (anti-HBc) 
Other Serology 
    Hepatitis B core IgM antibody 
Anti-nuclear antibody (ANA) 
    Hepatitis B core IgG antibody 
Anti-smooth muscle antibody (ASMA) a 
    HBV DNA d 
Anti-actin antibody b 
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Hepatis C virus (HCV) testing: 
Epstein-Barr virus (EBV) testing: 
    HCV antibody 
    EBV antibody 
    HCV RNA d 
    EBV DNA d 
Hepatitis D virus (HDV) testing: 
Cytomegalovirus (CMV) testing: 
    HDV antibody 
    CMV antibody 
Hepatitis E virus (HEV) testing: 
    CMV DNA d 
    HEV IgG antibody 
Herpes simplex virus (HSV) testing: 
    HEV IgM antibody 
    HSV (Type 1 and 2) antibody  
    HEV RNA d 
    HSV (Type 1 and 2) DNA d 
Microbiology c 
Liver kidney microsomal type 1 (LKM-1) antibody 
Culture: 
    Blood 
    Urine 
 
Abbreviations: Ig = immunoglobulin; INR = international normalized ratio; PT-INR=prothrombin time-international 
normalized ratio  
 
a 
Not required if anti-actin antibody is tested. 
b 
Not required if anti-smooth muscle antibody (ASMA) is tested. 
c 
Assayed ONLY by investigator-designated local laboratory; no central testing available. 
d 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both.
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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 diabetes 
mellitus and related clinical traits or complications, including nonalcoholic 
steatohepatitis or obesity and related diseases. They may also be used to develop 
tests or assays, including diagnostic tests related to LY3437943, study 
interventions related to this drug class, or diabetes mellitus and related clinical 
traits or complications, including nonalcoholic steatohepatitis or obesity. Genetic 
research may consist of the analysis of one or more candidate genes, the analysis 
of genetic markers throughout the genome, or analysis of the entire genome.  
● 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 diabetes mellitus 
and related clinical traits or complications, including nonalcoholic steatohepatitis 
or obesity continues but no longer than 15 years or other period as per local 
requirements.  
 
 
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10.7. 
Appendix 7: World Health Organization Classification of Diabetes 
and Diagnostic Criteria 
Type 1 Diabetes: Type 1 diabetes is judged to be present when the classical symptoms of 
diabetes (thirst, polyuria, wasting and stupor, or coma) are associated with readily detectable 
concentrations of glucose and ketone bodies in the blood and urine. Insulin treatment is 
necessary not only to control hyperglycemia but also to prevent spontaneous ketosis and death. 
Type 2 Diabetes: Type 2 diabetes, although often asymptomatic, may also present with classical 
hyperglycemic symptoms (thirst, polyuria, and weight loss), but despite hyperglycemia and 
ketone bodies are present in only low concentrations in the blood and urine. Coma is rare in 
type 2 diabetes but may result from extreme hyperglycemia and hyperosmolarity; lactic acidosis 
or ketoacidosis can also occur in fulminating illness (for example, severe infection or mesenteric 
artery thrombosis) due to an acute increase in insulin requirements, but spontaneous ketosis does 
not occur. Some patients with type 2 diabetes later progress to a state of absolute insulin 
deficiency (Alberti and Zimmet 1998).  
 
 
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10.8. 
Appendix 8: New York Heart Association Functional Classification 
IV CHF 
 
New York Heart Association (NYHA) classification NYHA grading MET*  
Class I No limitations. Ordinary physical activity does not cause undue fatigue, dyspnea, or 
palpitations (asymptomatic LV dysfunction). >7  
 
Class II Slight limitation of physical activity. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or angina pectoris (mild CHF). 5  
 
Class III Marked limitation of physical activity. Less than ordinary physical activity leads to 
symptoms (moderate CHF). 2–3  
 
Class IV Unable to carry on any physical activity without discomfort. Symptoms of CHF present 
at rest (severe CHF). 1.6  
 
*MET (metabolic equivalent) is defined as the resting VO2 for a 40-year-old, 70-kg man. 1 MET 
= 3.5 mL O2 /min/kg body weight. 
 
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10.9. 
Appendix 9: Protocol GZBD Standardized Protocols for the 
Measurement of Height, Weight, Waist Circumference, Vital Signs, 
ECG, SMBG and MNSI 
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 capable of measuring weight in kilograms to 1 decimal place. 
 
All weights for a given participant should be measured using the same scale, whenever 
possible, at approximately the same time in the morning after evacuation of bladder 
contents.  
 
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 and 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. 
Vital Sign Measurements 
 
Vital sign measurements (blood pressure 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 blood pressure needs to be recorded in the eCRF.  
 
Blood pressure must be taken with an automated arm blood pressure 
equipment with full range of cuff sizes up to XL. 
 
If blood pressure and pulse measurements are taken separately, pulse should 
be taken prior to blood pressure.  
Note: In the event pulse measurement cannot be taken via an automated blood pressure 
instrument, the preferred location for measurement of pulse is the radial artery.  
Orthostatic Vital Sign Measurements 
 
Orthostatic vital sign measurements (blood pressure 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 
 
Electrocardiograms should be collected at least 30 minutes prior to collection of 
blood samples for laboratory testing, including PK samples. 
 
Electrocardiograms should be recorded after the participant has been supine for 5 
minutes in a quiet room.  
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 
36 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). 
Self-Monitoring of Blood Glucose 
During the trial, participants will monitor their blood glucose to assess efficacy of study 
interventions, using glucometers provided by the sponsor. Procedures described in this section 
will be initiated immediately after participant eligibility is confirmed at Visit 2.  
 
Glucose self-monitoring will consist of daily FBG measurements and QW 4-point BG 
measurements consisting of fasting (before morning meal/after awakening), before mid-day 
meal, dinner, and bedtime. In addition, a 7-point daily glucose profile consisting of 
measurements obtained before each meal, approximately 2 hours after each meal, and at bedtime 
per schedule provided in Section 1.3 (SoA). The complete 7-point profile must be collected on a 
single day. If a participant does not complete the entire profile on a single day, all 7 points must 
be collected on a subsequent day. At the weeks when 7-point daily BG profile is taken, 
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participants will not be required to perform weekly 4-point daily BG profiles. All self-monitoring 
BG values will be recorded in participants’ diaries and will be discussed with the site personnel 
at each scheduled clinic visit. All events of hypoglycemia should also be recorded in the 
participant diary, according to instructions.  
 
The 7-point self-monitoring of blood glucose values and all hypoglycemic events should be 
entered into the eCRF.  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.10. 
Appendix 10: Patient-Reported Outcomes 
When feasible, the self-administered questionnaires will be translated into the native language of 
the participant, linguistically validated and administered according to the SoA (Section 1.3). The 
language of the signed ICF will be considered the 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 questionnaire(s) is not 
collected due to a translation not being available, this will not be considered a protocol deviation.  
When the PRO questionnaire(s) is collected as per the SOA, the questionnaire(s) 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. 
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 is 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 three aspects of eating behavior (Stunkard and Messick 1985) 
 dietary restraint (21 items)  
 disinhibition (16 items), and  
 perceived hunger (14 items).  
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 
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of hunger. Higher domain scores denote higher levels of restrained eating, 
disinhibited eating, and predisposition to hunger, respectively. 
 Appetite Visual Analog Scale 
The aim of the appetite Visual Analog Scale (VAS) is to determine the effects of 
study treatments on appetite sensations and desire for specific foods. 
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. 
 
The VAS scales will be analyzed as continuous variables on the 0-100 scale for 
individual components. Overall appetite score is calculated as the average of the 4 
individual scores (satiety + fullness + [100-prospective food consumption] + [100-
hunger]/4) (van Can et al. 2014; Flint et al. 2000). The higher overall appetite 
score indicates less appetite and the lower score indicates more appetite. 
 
 
 
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10.11. 
Appendix 11: Metabolic Mechanistic Biomarkers  
 
Mechanistic biomarkers will be measured at longitudinal intervals (longitudinal biomarkers) 
or less frequently to correspond with interim analysis, primary and secondary endpoints 
(endpoint biomarkers). Results will not be provided to the investigative sites. To explore 
potential mechanisms of action related to changes in glucose, lipid, or nutrient metabolism, 
the following markers will be assessed:  
 Biomarkers related to insulin sensitivity: fasting insulin, fasting C-peptide, 
homeostasis model assessment of insulin resistance ([HOMA2-IR] computed with 
fasting glucose and fasting insulin or fasting C-peptide), insulin-like growth factor 
binding protein 2 (IGFBP-2), total adiponectin, 
 
 and leptin 
 Biomarkers related to pancreatic beta or alpha cell function: homeostasis model 
assessment of beta-cell function ([HOMA2-B] computed with fasting glucose and 
fasting insulin or fasting C-peptide), intact proinsulin, intact proinsulin/C-peptide 
ratio, intact proinsulin/insulin ratio, and fasting glucagon  
 
 
 Biomarker of fatty acid oxidation: beta-hydroxybutyrate 
 Biomarkers of lipolysis: free fatty acids and glycerol 
 Biomarker of purine metabolism: uric acid 
 Biomarkers of bone formation or resorption: C-terminal telopeptide of Type I 
collagen (CTX-1) and procollagen Type I N-terminal propeptide (P1NP) 
 Biomarkers related to cardiovascular risk: apolipoprotein B (ApoB) and 
apolipoprotein C-III (Apo C3).  
Metabolic Mechanism 
Longitudinal Biomarkers 
Endpoint Biomarkers 
Insulin sensitivity 
HOMA2-IR (computed with fasting 
glucose and with fasting insulin or 
fasting C-peptide)  
IGFBP-2  
 
Total adiponectin  
 
Leptin 
Pancreatic beta cell function 
HOMA2-B (computed with fasting 
glucose and with fasting insulin or 
fasting C-peptide) 
Intact proinsulin/C-peptide ratio 
Intact proinsulin/insulin ratio 
 
 
Fatty acid oxidation 
 
Beta-hydroxybutyrate 
Lipolysis 
Free fatty acids 
Glycerol 
 
Purine metabolism 
 
Uric acid 
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Metabolic Mechanism 
Longitudinal Biomarkers 
Endpoint Biomarkers 
Bone formation or resorption 
 
CTX-1 
P1NP 
Cardiovascular risk 
 
ApoB  
Apo C3 
 
 
 
 
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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 GCP, enabling 
participants to continue safely in the study and maintaining the integrity of the study.  
Informed consent 
Additional consent from the participant will be obtained, if required, for 
 participation in remote visits, as defined in Section “Remote Visits” 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities.  
Changes in study conduct during exceptional circumstances 
Changes in study conduct not described in this appendix, or not consistent with applicable local 
regulations, are not allowed. 
The following changes in study conduct will not be considered protocol deviations. 
 
 
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Remote visits      
Types of remote visits 
Telemedicine:  
Telephone or technology-assisted virtual visits, or both, are acceptable to 
complete appropriate assessments. Assessments to be completed in this manner include, 
but are not limited to, AEs, PCs, concomitant medications, and review of study 
participant diary (including study drug compliance). 
 
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, physical 
assessments, vital signs, PRO, collection of blood samples, and health information.  
 
Other alternative locations: Laboratory draws and ECGs may be done at an alternate 
location in exceptional circumstances. 
Data capture 
In source documents and the CRF, the study site should capture the visit method, with a specific 
explanation for any data missing because of missed in-person site visits. 
Safety reporting 
Regardless of the type of remote visits implemented, the protocol requirements regarding the 
reporting of AEs, SAEs, and PCs remain unchanged.  
Return to on-site visits 
Every effort should be made to enable participants to return to on-site visits as soon as 
reasonably possible, while ensuring the safety of both the participants and the site staff. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
Study intervention and ancillary supplies (including participant diaries) 
When a participant is unable to go to the site to receive study supplies during normal on-site 
visits, the site should work with the sponsor to determine appropriate actions. These actions may 
include  
 asking the participant to go to the site and receive study supplies from site staff 
without completion of a full study visit 
 asking the participant’s designee to go to the site and receive study supplies on a 
participant’s behalf, and 
 arranging delivery of study supplies. 
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These requirements must be met before action is taken: 
 Alternate delivery of study intervention should be performed in a manner that does 
not compromise treatment blinding and ensures product integrity. The existing 
protocol requirements for product accountability remain unchanged, including 
verification of participant’s receipt of study supplies. 
 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 screening visit are valid for a maximum of 30 days. The following rules will be applied for 
active, nonrandomized participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If paused for less than 30 days from screening: the participant will proceed to the next 
study visit per the usual SoA, provided that randomization visit must be conducted 
within 30 days from first screening.  
o The site should conduct the next visit if the participant’s eligibility criteria are 
confirmed, and the site should document the reason for delay. 
o Due to the pause in screening, sites should also reconfirm the impacted 
participant’s consent and document this confirmation in the source 
documentation. 
 If screening is paused for more than 30 days from screening: the participant must be 
discontinued because of screening interruption due to an exceptional circumstance. 
This is documented as a screen fail in the CRF. The participant can reconsent and be 
rescreened as a new participant as described in the protocol. This rescreen is in 
addition to the one allowed by the main protocol. The screening procedures per the 
usual SoA should be followed, starting at screening visit to ensure participant 
eligibility by randomization visit. 
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. 
 
 
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This table describes the allowed adjustments to visit windows. 
 
Visit Number Tolerance 
Visit 3 
through Visit 
6 
Within 7 days from the intended date, or up to 7 days after 
the intended date 
Visit 7 
through Visit 
11 
Within 10 days from the intended date, or up to 10 days 
after the intended date 
Visit 12 
through Visit 
13 
Within 14 days from the intended date, or up to 14 days 
after the intended date 
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 intervention 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 or 
shipment records of study intervention and relevant communications, including 
delegation, should be filed with site study records. 
Source documents at alternate locations 
 Source documents generated at a location other than the study site should be 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 
AC 
assessment committee 
ADA 
anti-drug 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 
AST 
aspartate aminotransferase 
BG 
blood glucose 
blinding/masking 
A double-blind study 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 
CEC 
clinical endpoint committee 
CHF 
congestive heart failure 
CKD-EPI 
Chronic Kidney Disease-Epidemiology 
CIOMS 
Council for International Organizations of Medical Sciences 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
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. 
CSR 
clinical study report 
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CT 
computed tomography 
CTA 
Clinical Trial Agreement 
DIO 
diet-induced obese 
DPP-4 
dipeptidyl-peptidase-4 
EAS 
efficacy analysis set 
ECG 
electrocardiogram 
EDC 
electronic data capture system 
eCRF 
electronic case report form 
ED 
early discontinuation 
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. 
FAS 
full analysis set 
FBG 
fasting blood glucose 
FSH 
follicle-stimulating hormone 
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 
GPS 
Global Patient Safety 
HbA1c 
hemoglobin A1c 
HDL 
high-density lipoprotein 
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hERG 
human ether-a-go-go-related gene 
HR 
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. 
INR 
international normalized ratio 
interim analysis 
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created or locked. 
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form. 
IRB 
Institutional Review Boards 
ISR 
injection site reaction 
IWRS 
interactive web-response system 
LDL 
low-density lipoprotein 
MAD 
multiple ascending dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEN 
multiple endocrine neoplasia 
MEN2 
multiple endocrine neoplasia syndrome type 2 
MMRM 
mixed-model for repeated measures 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid carcinoma 
NAFLD 
nonalcoholic fatty liver disease 
NYHA 
New York Heart Association 
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OTC 
over-the-counter 
participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PK/PD 
pharmacokinetics/pharmacodynamics 
PR 
pulse rate 
PRO 
patient-reported outcomes/ 
QW 
once weekly 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SDP 
single-dose pen 
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-monitoring of blood glucose 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
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. 
Tx 
treatment 
ULN 
upper limit of normal 
VAS 
visual analog scale 
VLDL 
very low-density lipoprotein 
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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 b: 10-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 amendment summary of changes table below. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Events 
Addition of the following note 
to  Patient-Reported Outcomes 
(PROs), “If a translation is not 
available in the native language 
of a participant at baseline, the 
PRO questionnaire(s) will not 
be administered for that 
participant for the duration of 
the trial (Appendix 10.10)”  
To have translation of PRO 
questionnaire(s) available in 
native language for participants 
 
 
Section 4.1.1  
Overview of Study 
Periods 
Addition of “when collected” 
for PROs at Visit 3 and during 
maintenance period (Visits 9-
13) 
To be aligned with PROs in 
Schedule of Events 
Section 8.3.1 Timing and 
Mechanism for 
Collecting Events 
Change of Pregnancy eCRF to 
SAE eCRF 
Editorial consistency 
Section 10.10 Appendix 
10 Patient-Reported 
Outcomes 
Added information on 
translation of PRO 
questionnaire(s) not being 
available in the native language 
of a participant at baseline 
To have translation of PRO 
questionnaire(s) available in 
native language for participants 
 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Removed uric acid from 
clinical chemistry.  
To maintain internal document 
consistency. It is presented in 
Appendix 11 as biomarker of 
purine metabolism 
Added P800 to exploratory 
samples 
Addition of plasma metabolic 
marker 
Section 10.9 Appendix 9: 
Protocol GZBD 
Standardized Protocols 
for the Measurement of 
Updated electrocardiogram 
tracings to be collected at 
baseline, 24 and 36 weeks and 
To maintain consistency with 
Section 8.2.3 
(Electrocardiograms) 
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Section # and Name 
Description of Change 
Brief Rationale 
Height, Weight, Waist 
Circumference, Vital 
Signs, ECG, SMBG and 
MNSI  
will be assessed qualitatively 
by a blinded cardiologist 
 
Amendment a: March 1, 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 amendment summary table. 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 
Schedule of 
Events 
Diary dispensation and return has 
been updated. An eGRF 
procedure was added at Visit 8 
(Week 12) and removed at Visit 
12 (Week 30). 
The Schedule of Activities was updated 
to match operational changes related to 
diaries and to align eGFR visits with 
clinical chemistry visits. 
Section 5.1 
Inclusion 
Criteria 
The sentence “Female 
participants should not be 
breastfeeding”  was added to 
Inclusion criteria 7. 
Text added for clarification 
Section 8.3.2 
Adverse 
Events of 
Special 
Interest 
The section heading was changed 
from “Safety Topics of Special  
Interest” to “Adverse Events of 
Special Interest”. “Safety topics” 
was changed to “adverse events” 
throughout the section. 
Corrected heading to match template.  
Section wording was corrected to match 
the heading. 
Section 10.4 
Contraceptive 
Guidance-
Female 
participants 
who become 
pregnant 
 
The greater than sign was 
changed to greater than or equal 
to in the following sentence: “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.” 
Corrected error 
 
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119 
11. 
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