A Master Protocol for a Randomized, Controlled, Clinical Trial of Multiple Interventions for Chronic Weight Management in Adult Participants With Obesity or Overweight
Phase: PHASE2
Conditions: Obesity, Overweight
Sponsor: Eli Lilly and Company

Protocol W8M-MC-CWMM(d)
A Master Protocol for a Randomized, Controlled Clinical Trial of Multiple Interventions for 
Chronic Weight Management in Adult Participants with Obesity or Overweight
NCT06143956
Approval Date: 12-Dec-2025

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Master Protocol W8M-MC-CWMM(d) 
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Title Page 
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of the investigational interventions named herein, 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. 
Master Protocol Title: 
A Master Protocol for a Randomized, Controlled Clinical Trial of Multiple Interventions for 
Chronic Weight Management in Adult Participants with Obesity or Overweight 
Protocol Number: W8M-MC-CWMM 
Amendment Number:  CWMM (d) 
Compound: Multi-molecule code LY900038 
Brief Title: 
Chronic Weight Management Master Protocol 
Study Phase: 2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Number: 
IND: 163848 
Document ID: VV-CLIN-077527 
Approval Date: Protocol Amendment (d) Electronically Signed and Approved by Lilly on date 
provided below.  
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Medical monitor name and contact information will be provided separately. 
 
 
 
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Protocol Amendment Summary of Changes Table  
 
DOCUMENT HISTORY 
Document 
Date 
Amendment c 
04-Feb-2025 
Amendment b 
18-Jul-2024 
Amendment a 
13-Aug-2023 
Original Protocol 
04-May-2023 
Amendment [d]  
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The protocol was amended to update the exclusion criteria related to hepatitis B and C to align 
with current guidelines. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Deleted secondary objective 
“To compare the effect of the 
primary intervention versus the 
primary control for weight 
reduction at 
” and the 
corresponding endpoint 
“percent change from baseline 
in body weight” 
To retain consistency with 
Section 3. 
Deleted “
” throughout 
the section 
1.3.2. Visit 401 – 
Screening 
 
Added a statement that if HCV 
antibody test is positive, HCV 
RNA test needs to be 
performed. 
To clarify the laboratory tests to 
be done and provide guidance on 
how to interpret them.  
Added a row “Obtain patient 
number using IWRS” at the 
time of first study consent 
 
To ensure participant 
identification and linkage to 
IWRS for randomization and 
dosing. 
Placed “Register visit with 
IWRS” below “Obtain patient 
number using IWRS” and 
To retain the sequence of events 
and to enhance clarity 
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Section # and Name 
Description of Change 
Brief Rationale 
retained it only for screening 
visit. 
Removed “Includes obtaining 
participant identifier from 
IWRS. Only 1 participant 
number is required” 
To avoid repetition 
Removed “X” from 
prescreening visit in “Register 
visit with IWRS” 
Updated for clarity 
3. Objectives, Endpoints, 
and Estimands 
Deleted secondary objective 
“To compare the effect of the 
primary intervention versus the 
primary control for weight 
reduction at 
” and the 
corresponding endpoint 
“percent change from baseline 
in body weight” 
To avoid duplication with the 
primary endpoint. 
Modified estimand language to 
remove the mention of 
“percent change in body 
weight from baseline at 
 
” 
Deleted “
” throughout 
the section 
To allow flexibility for ISAs to 
assess the primary endpoint at 
their protocol-specified primary 
time points, which may differ 
from 
. 
 
 
 
 
 
 
 
 
Clarification for consistency 
with other sponsor-run studies. 
5.2. Exclusion Criteria  
Modified Exclusion Criterion 
29 
Updated per the latest Lilly 
protocol guidance 
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Section # and Name 
Description of Change 
Brief Rationale 
Modified Exclusion Criterion 
37 to add “with the exception 
of highly effective 
contraceptive methods if 
applicable and as stated within 
the respective ISA” 
Clarification to support ISA 
individualized contraception 
guidance.  
Modified exclusion criterion 
41 to add “Adderall” 
Clarification  
5.4. Screen Failures  
Clarified that screen failures 
from an ISA undergoing 
CWMM master protocol 
rescreening may not require 
repeating all V401 screening 
activities if prior procedures 
were completed within 
 
 of the participant’s 
randomization to a treatment in 
an ISA and that the original 
laboratory data from previous 
Patient ID will be transferred 
over to the new Patient ID. 
Clarification to prevent 
unnecessary blood draws or 
procedures in instances where a 
screen failure from 1 ISA is 
eligible for rescreening under 
CWMM.  
8.2.11. Hepatitis B and 
Hepatitis C Testing and 
Monitoring 
Added hepatitis C testing and 
monitoring details 
Updated per the latest Lilly 
protocol guidance 
9.3.3.1. Efficacy 
Analysis. 
Deleted the first secondary 
endpoint “mean percent change 
of body weight (kg) from 
randomization at 
” 
To align with changes made at 
the Objectives, Endpoints and 
Estimands section 
 
Deleted “
” throughout 
the section 
10.2. Appendix 2: 
Clinical Laboratory Tests 
Added content for hepatitis 
virus test in serology 
Updated for clarity 
Throughout the protocol 
Minor editorial and document 
formatting revisions were 
made. 
Minor; therefore, have not been 
summarized. 
 
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Table of Contents  
Title Page ........................................................................................................................................1 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
 
 
1.3. 
Schedule of Activities (SoA) ..........................................................................................14 
1.3.1. 
Visit 601 – Prescreening .................................................................................................14 
1.3.2. 
Visit 401 – Screening ......................................................................................................14 
1.3.3. 
Activities Conducted after Randomization to a Study 
Intervention .....................................................................................................................18 
2. 
Introduction ...................................................................................................................19 
2.1. 
Study Rationale ...............................................................................................................20 
2.2. 
Background .....................................................................................................................20 
2.2.1. 
Intervention Selection: Adding or Stopping Intervention-Specific 
Appendices ......................................................................................................................20 
2.2.2. 
Governance .....................................................................................................................21 
2.3. 
Benefit/Risk Assessment ................................................................................................21 
3. 
Objectives, Endpoints, and Estimands .......................................................................22 
4. 
Study Design ..................................................................................................................25 
4.1. 
Overall Design ................................................................................................................25 
4.1.1. 
Design Outline ................................................................................................................26 
4.2. 
Scientific Rationale for Study Design ............................................................................27 
4.3. 
Justification for Dose ......................................................................................................28 
4.4. 
End of Study Definition ..................................................................................................28 
5. 
Study Population ...........................................................................................................29 
5.1. 
Inclusion Criteria ............................................................................................................29 
5.2. 
Exclusion Criteria ...........................................................................................................30 
5.3. 
Lifestyle Considerations .................................................................................................34 
5.4. 
Screen Failures ................................................................................................................35 
5.5. 
Criteria for Temporarily Delaying Randomization of a 
Participant .......................................................................................................................36 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................37 
6.1. 
Study Intervention(s) Administered................................................................................37 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................37 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................37 
6.4. 
Study Intervention Compliance ......................................................................................38 
6.5. 
Dose Modification ..........................................................................................................38 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................38 
6.7. 
Treatment of Overdose ...................................................................................................38 
6.8. 
Prior and Concomitant Therapy ......................................................................................38 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................40 
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7.1. 
Discontinuation of Study Intervention ............................................................................40 
7.1.1. 
Hepatic Criteria for Study Drug Interruption or Discontinuation ...................................41 
7.1.2. 
QTc Stopping Criteria .....................................................................................................41 
7.1.3. 
Temporary Interruption of Study Intervention ...............................................................41 
7.1.4. 
Rechallenge .....................................................................................................................41 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................42 
7.3. 
Lost to Follow Up ...........................................................................................................42 
8. 
Study Assessments and Procedures.............................................................................43 
8.1. 
Efficacy Assessments .....................................................................................................43 
8.1.1. 
Bioelectrical Impedance Analysis...................................................................................44 
8.2. 
Safety Assessments .........................................................................................................44 
8.2.1. 
Vital Signs .......................................................................................................................44 
8.2.2. 
Physical Examinations ....................................................................................................45 
8.2.3. 
Electrocardiograms .........................................................................................................45 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................46 
8.2.5. 
Major Adverse Cardiovascular Events ...........................................................................47 
8.2.6. 
Deaths .............................................................................................................................47 
8.2.7. 
Hepatobiliary Disorders ..................................................................................................47 
8.2.8. 
Acute Renal Events .........................................................................................................47 
8.2.9. 
Pregnancy Testing ...........................................................................................................47 
8.2.10. Hepatic Safety Monitoring, Evaluation, and Criteria for Study 
Drug Interruption or Discontinuation .............................................................................48 
8.2.11. Hepatitis B and Hepatitis C Testing and Monitoring......................................................52 
8.2.12. Mood Changes, Suicidal Ideation, and Suicidal Behavior Risk 
Monitoring ......................................................................................................................53 
8.2.13. Additional Safety Data and Sample Collections .............................................................54 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................54 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................55 
8.3.2. 
Pregnancy ........................................................................................................................57 
8.3.3. 
Adverse Events of Special Interest .................................................................................58 
8.4. 
Pharmacokinetics ............................................................................................................58 
8.5. 
Pharmacodynamics .........................................................................................................58 
8.6. 
Genetics ..........................................................................................................................58 
8.7. 
Biomarkers ......................................................................................................................58 
8.8. 
Immunogenicity Assessments.........................................................................................58 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics .......................................................................................................................58 
9. 
Statistical Considerations .............................................................................................59 
9.1. 
Statistical Hypotheses .....................................................................................................59 
9.1.1. 
Multiplicity Adjustment ..................................................................................................59 
9.2. 
Analysis Sets ...................................................................................................................60 
9.3. 
Statistical Analyses .........................................................................................................60 
9.3.1. 
General Considerations ...................................................................................................60 
9.3.2. 
Primary Endpoint Analysis .............................................................................................62 
9.3.3. 
Secondary Endpoint(s) Analysis .....................................................................................62 
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9.3.4. 
Exploratory Endpoint(s) Analysis...................................................................................63 
9.3.5. 
Safety Analyses ...............................................................................................................63 
9.3.6. 
Other Analyses ................................................................................................................63 
9.4. 
Interim Analysis ..............................................................................................................64 
9.5. 
Sample Size Determination ............................................................................................64 
10. 
Supporting Documentation and Operational Considerations ..................................66 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................66 
10.1.1. Regulatory and Ethical Considerations ...........................................................................66 
10.1.2. Financial Disclosure........................................................................................................67 
10.1.3. Informed Consent Process ..............................................................................................67 
10.1.4. Data Protection................................................................................................................67 
10.1.5. Committees Structure......................................................................................................68 
10.1.6. Dissemination of Clinical Study Data.............................................................................68 
10.1.7. Data Quality Assurance ..................................................................................................69 
10.1.8. Source Documents ..........................................................................................................71 
10.1.9. Study and Site Start and Closure ....................................................................................71 
10.1.10. Publication Policy ...........................................................................................................72 
10.1.11. Investigator Information .................................................................................................72 
10.1.12. Sample Retention ............................................................................................................72 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................73 
10.2.1. Clinical Laboratory Tests ................................................................................................73 
10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: 
Definitions and Procedures for Recording, Evaluating, Follow-
up, and Reporting ............................................................................................................76 
10.3.1. Definition of AE .............................................................................................................76 
10.3.2. Definition of SAE ...........................................................................................................77 
10.3.3. Definition of Product Complaints ...................................................................................78 
10.3.4. Recording and Follow-Up of AE and/or SAE and Product 
Complaints ......................................................................................................................79 
10.3.5. Reporting of SAEs ..........................................................................................................80 
10.3.6. Regulatory Reporting Requirements ...............................................................................81 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ..........................................................82 
10.4.1. Definitions.......................................................................................................................82 
10.4.2. Contraception Guidance..................................................................................................82 
10.5. 
Appendix 5: Genetics......................................................................................................83 
10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments ....................................................................................................................84 
10.7. 
Appendix 7: New York Heart Association Functional 
Classification of Heart Failure ........................................................................................86 
10.8. 
Appendix 8: Standardized Protocols for the Measurement of 
Height, Weight, Waist Circumference, and Vital Signs .................................................87 
10.9. 
Appendix 9: Diet and Physical Activity Suggestions for Sites 
without Programs ............................................................................................................89 
10.9.1. Diet ..................................................................................................................................89 
10.9.2. Physical Activity .............................................................................................................89 
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10.10. 
Appendix 10: Medical Device Adverse Events (AEs), Adverse 
Device Effects (ADEs), Serious Adverse Events (SAEs), and 
Device Deficiencies: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ............................................................................91 
10.11. 
Appendix 11: Country-Specific Requirements ...............................................................92 
10.12. 
Appendix 12: Provisions for Changes in Study Conduct during 
Exceptional circumstances ..............................................................................................93 
10.13. 
Appendix 13: Requirements for ISA Design ..................................................................98 
10.13.1. Activities during an ISA Treatment Period ....................................................................98 
10.13.2. Activities during a Posttreatment Follow-up Period .....................................................101 
10.13.3. Activities during an Early Discontinuation Visit ..........................................................102 
10.14. 
Appendix 14: Abbreviations and Definitions ...............................................................103 
10.15. 
Appendix 15: Protocol Amendment History ................................................................108 
11. 
References ....................................................................................................................113 
 
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o ISA-specific objectives and endpoints 
o ISA-specific safety monitoring activities, and 
o ISA-specific outcomes measurements and statistical analyses methods. 
Each ISA includes an SoA applicable from baseline through the time of the participant’s 
last planned study visit. Any ISA-specific screening activities will be included in the 
relevant ISA SoA. 
Brief Summary: 
Study participants will be adults with obesity or overweight. Each ISA provides a brief summary 
of the health measurements or outcomes, study interventions, treatment durations, and overall 
study duration for that ISA. 
Study Population: 
Individuals included in this study will be at least 18 years old with obesity or overweight.  
Additionally, participants will have had a stable body weight for the 3 months prior to 
randomization.  
Number of Participants: 
An upper limit of 
 will be enrolled within each ISA to 
ensure 
. 
Intervention Groups and Duration: 
Each ISA specifies the intervention groups and study duration for that ISA. 
Ethical Considerations of Benefit/Risk: 
Each ISA provides intervention-specific benefit/risk information for that ISA. 
Data Monitoring Committee: No 
These committees will be established to support the master protocol and ISA teams: 
 Internal Assessment Committee, and 
 Clinical Event Committee. 
 
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1.2. 
Schema  
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2. 
Introduction  
Study W8M-MC-CWMM (CWMM) is a Phase-2 master protocol to accelerate the development 
of novel treatments for chronic weight management. This platform trial provides a framework to 
enable the evaluation of safety and efficacy of different interventions through the use of 
intervention-specific appendices (ISAs). See Sections 2.2 and 4 for details on study structure and 
design. 
Obesity epidemiology 
Obesity is a global epidemic that is associated with increased morbidity and mortality (Sarma et 
al. 2021). Obesity is associated with over 200 health complications, including conditions that 
significantly impact morbidity and mortality and contribute to excess health care costs (Wilding 
and Jacob 2021). In 2014, obesity-related health care costs globally were estimated at 
approximately 2 trillion dollars (US) (Tremmel et al. 2017). These prior values likely 
underestimate current costs owing to the continued increase in prevalence of obesity worldwide. 
Excess body weight is associated with significant morbidity and mortality. In 2015, excess body 
weight accounted for approximately 4 million deaths and 120 million disability-adjusted life 
years worldwide (GBD 2015 Obesity Collaborators et al. 2017). Increases in mortality are driven 
by both cardiovascular (CV) and non-CV causes, including cancer (Berrington de Gonzalez et al. 
2010). 
Obesity-related complications and conditions 
The impact of excess body weight on morbidity is through a large number of obesity-associated 
conditions (Machado et al. 2006; Van Thiel and Ramadori 2011; Lashinger et al. 2014; Garofalo 
et al. 2017; Chalasani et al. 2018; Müller et al. 2022; Kivimäki et al. 2022) including 
 atherosclerosis 
 ischemic heart disease 
 heart failure 
 stroke 
 diabetes mellitus 
 chronic kidney disease 
 nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, cirrhosis, and hepatocellular 
carcinoma 
 cancer, including breast, colorectal, kidney, endometrial, and pancreatic 
 obstructive sleep apnea, and 
 osteoarthritis. 
Effect of weight loss on clinical outcomes 
A reduction in body weight could potentially improve or reverse conditions frequently associated 
with increased morbidity and mortality. 
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Observational studies show that weight loss by metabolic surgery is associated with a reduction 
in coronary artery events, cerebrovascular events, heart failure, atrial fibrillation, nephropathy, 
overall cancer risk, and all-cause mortality, compared with non-surgical controls (Aminian et al. 
2019, 2020; Mentias et al. 2022; Tao et al. 2020; Khalid et al. 2022). These benefits could reflect 
direct relationships between change in weight and the observed outcome or be indirect via 
improvements in associated risk factors (Sutanto et al. 2021). 
Pharmacological treatments and unmet need 
FDA-approved weight loss medicines have been historically capable of providing weight loss of 
<10% (Srivastava and Apovian 2018), with some classes of agents carrying risks for adverse 
neurocognitive, psychiatric, or cardiovascular effects. The current generation of incretin-based 
medications provides superior weight loss (Wilding et al. 2021; Jastreboff et al. 2022) but still 
falls short of the weight loss achieved with surgical approaches to weight loss. Modest weight 
loss yields important medical benefits but has not been shown to produce the full spectrum of 
benefits observed with obesity surgery treatments. Further, achieving durable weight loss and 
realizing the full potential benefits remain a challenge, in particular for pharmacological 
approaches to weight loss. 
Therefore, there remains a significant unmet need for efficacious and durable weight loss 
therapies with a favorable safety profile. 
2.1. 
Study Rationale  
The purpose of this CWMM Phase-2 master protocol is to create a framework to evaluate the 
safety and efficacy of various investigational interventions for chronic weight management as 
hypotheses emerge. 
2.2. 
Background  
2.2.1. 
Intervention Selection: Adding or Stopping Intervention-Specific Appendices  
The CWMM master protocol defines a platform trial that will permit the evaluation of multiple 
investigational interventions for chronic weight management by the means of the introduction of 
new Phase-2 ISAs over time. Adding new ISAs will be based on 
● adequate safety, tolerability, and pharmacokinetic (PK) properties supportive of an 
intervention’s entry into development for a chronic weight management indication (see 
Section 2.2.2), and 
● regulatory and Ethical Review Boards or Institutional Review Boards (IRB) approval to 
add the new ISAs and new interventions to the platform trial. 
Future ISAs with new investigational drugs will cross-reference the IND for that investigational 
drug. 
The platform design is not an adaptive design, therefore, there is no plan to discontinue ISAs 
based on interim analyses or external new data. 
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2.2.2. 
Governance  
Selection of new interventions for investigation in this platform trial 
Eli Lilly and Company (Lilly) will be responsible for the selection of interventions to be added 
to, or removed from, clinical development on this platform trial. 
Periodic assessment of safety data in this platform trial 
An Internal Assessment Committee (IAC) may be established for the purpose of making periodic 
prespecified or ad hoc assessments of safety data in an unblinded fashion and to make 
recommendations for protocol modifications or other actions. This internal committee will be 
independent of the Lilly study teams. 
In addition, an external (independent) Clinical Event Committee (CEC) may be established, if 
specified in an ISA, for the purpose of adjudicating defined clinical events, in a blinded, 
consistent, and unbiased manner throughout the course of an ISA study. 
These and other governance considerations are further described in Section 10.1.5. 
Considerations for use of a common database in this platform trial 
Data collected for each ISA of this platform trial will be stored in a common database. To be 
considered for inclusion in this platform trial, investigations of other interventions must be 
amenable to trial designs conformable to the preestablished standardized structure of this 
common database. Section 10.13 outlines the minimum standards for the SoA for each ISA. 
2.3. 
Benefit/Risk Assessment  
Study interventions are not administered during CWMM Visit 401 (screening), and the screening 
procedures generally present little risk. Participants may benefit by receiving personal health 
information from the physical examination and other safety assessments. 
Intervention-specific benefit/risk information is provided in the relevant ISA. 
In addition, information about the known and expected benefits and risks and reasonably 
expected AEs of the study intervention may be found in the Investigator’s Brochure (IB) for each 
intervention evaluated in an ISA. 
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 Population: participants who meet the inclusion criteria. Further details can be found in 
Sections 5 and 9. 
 Endpoint: percent change in body weight from baseline to the primary time point. 
 Treatment condition: the randomized treatment with allowance for down-titration based 
on gastrointestinal (GI) tolerability, unless otherwise specified in the ISA. 
 Population-level summary: Mean percent changes in body weight between the primary 
intervention and primary control. ICEs include permanent discontinuation of any study 
drug or specified in the ISA, which is handled by the hypothetical strategy. Additional 
ICEs may be specified in an ISA-specific protocol when appropriate. Dose modification 
and interruption will not be considered as ICEs because dose modification and 
interruption are part of the treatment condition. Down-titration will not be considered as 
ICEs for the estimand definition, unless otherwise specified in the ISA. 
Rationale for use of an “efficacy” estimand: This Phase 2 chronic weight management platform 
trial aims to study the efficacy of various investigational agents under the ideal condition that all 
participants adhere to the randomized treatment. 
Additional estimands may be explored for the primary objective. 
Estimands for secondary objective 
The estimand strategy applied to the primary objective will also be used for the secondary 
objectives, including: 
Difference between primary intervention and primary control as well as difference between the 
primary intervention and comparator (when applicable) in 
 change in body weight (kg) from baseline at the primary time point  
 incidence of study participants who achieve ≥5% body weight reduction at the primary 
time point  
 incidence of study participants who achieve ≥10% body weight reduction at the primary 
time point, and 
 change in body mass index (BMI) (kg/m2) from baseline at the primary time point Unless 
specified otherwise, safety and tolerability assessments will be guided by an estimand 
comparing the primary intervention doses with primary control irrespective of adherence 
to study drug, including data collected during the treatment period plus safety follow-up 
from participants who are randomly assigned and are exposed to at least 1 dose of study 
drug. 
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4. 
Study Design  
4.1. 
Overall Design  
Study design overview 
This is a randomized, double-blind, controlled, platform-type clinical trial to investigate the 
safety and efficacy of multiple interventions for chronic weight management simultaneously 
and/or sequentially. Section 1.2 illustrates the general schema. 
Master protocol and Intervention-Specific Appendices (ISAs) 
The overall protocol design consists of 2 components which, when combined, define the 
investigations to be conducted in this platform trial. 
 CWMM master protocol explains the master protocol 
o study concept 
o overall structure and governance 
o screening activities (Visit 401) 
o study entry and discontinuation criteria 
o objectives and endpoints 
o safety monitoring activities, and 
o statistical analyses methods applicable to all ISAs. 
The master protocol contains an SoA that lists activities that will be common to all 
studies undertaken using the master protocol (see Sections 1.3.1 and 10.13). 
 Individual ISAs provide information defining features that are specific or tailored to a 
given intervention, such as 
o specific interventions to be evaluated under the ISA, including intervention-
specific background information, benefit/risk information, and dose justification 
o ISA-specific screening activities (Visit 401) 
o ISA-specific study entry and discontinuation criteria 
o ISA-specific objectives and endpoints 
o ISA-specific safety monitoring activities, and 
o ISA-specific outcomes measurements and statistical analyses methods. 
Each ISA includes an SoA applicable from baseline through the time of the participant’s last 
planned study visit. Any ISA-specific screening activities will be included in the relevant ISA 
SoA. See Section 10.13.1 for activities and specific visits during an ISA Treatment Period. 
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4.1.1. 
Design Outline  
Pre-screening and Screening period 
Informed consent process 
To participate in studies using the master protocol, a participant must provide informed consent 
for the procedures described in this master protocol and in the relevant ISAs prior to initiating 
any screening procedures. This will mean signing more than 1 ICF, as illustrated in Section 1.2 
 a CWMM prescreening ICF, which grants consent only for procedures and assessments 
marked under V601. 
 a CWMM master protocol ICF, which describes the study objective and high-level 
design, and the required screening procedures, and  
 at least 1 ISA-specific ICF, which describes the ISA objective and design, the 
intervention risk and benefit information, required ISA treatment and posttreatment 
procedures, including risks associated with these procedures, and the approximate 
probability of being randomly assigned to investigational, comparator control(s) (if 
applicable), or placebo group. 
The ICF(s) must meet the regulatory and ethical requirements stated in Section 10.1, Appendix 1 
of this master protocol. 
Visit numbering 
There are up to 3 visits prior to randomization into a treatment group. The visits are designated 
as Visits 601, 401, and 402. On-treatment visit numbers are designated by the week of study 
treatment. The visit of randomization and first dose of study drug is Visit 0 (Week ), and if the 
next visit would be scheduled  weeks later, for example, then that visit would be designated as 
Visit  rather than Visit  The first posttreatment visit is designated as Visit 801. 
Prescreening 
An optional prescreening Visit 601 may be conducted at a traditional investigator site or other 
location associated with the investigator. HbA1c measurement may be performed through the 
central laboratory or at a local laboratory or via point-of-care testing, if permissible by local 
regulations and requirements. Local laboratories performing testing must be qualified in 
accordance with applicable local regulations. Registration of the visit with IWRS is required to 
obtain a participant identifier. The prescreening visit must be recorded in the CRF with the 
associated participant identifier.  
Confirm the participant meets applicable eligibility criteria before proceeding to Visit 401. It is 
recommended that the prescreening visit be performed within  weeks of Visit 401. Certain 
activities will be repeated at Visit 401 for confirmation of study eligibility, including collection 
of height and weight to calculate BMI and HbA1c measurement via the central laboratory. 
Screening (Visit 401) 
The screening period of the CWMM master protocol and ISAs may begin approximately 
 weeks before a participant receives study intervention in an ISA. All screening procedures for 
the CWMM master and relevant ISAs will be completed during Visit 401. Sections 5.1 and 5.2 
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of the CWMM master protocol provide the criteria by which participants will be screened for 
inclusion in, or exclusion from, the master protocol. Sections 5.1 and 5.2 of the relevant ISAs 
provide ISA-specific eligibility criteria. 
If the time between Visit 401 and randomization (Visit 0) takes more or less time than  weeks, 
it will not be considered a protocol deviation for any ISA. However, if this interval is greater 
than 
 weeks, the participant should be rescreened. 
Participants who have not fasted for Visit 401 will need to return to the site for collection of 
fasting parameters. This return visit will be considered part of Visit 401. 
Randomization to ISAs 
Participants found eligible according to all CWMM master protocol trial entry criteria, and all 
entry criteria of at least 1 available ISA, will be randomized or assigned to an ISAs during Visit 
401. The assignment to an ISA will not be blinded. 
Treatment and posttreatment periods 
The treatment period of an ISA begins at the end of the ISA-specific screening/lead-in period 
and starts with randomization to a treatment group. The duration of the treatment period may 
vary across ISAs. Participants will be randomly assigned to a treatment arm within an ISA at 
Visit 0. When the treatment period ends, participants in every ISA will have at least 1 
posttreatment follow-up visit (Visit 801). 
Some aspects of the treatment period are defined in this master protocol, as required features 
common to all studies (ISAs) performed under the master protocol/ISA structure. See the ISAs 
for procedures conducted during ISA-specific treatment and posttreatment study periods. 
Early discontinuation of study intervention 
Participants who permanently discontinue the study intervention early are encouraged to remain 
in the study for safety monitoring through the end of the study treatment period and to participate 
in posttreatment follow-up visits as specified in the master protocol and/or the relevant ISA 
(Section 7). 
4.2. 
Scientific Rationale for Study Design  
The following are rationales for key elements of the CWMM master protocol design. Rationales 
for endpoints, trial duration, and other key elements of study design are provided in the ISAs. 
Appropriateness of study population 
Adult participants who have BMI ≥27 kg/m2. This population will help elucidate the benefit/risk 
profile of the intervention and allow comparison across interventions. 
Use of control(s) 
A double-blind, randomized, controlled design limits bias for investigator assessments and for 
patient-reported outcomes and enables a clearer interpretation of the effects of an active 
intervention.  
Each ISA will have a concurrent control arm. Most ISAs will include a placebo control, serving 
this purpose as well as offering the opportunity for partial placebo borrowing (sharing of data 
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from placebo participants across ISAs), which over time can limit the number of patients 
exposed to inactive therapy. There is also a possibility for active-controlled trials comparing 2 
investigational interventions or comparing an investigational intervention to an approved 
product. As data accumulate, there is a similar opportunity for borrowing of data from active 
intervention arms, to be evaluated within the context of each ISA. 
The CWMM master protocol is designed to maintain consistency in the population across ISAs, 
within reason, to enable such efficiencies in the use of trial participant data. 
Optional prescreening 
Optional prescreening is included in the study design to reduce the number of screen failures. 
Race and ethnicity 
In this study, collection of demographic information includes ethnicity (in the United States and 
outside of the US as allowable by law) and race. The scientific rationale is based on the need to 
assess response in safety and/or efficacy based on race or ethnicity. Such a need can be 
addressed only if the relevant data are collected. 
4.3. 
Justification for Dose  
Justifications for doses of investigational interventions are provided in the relevant ISA. 
4.4. 
End of Study Definition  
The end of the master protocol will occur when all ISAs are complete, and no new ISAs 
are planned to be conducted under this master protocol. 
For each ISA, the end of the study is defined as the date of the last scheduled procedure of the 
last participant assigned to treatment in that ISA. 
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5. 
Study Population  
The study population is defined by the inclusion and exclusion criteria detailed here in the master 
protocol, together with any additional criteria defined in the concurrently evaluated ISA(s). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria before receiving a dose of study intervention as part of an ISA. 
Participant eligibility under the master protocol must be met to be eligible for randomization to 
an ISA. Additional eligibility criterion may apply for each particular ISA. 
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. 
For rescreening and retesting activities within the screening period, see Section 5.4. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in ISAs under the master protocol only if all of the 
following criteria apply: 
Age 
1. Participant must be 18 or the legal age of consent in the jurisdiction in which the study is 
taking place to 75 years of age inclusive, at the time of signing the informed consent. 
Weight 
2. Have a BMI of 
 ≥30 kg/m2, or  
 ≥27 kg/m2 and <30 kg/m2, with at least 1 weight-related comorbidity (for example 
hypertension, type 2 diabetes, dyslipidemia, cardiovascular disease, obstructive sleep 
apnea, hyperuricemia/gout, PCOS, urinary incontinence, osteoarthritis, chronic lower 
back pain/knee pain, metabolic dysfunction-associated steatotic liver disease 
[MASLD] or metabolic dysfunction-associated steatohepatitis [MASH], or chronic 
kidney disease). 
3. Have had a stable body weight for the 3 months prior to randomization (<5% body 
weight gain and/or loss). 
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Informed consent 
4. Capable of giving signed informed consent as described in Section 10.1.3, Appendix 1, 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this master protocol and in the relevant ISAs. 
Note: Contraceptive use should be consistent with local regulations regarding the 
methods of contraception for persons participating in clinical studies. For contraception 
requirements, see the relevant ISA. 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
Obesity related 
5. Have a prior or planned surgical treatment for obesity (except prior liposuction or 
abdominoplasty, if performed >1 year prior to screening). 
6. Have obesity induced by other endocrinologic disorders (for example, Cushing’s 
syndrome) or diagnosed monogenic or syndromic forms of obesity (for example, 
Melanocortin 4 Receptor deficiency or Prader–Willi Syndrome). 
7. Have or plan to have endoscopic and/or device-based therapy for obesity or have had 
device removal within the last 6 months prior to screening, including but not limited to 
 mucosal ablation 
 gastric artery embolization 
 intragastric balloon, and 
 duodenal-jejunal endoluminal liner. 
Other medical 
8. Have Type 1 diabetes mellitus, latent autoimmune diabetes in adults, or history of 
ketoacidosis or hyperosmolar coma. 
9. Have a history of significant active or unstable major depressive disorder or other severe 
psychiatric disorder, for example, schizophrenia, bipolar disorder, or other serious mood 
or anxiety disorder, within the last 2 years. 
Note: Participants with major depressive disorder or generalized anxiety disorder whose 
disease state is considered stable for the past 2 years and expected to remain stable 
throughout the course of the study, in the opinion of the investigator, may be considered 
for inclusion if they are not on excluded medications. 
10. Have a lifetime history of suicide attempt. 
11. Have a Patient Health Questionnaire-9 (PHQ-9) score of 15 or more at Visit 401 or 
Visit 0, prior to randomization within an ISA. 
12. Are, in the judgment of the investigator, actively suicidal and therefore deemed to be at 
significant risk for suicide. 
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13. On the Columbia Suicide-Severity Rating Scale (C-SSRS) at Visit 401 or Visit 0, prior to 
randomization, have 
 answered “yes” to either Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS and the ideation occurred within the past month. 
OR   
 answered “yes” to any of the suicide-related behaviors on the “suicidal behavior” 
portion of the C-SSRS and the behavior occurred within the past month.  
14. Have poorly controlled hypertension (that is, mean seated systolic BP ≥160 mm Hg or 
mean seated diastolic BP ≥100 mm Hg) at screening, renal artery stenosis, or evidence of 
labile BP including symptomatic postural hypotension. 
15. Have an elevated resting pulse rate (PR) (mean >100 bpm) or reduced resting pulse rate 
(mean <50 bpm) at screening. 
16. 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. 
17. Have ongoing or a history of frequent intermittent or chronic tachyarrhythmia syndromes, 
such as atrial fibrillation, supraventricular tachycardia, and positional orthostatic 
tachycardia syndrome. 
Note: Participants with a history of premature atrial contractions or premature ventricular 
contractions may be included. 
18. Have ongoing or a history of bradyarrhythmias other than sinus bradycardia. 
19. Have a history of NYHA Functional Classification III or IV congestive heart failure (see 
Section 10.7). 
20. Have a screening electrocardiogram (ECG) with abnormalities that may interfere with the 
interpretation of changes in ECG intervals as determined by the investigator. 
21. Have a personal or family history of long QT syndrome, a family history of sudden death 
in a first-degree relative (parents, siblings, or children) before the age of 40 years, or a 
personal history of unexplained syncope within the last year. Use of prescription or over-
the-counter medications known to significantly prolong the QT or corrected QT interval 
(QTc) interval at screening. 
22. Have a history of symptomatic gallbladder disease within the past 2 years, defined by the 
presence of gallstones on an imaging study and abdominal pain attributed to the 
gallstones by the participant’s physician; subjects who had a procedure to remove the 
gallstones and/or the gallbladder (cholecystectomy), with no long-term complications, are 
eligible for participation if the procedure was completed at least 3 months prior to 
screening. 
23. Have signs and symptoms of any liver disease other than nonalcoholic fatty liver disease, 
or any of the following, as determined by the central laboratory during screening: 
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 alanine aminotransferase (ALT) level >3.0x upper limit of normal (ULN) for 
the reference range 
 alkaline phosphatase (ALP) level ≥1.5x ULN for the reference range, or 
 total bilirubin (TBL) ≥1.5x ULN for the reference range, except for cases of 
known Gilbert’s Syndrome. 
24. Have evidence of hypothyroidism or hyperthyroidism based on clinical evaluation and/or 
an abnormal thyroid-stimulating hormone that, in the opinion of the investigator, would 
pose a risk to patient safety. Subjects on a stable dose of thyroid replacement therapy for 
at least the prior 3 months who are clinically euthyroid and who are anticipated to remain 
on this dose throughout the trial period may be eligible if they meet the other criteria. 
25. Have evidence of a significant, uncontrolled endocrine abnormality, for example, 
thyrotoxicosis or adrenal crisis, in the opinion of the investigator. 
26. Have a history of an active or untreated malignancy or are in remission from a 
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. 
27. Have evidence of human immunodeficiency virus (HIV) and/or positive HIV antibodies 
historically or at screening. 
28. Have evidence of hepatitis B and/or positive hepatitis B surface antigen (Section 8.2.11). 
29. Have hepatitis C as defined by a positive hepatitis C virus (HCV) RNA test  
30. Have a history of any other condition, such as known drug or alcohol abuse, diagnosed 
eating disorder, or other psychiatric disorder, that, in the opinion of the investigator, may 
preclude the participant from following and completing the protocol. 
31. Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14 
units per week (females) (1 unit = 12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 
1.5 oz or 45 mL of distilled spirits). 
32. Have a history of frequent use of marijuana or tetrahydrocannabinol (THC-containing 
products) within 3 months of enrollment or unwillingness to abstain from marijuana or 
THC-containing products use during the trial. Patients should refrain from using during 
study participation. 
Note: If a participant has used cannabidiol oil during the past 3 months but agrees to 
refrain from use for the duration of the study, the participant can be enrolled. 
33. Have had a transplanted organ (corneal transplants [keratoplasty] are allowed) or are 
awaiting an organ transplant. 
34. Have had a blood donation of greater than 500 mL within 8 weeks prior to study 
screening, or a blood transfusion or severe blood loss within the prior 3 months, or have 
known hemoglobinopathy (for example, hemolytic anemia and sickle cell anemia), or 
have a hemoglobin value <11 g/dL (males) or <10 g/dL (females) at screening.  
Note: Blood donation criteria should be consistent with local regulations. 
35. Have evidence of a significant active, uncontrolled medical condition, or a history of any 
medical problem capable of constituting a risk when taking the study medication or 
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interfering with the interpretation of data, as judged by the screening investigator at 
screening. 
36. 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 9 months. 
Prior/concomitant therapy 
37. Unless otherwise specified, all concomitant medications should be at a stable dose for at 
least 3 months prior to randomization (with the exception of highly effective 
contraceptive methods if applicable and as stated within the respective ISA).  
38. Are receiving or have received within 3 months prior to screening chronic (>2 weeks) 
systemic glucocorticoid therapy, excluding topical, intraocular, intranasal, inhaled, or 
single intraarticular injection. 
39. Have current treatment with or a history of treatment with (within 3 months prior to 
screening) medications that may cause significant weight gain including, but not limited 
to, tricyclic antidepressants, atypical antipsychotics, and mood stabilizers. However, 
participants at a stable dose (greater than 6 months and with no expectation that the dose 
will change within the next year) and who are weight stable for the last 3 months on these 
medications may be included in the study.  
Examples of such medications 
 imipramine 
 amitriptyline 
 mirtazapine 
 paroxetine 
 phenelzine 
 chlorpromazine 
 thioridazine 
 clozapine 
 olanzapine 
 valproic acid and its derivatives, and 
 lithium. 
40. Within 3 months prior to screening, have taken medications (prescribed or over the 
counter) or alternative remedies (including herbal or nutritional supplements) that 
promote weight loss 
Examples include, but are not limited to 
 Saxenda® (liraglutide 3.0 mg) or other GLP-1 RA 
 Xenical®/alli® (orlistat) 
 Meridia® (sibutramine) 
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 Acutrim (phenylpropanolamine) 
 Sanorex® (mazindol) 
 Adipex-P® or LomairaTM (phentermine) 
 BELVIQ® (lorcaserin) 
 Qsymia® (phentermine/topiramate combination) 
 Contrave® (naltrexone/bupropion) 
 Zepbound® or Mounjaro® (tirzepatide)  
 Wegovy® or Ozempic® (semaglutide), and 
 other similar body weight loss medication, including over-the-counter 
medications. 
41. Are taking a central nervous system stimulant, for example, Ritalin-SR
, Adderall XR®, 
with the exception of caffeinated beverages. 
42. Evidence of regular use, in the opinion of the investigator, of known drugs of abuse. 
Prior/concurrent clinical study experience 
43. Are currently enrolled in any other clinical study involving an investigational product or 
any other type of medical research judged not to be scientifically or medically compatible 
with this study. 
44. Have participated, within the last 3 months, in a clinical study and received 
pharmacologic treatment, whether active or placebo. If the study involved an IP, at least 5 
elimination half-lives or 3 months, whichever is longer, should have passed. 
45. Have participated, within the last 12 months, in a clinical study of weight loss medication 
and received pharmacologic treatment, whether active or placebo. 
Other exclusions 
46. Are females who are currently pregnant or breastfeeding, or who intend to become 
pregnant or to breastfeed at any time during the study or within 20 weeks or 5 half-lives, 
whichever is longer, after receiving the last dose of study intervention. 
47. 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. 
48. Are employees of Lilly or are employees of a third-party organization involved in the 
study that requires exclusion of their employees. 
49. 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), site personnel will provide diet and physical activity counseling and 
will encourage the participants to be compliant with diet and physical activity 
recommendations. 
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Diet – Participants should follow the diet recommendations provided by the study site or given 
in Section 10.9.1. 
For most 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. 
Caffeine, alcohol, and tobacco – Except when fasting is required, participants will be allowed 
to maintain their regular caffeine consumption throughout the study period. 
Alcohol will not be permitted at least 24 hours prior to the study site visits, until the participant 
has been discharged from the clinical research site. 
Participants should not consume more than 10 cigarettes or equivalent per day. 
Physical activity – Participants may be advised by the study site to increase their regular levels 
of physical activity during the study per suggestions in Section 10.9.2. Participants will be 
advised to avoid strenuous physical activity within 24 hours prior to each study site visit if 
possible. 
Blood donation – Study participants should be instructed not to donate blood or blood products 
during the study and for  weeks following the study. 
5.4. 
Screen Failures  
Consenting to, and screening for the CWMM master protocol and relevant ISAs will occur prior 
to participants being randomized or assigned to an ISA. 
A screen failure occurs when a participant who consents to screening as above but is not 
subsequently randomized to any ISA or is randomized to an ISA but is not randomized to 
treatment. A minimal set of screen failure information is required to ensure transparent reporting 
of screen failures 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). 
Individuals who are not eligible for participation in this master protocol or are ineligible for 
relevant ISAs (screen failure) may be rescreened. If a participant does not complete screening 
procedures within 
 weeks of signing the informed consent forms to confirm eligibility for the 
master and applicable ISAs, the participant is considered a screen failure. Individuals may 
rescreen 2 times. 
Rescreened participants should be assigned a new participant number. Each time master protocol 
or ISA rescreening is performed, the individual must sign a new master protocol ICF and ISA 
ICF(s), as applicable. A screen failure from an ISA who undergoes rescreening under the 
CWMM master protocol may not require repeating all V401 screening activities if the activities 
have been completed within 
 weeks of the participant’s randomization to a treatment in an 
ISA. The original laboratory data from the previous participant number will be transferred to the 
new participant number in instances where this is applicable. 
Repeating laboratory tests during the screening period or repeating screening tests to comply 
with the protocol-designated screening period does not constitute rescreening. 
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5.5. 
Criteria for Temporarily Delaying Randomization of a Participant  
This section is not applicable to this master protocol. All entry criteria must be met within the 
specified intervals in the SoA. 
A study site could experience a period of time in which no ISA is active at that site. During that 
time period, screening for the master protocol may continue, but the allowed screening duration 
of the master protocol, defined in Section 1.3.1 in weeks relative to Week  must still be 
observed. Participants who have not been assigned to an active ISA before the end of the master 
protocol screening visit (Visit 401) must undergo rescreening if they wish to continue their study 
participation. 
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6. 
Study Intervention(s) and Concomitant Therapy  
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to or used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
Study interventions and, if applicable, investigational medical devices are described in the ISAs. 
6.2. 
Preparation, Handling, Storage, and Accountability  
See the relevant ISA. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
Blinding will be maintained throughout the conduct of studies performed under this master 
protocol. Instances where unblinding may be undertaken are described in the separate 
Unblinding Plan. 
Method of treatment assignment 
Assignment to the ISAs and to the treatment groups within the ISAs will be determined by a 
computer-generated random sequence using an interactive web-response system (IWRS). The 
randomization ratios are specified in the individual ISAs. ISAs will have randomization ratio 
details which will depend on anticipated timing of ISA entry, number of active ISAs, required 
number of participants to be assigned to an active treatment group in the ISA, and desired 
number of placebo participants to maintain the blind and minimize bias. 
Emergency unblinding 
Emergency unblinding for AEs 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 actions resulting in an unblinding event are recorded and reported by the IWRS. 
The investigator has the sole responsibility for determining if unblinding of a participants’ 
intervention assignment is warranted in case of an emergency. Participant safety must always be 
the first consideration in making such a determination. If the investigator decides that unblinding 
is warranted, it is the responsibility of the investigator to promptly document the decision and 
rationale and notify the sponsor as soon as possible. 
Discontinuation after unblinding 
If an investigator, site staff performing assessments, or participant is unblinded, the participant 
must be permanently discontinued from study intervention but should continue in the study for 
efficacy and safety endpoint evaluations and monitoring for all visits. 
Additional measures to minimize bias 
Additional measures to minimize bias may be described in the ISAs. 
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6.4. 
Study Intervention Compliance  
This CWMM master protocol section describes compliance for all ISAs. If there are additional 
ISA-specific measures to assure or assess compliance or adherence, these measures will be 
described in an individual ISA. 
Participant compliance with ISA study interventions should be assessed at each visit. 
In addition to the assessment of a participant’s compliance with administration of study 
interventions, other aspects of compliance with the study treatments should be assessed at each 
visit based on the participant’s adherence to the visit schedule, completion of study diaries when 
applicable, and any other parameters the investigator considers necessary. 
Participants considered to be poorly compliant with their study intervention 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. Additionally, any specific management of 
treatment exposures required as a result of poor compliance will be guided by language in the 
ISAs. 
6.5. 
Dose Modification  
Dose modifications, if allowed, are described in the relevant ISA. 
6.6. 
Continued Access to Study Intervention after the End of the Study  
Study intervention will not be available at the end of any ISA. 
6.7. 
Treatment of Overdose  
See the relevant ISA. 
6.8. 
Prior and Concomitant Therapy  
Newly prescribed medications 
Investigative site staff will inform participants they must consult with the investigator or a 
designated site staff member upon being prescribed any new medications during the screening 
period or following assignment to an ISA. 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. 
If the need for additional concomitant medication arises, the participant may be continued in the 
study and on study intervention if, in the investigator’s opinion, the addition of the new 
medication does not pose a safety risk and the medication is not excluded. If an additional 
concomitant medication is started, the sponsor should be informed as soon as possible. 
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Permitted medications 
Participants will be permitted to use concomitant medications that they require during the study, 
except certain medications, for example, other medications for weight management, that may 
interfere with the assessment of safety and efficacy characteristics of the study treatments. 
Doses of other prescription medications for treatment of concurrent medical conditions should 
remain constant during the study unless an adjustment is medically indicated. For example, doses 
of antihypertensive medication may be reduced if the participant’s BP declines significantly 
during the study. 
Any medication or vaccine (including over the counter or prescription medicines and 
acetaminophen/paracetamol), vitamins, and/or herbal supplements that the participant is 
receiving at the time of enrollment or receives during the study must be recorded in the case 
report form (CRF). Nonsteroidal anti-inflammatory medications (including ibuprofen and 
aspirin), acetaminophen, cough suppressants, antihistamines, antibiotics, and topical ointments 
may be used on an as-needed basis without notifying the sponsor and are not restricted by the 
stable dosing requirements listed earlier. 
Prohibited medications 
Treatment with, or initiation of, medications that are excluded in the entry criteria (Section 5.2 in 
this master protocol and, if applicable, in the relevant ISA) may not be used during the study. 
Some medications required for the management of incident diabetes or incident heart failure 
(sodium-glucose cotransporter-2 [SGLT2] inhibitors) may be allowed in some ISAs. Specific 
details may be found in the ISA. 
Hormone replacement therapy in postmenopausal females and contraceptives containing an 
estrogen and a progestin (oral or transdermal system) in premenopausal females should not be 
started after entering the study. If initiation of such hormonal therapies during the course of the 
study is deemed necessary by the participant’s clinical care team, this may be allowable after 
consultation with the study medical monitor. 
The sponsor should be contacted if a participant starts treatment with a medication that is 
prohibited by the protocol. 
Prescription or over-the-counter medications that are indicated for weight loss are exclusionary if 
used within 3 months prior to screening or between screening and randomization. These 
medications are also not allowed at any time during the treatment period. If started after 
randomization, the medications should be immediately withdrawn. Participants who refuse to 
withdraw the weight loss medications must be discontinued from study intervention (see Section 
7.1). 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
The following sections describe reasons for 
● temporary or permanent discontinuation of a participant’s dosing (discontinuation of 
study intervention), and 
● discontinuation (withdrawal) of a participant from the study. 
For discontinuation of study sites, of ISAs, or of this master protocol as a whole, see 
Section 10.1.9. 
7.1. 
Discontinuation of Study Intervention  
Continuing in the study after discontinuation of study intervention 
When necessary, a participant may be permanently discontinued from study intervention. If 
so, the participant should discontinue the study intervention (treatment) and remain in the study 
and follow select procedures for all remaining study visits, as shown in the SoA of the ISA. 
See this master protocol (Section 8) and the relevant ISA (Section 1.3 [SoA] and Section 8) for 
data to be collected at the time of discontinuation from the study intervention and for activities in 
the posttreatment follow-up period and for any further evaluations that need to be completed. 
Contact the relevant ISA’s Lilly-designated medical monitor to determine procedures that may 
not be necessary for participants who discontinue the study intervention early. 
Possible reasons for discontinuation of study intervention 
The following reasons for early permanent discontinuation of study intervention apply to any 
ISA conducted under this master protocol. 
 Participant decision 
o the participant or the participant’s designee, for example, parents or legal guardian, 
requests to discontinue investigational product. 
 Investigator decision 
o the investigator decides that the participant should be discontinued from the study 
medication. 
 If participants answered “yes” to Question 4 or Question 5 on the “Suicidal Ideation” 
portion of the C-SSRS or answered “yes” to any of the suicide-related behaviors on the 
Suicidal Behavior portion of the C-SSRS. A psychiatrist or appropriately trained 
professional may assist in the decision to discontinue the participant. 
 If the investigator determines that a systemic hypersensitivity reaction has occurred 
related to study intervention administration, the participant may be permanently 
discontinued from the study intervention, and the Lilly-designated medical monitor 
should be notified. If the investigator is uncertain about whether a systemic 
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hypersensitivity reaction has occurred and whether discontinuation of study intervention 
is warranted, the investigator may consult the sponsor. 
 Any non-study medication for weight loss is given for more than 1 week, or more than 1 
dose of weekly medication. 
 Participants will be discontinued from the investigational product in the following 
circumstances: 
o diagnosis of cirrhosis after randomization 
o diagnosis of an active or untreated malignancy (other than basal or squamous cell 
skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) after 
randomization 
o any treatment-emergent adverse event (TEAE), SAE, or clinically significant 
laboratory value for which the investigator believes that permanent study drug 
discontinuation is the appropriate measure to be taken 
o a female participant becomes pregnant, and 
o diagnosis of Type 1 diabetes mellitus or latent autoimmune diabetes in adults. 
 If the participant develops any exclusion criterion during the course of the study, the 
investigator should call the sponsor to determine whether discontinuation of study drug is 
necessary, and 
 Significant noncompliance with the protocol. 
 
7.1.1. 
Hepatic Criteria for Study Drug Interruption or Discontinuation  
Refer to Section 8.2.10 for hepatic criteria for study drug interruption or discontinuation. 
7.1.2. 
QTc Stopping Criteria  
If a clinically significant finding is identified, including but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula (QTcF) after enrollment, the investigator or 
qualified designee will determine if the participant can continue the study intervention and if any 
change in participant management is needed. This review of the ECG printed at the time of 
collection must be documented. Any new clinically relevant finding should be reported as an 
adverse event (AE). 
7.1.3. 
Temporary Interruption of Study Intervention  
During the treatment period of an ISA, the investigator may interrupt a participant’s study 
intervention, for example, due to an AE or a clinically significant laboratory value. The dates of 
study intervention interruption and restart must be documented. 
Details regarding temporary discontinuation or interruption and re-introduction of study 
intervention, if applicable, are described in the ISAs. 
7.1.4. 
Rechallenge  
Details regarding restarting study intervention, if applicable, are described in the ISAs. 
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7.2. 
Participant Discontinuation/Withdrawal from the Study  
Discontinuation is expected to be uncommon. 
A participant may withdraw from the master protocol or ISA 
● at any time at the participant’s own request for any reason or without providing 
any reason 
● at the request of the participant’s designee (for example, parents or legal 
guardian) 
● at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons 
● if enrolled in any other clinical study involving an investigational product, or 
enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study, and 
● if the participant, for any reason, requires treatment with a therapeutic agent that 
is prohibited by the protocol and has been demonstrated to be effective for 
treatment of the study indication. In this case, discontinuation from the study 
occurs prior to introduction of the new agent. 
At the time of discontinuing from the study, if possible, the participant will complete procedures 
for an early discontinuation visit and posttreatment follow-up, if applicable, as shown in the SoA 
of the relevant ISA. If the participant has not already discontinued the study intervention, the 
participant will be permanently discontinued from the study intervention at the time of the 
decision to discontinue the study. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. If a participant 
withdraws from the study, the participant may request destruction of any samples taken and not 
tested, and the investigator must document this in the site study records. 
7.3. 
Lost to Follow Up  
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the study site. Site personnel or designee are expected to 
make diligent attempts to contact participants who fail to return for a scheduled visit or were 
otherwise unable to be followed up by the site. 
 
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8. 
Study Assessments and Procedures  
Study procedures and their timing are summarized in the CWMM master protocol SoA (Section 
1.3) and in the SoA of the relevant ISA. 
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 CWMM and relevant study design elements, including those specified in the 
SoA and the inclusion and exclusion criteria, is essential and required for proper study execution. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria, including establishing eligibility for the CWMM master protocol and 
all currently available ISAs at the time of screening. Additionally, participant eligibility for a 
given ISA will be confirmed at the time of randomization to treatment within the ISA. 
Unless otherwise specified in the relevant ISA, safety and efficacy assessments and sample 
collections should be completed prior to dosing at the dosing visits. 
8.1. 
Efficacy Assessments  
Efficacy-related assessments occur at visits specified in the CWMM master protocol SoA 
(Section 1.3) and in the relevant ISA. 
Efficacy endpoints are described in this master protocol and the relevant ISA. 
Primary 
The primary efficacy measure is percent change body weight from baseline at the primary time 
point. Body weight measurements will be collected at specific clinic visits as summarized in the 
CWMM SoA (Section 1.3.1) and the SoA of the relevant ISA. Methods for measuring body 
weight are described in CWMM Section 10.8. 
Secondary 
The following secondary efficacy measure will be collected or calculated at the times shown in 
the CWMM SoA (Section 1.3.1) and the SoA of the relevant ISA: 
 body weight, and 
 BMI 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.1.1. 
Bioelectrical Impedance Analysis  
A whole-body bioelectrical impedance analyzer will be used to assess endpoints related to body 
composition, as detailed in Section 10.13.  
8.2. 
Safety Assessments  
Visits and safety assessments 
Safety assessments occur at visits specified in this master CWMM master protocol SoA (Section 
1.3) and in the SoA of the relevant ISA. 
Data collection and reporting 
The AE data collection and reporting requirements are described in Section 8.3 and Section 10.3, 
Appendix 3. 
For some interventions studied under this master protocol, there may be predefined adverse 
events of special interest (AESIs) or safety topics for monitoring beyond what is specified in this 
Master Protocol. If so, appropriate additional sample or data collections for AESIs or safety 
topics for monitoring will be specified in the ISAs. 
Safety data monitoring 
Each site’s principal investigator will monitor safety data from their site throughout the study. 
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. 
Sponsor safety monitoring 
The sponsor will monitor the safety data, including AEs and SAEs, discontinuations, vital signs, 
and clinical laboratory results by means of periodic blinded reviews and by other appropriate 
methods. The SAE reports will be reviewed in real time and across studies and will include 
review of applicable clinical safety and epidemiological publications from the literature. If this 
safety monitoring activity uncovers an issue that needs to be addressed by unblinding at the 
individual or group level, members of the IAC can conduct additional analyses of the safety data. 
The IAC is an advisory group for this study formed to protect the integrity of the study in 
unblinded safety data reviews. See Section 10.1, Appendix 1, Section 10.1.5. 
Appropriateness of safety assessments 
The safety assessments used in this study are routine elements of clinical health assessment and 
Phase 2 drug development. 
Safety assessments described in this master protocol and in ISAs 
The following sections describe safety assessments applicable to all ISAs. 
See the ISAs for any additional safety assessments that may be applicable to a particular ISA. 
8.2.1. 
Vital Signs  
For each participant, vital sign measurements should be conducted according to the SoA (Section 
1.3) and following the study-specific recommendations for performing these measurements 
included in Section 10.8. 
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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 CRF. 
8.2.2. 
Physical Examinations  
For each participant, measurements including height and weight should be conducted according 
to the master protocol SoA and the ISA-specific SoA and following the study-specific 
recommendations for performing these measurements included in Section 10.8. 
A complete physical examination will include, at a minimum, assessments of the 
• skin, including feet 
• cardiovascular system 
• respiratory system 
• GI system 
• neurological system, and 
• thyroid. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
8.2.3. 
Electrocardiograms  
Prior to collecting any blood samples, 12-lead ECGs will be collected for each participant as 
specified in the CWMM master protocol SoA (Section 1.3) and ISA SoA. 
ECGs may also be collected at visits specified in the relevant ISA and at additional visits or time 
points when deemed clinically necessary. 
 All V401 screening ECGs are to be collected locally. 
 All digital single and triplicate ECGs, as applicable in an ISA, will be obtained using 
centrally provided ECG machines and will be electronically transmitted to a designated 
central ECG laboratory. 
 12-lead ECGs should be obtained after the participant has rested in a supine (or semi-
supine) position for at least 10 minutes. 
ECGs should be collected prior to collection of blood samples for laboratory testing, including 
PK samples. 
For ECGs recorded in triplicate, consecutive replicate ECGs will be obtained at approximately 1-
minute intervals and within 30 minutes prior to PK collection. 
ECGs may be obtained at additional times, when deemed clinically necessary. Collection of 
more ECGs than expected at a particular time point is allowed when needed to ensure high-
quality records. 
ECGs 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, to determine whether the participant meets entry criteria or 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 
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receives the first dose of the investigational treatment should be reported in the CRF and to Lilly 
or its designee as an AE. The investigator (or qualified designee) must document their review of 
the ECG printed at the time of evaluation. 
After enrollment, if a clinically significant increase in the QT/QTc interval from baseline or 
other clinically significant quantitative or qualitative change from baseline is identified by the 
investigator, the participant will be assessed by the investigator for symptoms (for example, 
palpitations, near syncope, or syncope) and to determine whether the participant can continue in 
the study. The investigator or qualified designee is responsible for determining if any change in 
participant management is needed and must document his/her review of the ECG printed at the 
time of evaluation from at least 1 of the replicate ECGs from each time point. The central ECG 
laboratory will perform a basic quality control check (for example, demographics and study 
details) of the digital ECG and then store the ECGs in a database. At a future time, the stored 
ECG data may be over-read by a cardiologist at the central ECG laboratory for further evaluation 
of machine-read measurements or to meet regulatory requirements. 
ECGs will also be machine read for central evaluation of ECG parameters. The machine-read 
ECG intervals and HR may be used for data analyses and report-writing purposes, unless a 
cardiologist over-reading of the ECGs is conducted prior to completion of the final study report 
(in which case, the over-read data will be used). 
8.2.4. 
Clinical Safety Laboratory Tests  
Section 10.2 and the SoA (Section 1.3) lists the clinical laboratory tests to be performed during 
the screening period of this master protocol. See the relevant ISA for clinical laboratory tests to 
be performed during the study periods of an ISA. 
All protocol-required laboratory assessments, as defined in the ISAs and in this master protocol, 
must be conducted in accordance with the SoAs, standard collection requirements, and the 
laboratory manuals. 
Report the information as an AE 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. 
Reviewing and recording test results 
The investigator must review the laboratory results, document this review, and report any 
clinically relevant changes occurring during the study as an AE. The laboratory results 
must be retained with source documents unless a Source Document Agreement or 
comparable document cites an electronic location that accommodates the expected 
retention duration. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
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Repeat testing after a clinically significant abnormal finding 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or 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 Lilly-designated medical monitor. 
If such values do not return to normal or baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor notified. 
8.2.5. 
Major Adverse Cardiovascular Events  
Nonfatal and fatal 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 and fatal cardiovascular AEs to be adjudicated include 
 myocardial infarction 
 cerebrovascular events, including cerebrovascular accident (stroke) and transient 
ischemic attack deaths due to cardiovascular or unexplained causes 
 hospitalization for unstable angina or heart failure, and 
 coronary interventions, such as coronary artery bypass graft or percutaneous coronary 
intervention. 
8.2.6. 
Deaths  
All deaths will be adjudicated by a committee of physicians external to Lilly. This committee 
will be blinded to treatment assignment. 
8.2.7. 
Hepatobiliary Disorders  
All events of treatment-emergent biliary colic, cholecystitis, or other suspected events related to 
gallbladder disease should be evaluated and additional diagnostic tests performed, as needed. In 
cases of elevated liver laboratory tests, hepatic monitoring should be initiated as outlined in this 
CWMM master protocol. 
8.2.8. 
Acute Renal Events  
Renal safety will be assessed based on repeated renal functional assessment as well as 
assessment of AEs suggestive of acute renal failure or worsening of preexisting chronic renal 
failure. 
8.2.9. 
Pregnancy Testing  
Pregnancy testing at Visit 401 
Serum pregnancy testing will be performed using a central study laboratory during the screening 
period of this master protocol (Sections 1.3 and 10.2). 
Pregnancy testing after Visit 401 
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Urine pregnancy testing after Visit 401 will be performed locally according to the SoA of the 
relevant ISA if required. If a urine pregnancy test is not available, a serum pregnancy test 
performed by a local laboratory is an acceptable alternative. 
If a urine pregnancy test is inconclusive at any visit, an additional serum pregnancy test should 
be performed. If the specified visit includes administration of study intervention, the pregnancy 
test must be “negative” within 24 hours before the study intervention is administered. 
Pregnancy testing at any time during the study 
Additional pregnancy testing may be performed at any time in the study, at the discretion of the 
investigator, if the participant’s menstrual period is missed or there is clinical suspicion of 
pregnancy, or as required by local law or regulation. 
Discontinuation of participants who are pregnant 
Participants who are pregnant will be permanently discontinued from the study intervention 
(Section 7.1). 
8.2.10. 
Hepatic Safety Monitoring, Evaluation, and Criteria for Study Drug 
Interruption or Discontinuation  
The following tables summarize actions to take based on abnormal hepatic laboratory or clinical 
changes. 
Participants with normal or near normal baseline (ALT, AST, or ALP <1.5x ULN) 
If this laboratory value is observed… 
Then… 
Initiate or 
continue 
close hepatic 
monitoring 
Initiate  
comprehensive 
evaluation 
Interrupt or 
discontinue  
study drug 
ALT or AST ≥3x ULN 
X 
 
 
ALP ≥2x ULN  
X 
 
 
TBL ≥2x ULNb 
X 
 
 
ALT or AST ≥5x ULN 
X 
X 
 
ALP ≥2.5x ULN 
X 
X 
 
ALT or AST ≥3x ULN with hepatic signs or symptomsa  
X 
X 
X 
ALT or AST ≥5x ULN for more than 2 weeks  
X 
X 
X 
ALT or AST ≥8x ULN 
X 
X 
X 
ALT or AST ≥3x ULN and TBL ≥2x ULNb or INR ≥1.5 
X 
X 
X 
ALP ≥3x ULN  
X 
X 
X 
ALP ≥2.5x ULN and TBL ≥2x ULNb 
X 
X 
X 
ALP ≥2.5x ULN with hepatic signs or symptomsa 
X 
X 
X 
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
b In participants with Gilbert’s syndrome, the threshold for TBL may be higher. 
 
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Participants with elevated baseline (ALT, AST, or ALP ≥1.5x ULN) 
If this laboratory value is observed… 
Then… 
Initiate or 
continue 
close hepatic 
monitoring 
Initiate  
comprehensive 
evaluation 
Interrupt 
or 
discontinue  
study drug 
ALT or AST ≥2x baseline  
X 
 
 
ALP ≥2x baseline  
X 
 
 
TBL ≥2x ULNb 
X 
 
 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) 
X 
X 
 
ALP ≥2.5x baseline 
X 
X 
 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) with hepatic signs or symptomsa  
X 
X 
X 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) for more than 2 weeks  
X 
X 
X 
ALT or AST ≥4x baseline or ≥400 U/L (whichever occurs 
first) 
X 
X 
X 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) and TBL ≥2x ULNb or INR ≥1.5 
X 
X 
X 
ALP ≥3x baseline  
X 
X 
X 
ALP ≥2.5x baseline and TBL ≥2x ULNb 
X 
X 
X 
ALP ≥2.5x baseline with hepatic signs or symptomsa 
X 
X 
X 
If this laboratory value is observed… 
Then… 
Initiate or 
continue 
close hepatic 
monitoring 
Initiate  
comprehensive 
evaluation 
Interrupt 
or 
discontinue  
study drug 
ALT or AST ≥2x baseline  
X 
 
 
ALP ≥2x baseline  
X 
 
 
TBL ≥2x ULNb 
X 
 
 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) 
X 
X 
 
ALP ≥2.5x baseline 
X 
X 
 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) with hepatic signs or symptomsa  
X 
X 
X 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) for more than 2 weeks  
X 
X 
X 
ALT or AST ≥4x baseline or ≥400 U/L (whichever occurs 
first) 
X 
X 
X 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) and TBL ≥2x ULNb or INR≥1.5 
X 
X 
X 
ALP ≥3x baseline  
X 
X 
X 
ALP ≥2.5x baseline and TBL ≥2x ULNb 
X 
X 
X 
ALP ≥2.5x baseline with hepatic signs or symptomsa 
X 
X 
X 
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a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, 
fever, rash, and/or eosinophilia >5%. 
b In participants with Gilbert’s syndrome, the threshold for TBL may be higher. 
 
8.2.10.1. Close Hepatic Monitoring  
If a participant develops any 1 of these changes, initiate close hepatic monitoring: 
Participants with normal or near normal baseline 
(ALT, AST, or ALP <1.5x ULN) 
Participants with elevated baseline (ALT, AST, or 
ALP ≥1.5x ULN) 
ALT or AST ≥3x ULN or 
ALT or AST ≥2x baseline  
ALP ≥2x ULN or 
ALP ≥2x baseline  
TBL ≥2x ULNa   
TBL ≥2x ULNa 
a In participants with Gilbert’s syndrome, the threshold for TBL may be higher. 
 
Close hepatic monitoring should include these actions: 
 
Laboratory tests (Section 10.2), including ALT, AST, ALP, TBL, D. Bil, GGT, CK, and 
CBC with differential, should be checked within 48 to 72 hours of the detection of 
elevated liver tests to confirm the abnormality and to determine if it is increasing or 
decreasing. 
 
If the abnormality persists, clinical and laboratory monitoring should continue at a 
frequency of 2 to 3 times weekly until levels normalize or return to approximate baseline 
values.  
 
In addition to lab tests, basic evaluation for possible causes of abnormal liver tests should 
be initiated by the investigator in consultation with the Lilly-designated medical monitor. 
At a minimum, this evaluation should include physical examination and a thorough 
medical history, including current symptoms, recent illnesses (for example, heart failure, 
systemic infection, hypotension, or seizures), recent travel, concomitant medications 
(including over-the-counter), herbal and dietary supplements, history of alcohol drinking 
and other substance abuse. 
 
8.2.10.2. Comprehensive Hepatic Evaluation  
If a participant develops any 1 of the following laboratory or clinical changes, initiate a 
comprehensive hepatic evaluation.  
Participants with normal or near normal 
baseline (ALT, AST, or ALP <1.5x ULN) 
Participants with elevated baseline (ALT, AST, or ALP 
≥1.5x ULN) 
ALT or AST ≥5x ULN or 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) or 
ALP ≥2.5x ULN or 
ALP ≥2.5x baseline or 
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ALT or AST ≥3x ULN with hepatic signs or 
symptomsa or 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) with hepatic signs or symptomsa or 
ALT or AST ≥3x ULN and TBL ≥2x ULNb or 
INR ≥1.5 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) and TBL ≥2x ULNb or INR ≥1.5 
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
b In participants with Gilbert’s syndrome, the threshold for TBL may be higher. 
 
Comprehensive hepatic evaluation should include these actions: 
 
At a minimum, comprehensive hepatic evaluation should include physical examination 
and a thorough medical history, as outlined above, as well as tests for PT-INR; tests for 
viral hepatitis A, B, C, and E; tests for autoimmune hepatitis; and an abdominal imaging 
study (for example, ultrasound or CT scan).  
 
Based on the participant’s history and initial results, further testing should be considered 
in consultation with the Lilly-designated medical monitor, including tests for hepatitis D 
virus, 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, and additional tests including magnetic resonance 
cholangiopancreatography, endoscopic retrograde cholangiopancreatography, cardiac 
echocardiogram, or a liver biopsy.   
 
Clinical and laboratory monitoring should continue at a frequency of 1 to 3 times weekly 
until levels normalize or return to approximate baseline values.  
 
All the medical information and tests results related to the hepatic monitoring and 
comprehensive hepatic evaluation should be collected and recorded in a hepatic safety 
CRF.  
 
8.2.10.3. Study Drug Interruption or Discontinuation  
If a participant develops any 1 of the following laboratory or clinical changes, interrupt the study 
drug and continue close monitoring and comprehensive hepatic evaluation as described in 
Sections 8.2.10.1 and 8.2.10.2.  
Participants with normal or near normal 
baseline (ALT, AST, or ALP <1.5x ULN) 
Participants with elevated baseline (ALT, AST, or ALP 
≥1.5x ULN) 
ALT or AST ≥3x ULN with hepatic signs or 
symptomsa or 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) with hepatic signs or symptomsa or 
ALT or AST ≥5x ULN for more than 2 weeks 
or 
ALT or AST ≥3x baseline or ≥250 U/L 
(whichever occurs first) for more than 2 weeks or 
ALT or AST ≥8x ULN or 
ALT or AST ≥4x baseline or ≥400 U/L (whichever occurs 
first) or 
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ALT or AST ≥3x ULN and TBL ≥2x ULNb or 
INR ≥1.5 or 
ALT or AST ≥2x baseline or ≥250 U/L 
(whichever occurs first) and TBL ≥2x ULNb or INR ≥1.5 or 
ALP ≥3x ULN or 
ALP ≥3x baseline or 
ALP ≥2.5x ULN and TBL ≥2x ULNb or 
ALP ≥2.5x baseline and TBL ≥2x ULNb or 
ALP ≥2.5x ULN with hepatic signs or 
symptomsa 
ALP ≥2.5x baseline with hepatic signs or symptomsa  
a Examples of hepatic signs or symptoms: severe fatigue, nausea, vomiting, right upper quadrant abdominal pain, fever, rash, 
and/or eosinophilia >5%. 
b In participants with Gilbert’s syndrome, the threshold for TBL may be higher.  
 
Interruption or discontinuation of study drug should include these actions: 
 
While the participant is not receiving the study drug, clinical and laboratory monitoring 
should continue at a frequency of 1 to 3 times weekly until liver tests normalize or return 
to approximate baseline values.  
 
If the hepatic event continues past the anticipated end of the study (that is, data lock) the 
investigator should consult with the Lilly-designated medical monitor to determine the 
need for further data collection beyond the end date of the study (that is, data lock date). 
 
All the medical information and tests results related to the close hepatic monitoring and 
comprehensive hepatic evaluation should be collected and recorded in a hepatic safety 
CRF.  
 
Resumption of the study drug after interruption for a hepatic reason can be considered 
only in consultation with the Lilly designated medical monitor and only if the liver test 
results returned to near baseline and if a self-limited, non-study drug etiology is 
identified. Otherwise, the study drug should be permanently discontinued. 
8.2.11. 
Hepatitis B and Hepatitis C Testing and Monitoring  
Hepatitis B testing 
As specified in the SoA (Section 1.3), initial testing for HBV infection includes HbsAg and 
hepatitis B core antibody (HbcAb). 
 If HbsAg is negative and HbcAb is negative, the participant is not excluded. 
 If HbsAg is positive, the participant is excluded. 
 If HbsAg is negative and HbcAb is positive, further testing for HBV DNA is required. 
o If the screening HBV DNA is positive, the participant is excluded. 
If screening HBV DNA is negative, the participant is not excluded. Repeat testing for HBV 
DNA is required at least every 3 months during the study.
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Hepatitis C testing  
As specified in the SoA (Section 1.3), initial testing for HCV infection includes testing for anti-
HCV. 
 If anti-HCV is positive, a test for circulating HCV RNA is required. 
 If HCV RNA test is negative, the participant is not excluded. 
 If HCV RNA test is positive, the participant is excluded (see Section 5.2). 
Participants who have had HCV infection and have been successfully treated, defined as a 
sustained virologic response (HCV RNA by PCR negative for at least 24 weeks following 
treatment completion), are not excluded on the basis of HCV as long as HCV RNA test is 
negative at screening. 
 
8.2.12. 
Mood Changes, Suicidal Ideation, and Suicidal Behavior Risk Monitoring  
Participants who have obesity or are overweight are at increased risk for depression (Luppino et 
al. 2010). Depression can increase the risk for suicidal ideation and behavior. Therefore, study 
participants will be screened at trial entry and monitored during the study for depression, suicidal 
ideation, and suicidal behavior. 
Participants should be monitored appropriately and observed closely for suicidal ideation and 
behavior or any other unusual changes in behavior, especially at the beginning and end of the 
course of treatment, or at the time of dose changes, either increases or decreases. Consideration 
should be given to discontinuing the study medication in who experience signs of suicidal 
ideation or behavior, following a risk assessment. 
Baseline and treatment-emergent assessment of depression, suicidal ideation, and suicidal 
behavior will be monitored during the study using the C-SSRS and PHQ-9. Scores of the 
questionnaires must be reviewed by the investigator at the time of each visit, and appropriate 
actions as described below should be taken. 
8.2.12.1. C-SSRS  
Columbia Suicide-Severity Rating Scale (C-SSRS) is a scale that captures the occurrence, 
severity, and frequency of suicidal ideation and behavior during the assessment period via a 
questionnaire. The scale was developed by the National Institute of Mental Health trial group 
(TASA) for the purpose of being counterpart to the Columbia Classification Algorithm of 
Suicide Assessment categorization of suicidal events. 
For this study, the C-SSRS is adapted for the assessment of the ideation and behavior categories 
only. The Intensity of Ideation and Lethality of Behavior sections are removed. 
See Section 8.3.1.1 for the collection of the C-SSRS relative to nonleading (spontaneous) AE 
collection. 
8.2.12.2. PHQ-9  
The PHQ-9 questionnaire is a validated, participant-completed 9-item depression module of the 
Patient Health Questionnaire, which is used as a diagnostic instrument for common mental 
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disorders. The PHQ-9 consists of 9 items each scored on a scale of 0 = “not at all” to 3 = “nearly 
every day” with a recall period of “the last 2 weeks.” Major depression is diagnosed if 5 or more 
of the 9 depressive symptom criteria have been present at least “more than half the days” in the 
past 2 weeks, and 1 of the symptoms is depressed mood or anhedonia. As a severity measure, a 
higher score indicates greater severity (Kroenke et al. 2001). 
Participants will be referred to a Mental Health Professional if in the opinion of the investigator 
it is necessary for the safety of the participant or if at any time the participant has a PHQ-9 score 
≥15. 
8.2.13. 
Additional Safety Data and Sample Collections  
For some interventions, additional data or sample collections may be necessary when certain 
AEs occur. See the ISAs for any additional data or sample collections for such AEs and 
additional instructions, if applicable. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
The definitions of the following events can be found in Section 10.3: 
 AEs 
 SAEs, 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 intervention or the study (see Section 7). 
Care will be taken not to introduce bias when detecting events. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about event occurrences. 
After the initial report, the investigator is required to proactively follow each participant at 
subsequent visits or contacts. All SAEs and AEs of special interest (as defined in the ISAs) will 
be followed until resolution, stabilization, the event is otherwise explained, or the participant is 
lost to follow-up (as defined in Section 7.3). For PCs, the investigator is responsible for ensuring 
that follow-up includes any supplemental investigations as indicated to elucidate the nature 
and/or causality. Further information on follow-up procedures is provided in Section 10.3. 
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8.3.1.1. Adverse Event Monitoring with a Systematic Questionnaire  
Nonleading AE collection should occur prior to the collection of the C-SSRS. 
If a suicide-related event is discovered during the C-SSRS but was not captured during the 
nonleading AE collection, sites should not change the AE form. 
If an AE is serious or leads to discontinuation, it needs to be included on the AE form and the 
process for reporting SAEs is followed. 
8.3.2. 
Pregnancy  
Collection of pregnancy information 
Male participants with partners who become pregnant 
● The investigator will attempt to collect pregnancy information on any male 
participant’s female partner who becomes pregnant while the male participant is 
in this study. This applies only to male participants who receive study 
intervention. 
● After learning of a pregnancy in the female partner of a study participant, the 
investigator 
o will obtain a consent to release information from the pregnant female partner 
directly, and 
o within 24 hours after obtaining this consent, will record pregnancy 
information on the appropriate form and submit it to the sponsor. 
The female partner will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to 
the sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be 
reported regardless of gestational age, fetal status (presence or absence of 
anomalies), or indication for the procedure. 
Female participants who become pregnant 
The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. The initial information will be recorded on the 
appropriate form and submitted to the sponsor within 24 hours of learning of a participant's 
pregnancy. 
The participant will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow-up information on the participant and the neonate and the information will be 
forwarded to the sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks 
beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
gestational age, fetal status (presence or absence of anomalies), or indication for the procedure. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
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A spontaneous abortion (occurring at <20 weeks gestational age) or still birth (occurring at ≥20 
weeks gestational age) is always considered to be an SAE and will be reported as such. 
Any poststudy pregnancy-related SAE considered reasonably related to the study intervention by 
the investigator will be reported to the sponsor as described in protocol Section 8.3.1. While the 
investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. If the participant is discontinued from the study, follow the standard 
discontinuation process and continue directly to the follow-up phase. The follow-up on the 
pregnancy outcome should continue independent of intervention or study discontinuation. 
8.3.3. Adverse Events of Special Interest  
See the relevant ISA. 
8.4. 
Pharmacokinetics  
See the relevant ISA. 
Sample retention is described in Section 10.1.12. 
8.5. 
Pharmacodynamics  
See the relevant ISA. 
Sample retention is described in Section 10.1.12. 
8.6. 
Genetics  
See the relevant ISA. 
Sample retention is described in Section 10.1.12. 
8.7. 
Biomarkers  
See the relevant ISA. 
Sample retention is described in Section 10.1.12. 
8.8. 
Immunogenicity Assessments  
Immunogenicity may be evaluated in the ISAs governed by this protocol. Information on 
immunogenicity sample collection and assessment will be described in the ISA as applicable. 
Refer to Section 10.1.12, Appendix 1 for details on sample retention. 
8.9. 
Health Economics OR Medical Resource Utilization and Health 
Economics  
If applicable, see the relevant ISA. 
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9. 
Statistical Considerations  
The statistical analysis plan (SAP) for the CWMM master protocol and each respective ISA will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the common endpoints 
shared across all the ISAs. 
9.1. 
Statistical Hypotheses  
For each ISA of the CWMM master protocol, the primary null hypothesis is that there is no 
difference between the intervention and primary control on the primary endpoint and time point. 
The null hypothesis for secondary objectives is that there is no difference between the 
intervention and primary control for secondary endpoints at time points of interest. Intervention-
specific details regarding hypotheses and statistical testing will be detailed in the respective 
ISAs. 
9.1.1. 
Multiplicity Adjustment  
No adjustments or control for multiplicity will be performed unless specified in the ISA SAP. 
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9.2. 
Analysis Sets  
This table describes the populations and data points that will be used for statistical analyses 
within each ISA of the CWMM master protocol. Additional intervention-specific populations for 
analyses may be described in the ISAs: 
Participant Analysis Set 
Description 
Full analysis set (FAS) 
All randomized participants who meet the inclusion criteria. 
Safety analysis set (SAS) 
All participants who are exposed to investigational intervention. 
The following data point sets are defined: 
Data Point Sets 
Description 
DPS1 
Data points obtained during treatment period at or after 
randomization up to the date of discontinuation of any study drug 
or intercurrent events (ICEs) specified in respective ISAs. 
DPS2 
Data points obtained during treatment period at or after 
randomization regardless of adherence to study drug. 
DPS3 
Data points obtained during treatment period plus safety follow-
up period regardless of adherence to study drug. 
Abbreviation: DPS = data point set. 
FAS and DPS1 will be used to estimate the primary estimand (efficacy estimand) for primary 
and secondary objectives. 
FAS and DPS2 may be used to estimate the additional estimands for the primary and secondary 
objectives. 
SAS and DPS3 will be used to present safety data. 
For the efficacy analyses, participants will be included in the analyses according to the planned 
investigational intervention; whereas for safety analyses, participants will be included in the 
analyses according to the investigational intervention they actually received. 
9.3. 
Statistical Analyses  
9.3.1. 
General Considerations  
Statistical analyses of the CWMM master protocol and ISAs will be the responsibility of the 
sponsor or its designee. Multiple SAPs will be defined and used throughout the duration of the 
entire CWMM master protocol. A single CWMM master protocol SAP will be developed, as 
well as an ISA SAP, for each ISA. The CWMM master protocol SAP describes the statistical 
analyses that are common across the entire CWMM master protocol, and the analyses will be 
conducted within each ISA. The analyses in the CWMM master protocol SAP will include 
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 disposition reports 
 AE analyses 
 laboratory analyses 
 vital signs analyses 
 PK parameters analyses, and 
 efficacy analyses that do not depend on borrowing of comparator and primary control 
information from other ISAs. 
The ISA SAP will contain the statistical analyses unique for each ISA and may include 
 the proposed strategy of borrowing comparator and primary control information from 
other ISAs 
 if any partial borrowing of placebo information is implemented, the model used for the 
primary and secondary analyses, and 
 details of analyses that are unique to the ISA or analyses that may differ from what is 
specified in the CWMM master protocol SAP. 
If there is a discrepancy between the CWMM master protocol SAP and the ISA SAP, the 
methodology in the ISA SAP will be used. 
Changes to the CWMM master protocol data analyses methods will require an amendment only 
if they change a principal feature of the master protocol. Any other change to the data analyses 
methods, and the justification for making the change, will be described in the SAP and the 
clinical study report for each respective ISA. 
The initial ISA will not have an opportunity to prospectively borrow control information from 
other ISAs; borrowing control information may occur in subsequent ISA analyses when 
appropriate. Bayesian hierarchical modeling and other modeling approaches will be considered 
for borrowing information. Analysis details and impact on sample size will be provided in the 
ISA and its respective SAP. 
The CWMM master protocol SAP will be finalized prior to the unblinding of the first ISA. The 
ISA SAP will be finalized prior to the first unblinding of the respective ISA. 
The specific baseline definitions for each analysis will be provided in the CWMM master 
protocol SAP. 
All tests of treatment effects will be conducted at a 2-sided alpha level of 
, unless otherwise 
stated, and all confidence intervals will be given at a 2-sided 
% level. Unless otherwise stated 
in an ISA, the primary estimand of interest in comparing efficacy of primary intervention doses 
with the primary control is the “efficacy” estimand, which represents the effect of treatment in 
the hypothetical scenario where the patient did not discontinue study drug. The primary efficacy 
assessment, guided by the “efficacy” estimand, will be conducted using the FAS and DPS1 
dataset (see Analyses Sets table in Section 9.2). For the efficacy estimand, the hypothetical 
strategy is used to handle the ICEs (permanent discontinuation of study drug), so only data 
collected before the occurrence of any ICEs will be used in the mixed model for repeated 
measures (MMRM) analysis (Section 9.3.1). Efficacy measures will be implicitly imputed for 
visits occurring after the ICEs. 
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The summary statistics for continuous measures will include sample size, mean, standard 
deviation, median, minimum, and maximum. Unless stated otherwise in an ISA’s SAP, 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 an MMRM. Analysis of Heterogeneous Covariance (ANHECOVA) (Ye et al. 2022) may 
be used to make comparisons among treatment groups for continuous measurements with only 1 
postbaseline assessment. 
Summary statistics for categorical measures, including categorized continuous measures, will 
include sample size, frequency, and percentages. Fisher’s exact test will be used to examine the 
treatment difference in categorical outcomes. 
Logistic regression may be used to examine the treatment difference in binary efficacy outcomes. 
The negative binomial regression model may be used for the treatment comparison of discrete 
count measures if deemed appropriate. 
9.3.2. 
Primary Endpoint Analysis  
The primary efficacy assessment, guided by the “efficacy estimand,” will be conducted using the 
FAS and DPS1 dataset for the primary endpoint (percent change from baseline in body weight at 
the primary time point). 
The primary efficacy comparison will be based on the contrast between each treatment group 
(group of cohorts with the same target dose) of primary intervention and primary control at the 
ISA-specified primary time point from the MMRM analysis of percent change from baseline in 
body weight using the FAS and DPS1 dataset (Section 9.2). The analysis model and selection of 
covariance structure will be described in each ISA. 
Treatment comparisons will be performed for the primary objective at the full significance level 
of 
 
9.3.3. 
Secondary Endpoint(s) Analysis  
9.3.3.1. Efficacy Analyses  
The following secondary endpoints will be analyzed on the FAS and DPS1 dataset: 
• mean change from baseline in body weight (kg) from randomization at the primary time 
point  
• incidence of study participants who achieve the following criteria from randomization at the 
primary time point: 
o ≥5% body weight reduction 
o ≥10% body weight reduction, and 
• mean change in BMI (kg/m2) from randomization at the primary time point. 
Analyses of continuous endpoints, including change in body weight (kg), BMI (kg/m2), will be 
conducted in a manner similar to the primary efficacy analyses discussed in Section 9.3.2. 
Analyses for incidence of participants reaching ≥5% body weight reduction and ≥10% body 
weight reduction from baseline at the ISA-specified primary time point will be conducted using a 
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longitudinal logistic regression analysis. The analysis model, covariates, and selection of 
covariance structure will be described in the CWMM master protocol SAP and each ISA’s SAP. 
Additional secondary efficacy analyses may be performed, if deemed necessary and specified in 
master and/or the respective ISA SAP. 
9.3.4. 
Exploratory Endpoint(s) Analysis  
Details of the analyses will be provided in the CWMM master protocol SAP as well as each ISA 
SAP. 
9.3.5. 
Safety Analyses  
All safety analyses will be conducted on the safety analysis set and DPS3 (Section 9.2) for each 
ISA. Safety assessments will be guided by an estimand comparing safety of primary intervention 
to the primary control irrespective of adherence to study drug. 
For each ISA, AEs will be coded from the actual term using the Medical Dictionary for 
Regulatory Activities (MedDRA) and reported with preferred terms and system organ class. 
Summary statistics will be provided for incidence of TEAEs, SAEs, study discontinuation due to 
AEs, study drug discontinuation due to AEs, deaths, and other CV endpoints. Counts and 
proportions of participants experiencing AEs will be reported for each treatment group and each 
dose escalation subgroup, and Fisher’s exact test will be used to compare the primary 
intervention dose groups with the primary control. 
9.3.5.1. Central Laboratory Measures, Vitals and Electrocardiograms  
Values and change from baseline to postbaseline values of central laboratory measures, vital 
signs, and selected ECG parameters will be summarized for each treatment group at each 
scheduled visit. The details will be provided in the respective ISA SAP. 
9.3.5.2. Analysis of C-SSRS Data  
Suicide-related thoughts and behaviors occurring during treatment will be summarized based on 
responses to the C-SSRS consistent with the C-SSRS Scoring and Data Analysis Guide (C-SSRS 
WWW). 
9.3.6. 
Other Analyses  
Other safety analyses may be conducted. Details will be provided in the master SAP and each 
ISA’s SAP. 
9.3.6.1. Participant Disposition  
A detailed description of participant disposition will be provided, including a summary of the 
number and percentage of participants entered into the study and randomized, and number and 
percentage of participants who complete the study or discontinue, both overall and by reason for 
discontinuation for each ISA at the end of the study. Intervention-specific analyses are described 
in the respective ISAs’ SAP. A summary of important protocol deviations will be provided for 
each ISA. The percentage of participants discontinuing from each treatment will be compared 
using the Fisher’s exact test. Kaplan–Meier analyses of time from randomization to premature 
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discontinuation from study and premature discontinuation from study drug by treatment group 
will be provided. 
9.3.6.2. Participant Characteristics  
Demographics, baseline characteristics, medical history, and concomitant illness will be 
summarized by treatment group using the FAS. 
Additional intervention-specific analyses may be specified in each respective ISA. 
9.3.6.3. Concomitant Therapy  
Previous and concomitant medications will be summarized by drug class and each treatment 
group using the FAS for each ISA and will be presented by Anatomical Therapeutic Chemical 
drug classes using the latest version of the WHO drug dictionary. 
9.3.6.4. Treatment Compliance  
Treatment compliance with investigational product will be summarized by treatment for each 
ISA. Intervention-specific analyses are described in the relevant ISAs SAP. 
9.3.6.5. Pharmacokinetic/Pharmacodynamic Analyses  
Intervention-specific PK/PD analyses are described in the relevant ISAs. Details will be 
specified in a separate PK/PD analysis plan. 
9.3.6.6. Evaluation of Immunogenicity  
Immunogenicity assessments will be described in the ISAs as applicable. 
9.4. 
Interim Analysis  
The CWMM master protocol does not require or specify interim analyses for an ISA. If an 
interim analysis is planned for an ISA, the details (for example, timing, rationale, use of 
participants in other ISAs) will be provided in the ISA or ISA SAP. Unblinding details will be 
specified in a master unblinding plan document; ISA-specific unblinding plan documents will be 
developed as needed. 
9.5. 
Sample Size Determination  
An upper limit of approximately
% enrollment of females will be enrolled within each ISA to 
ensure a sufficiently large sample of males. The sample size and power for each ISA will be 
provided and justified in the ISA. Sample size determination based on the primary endpoint will 
be carried out as follows: When the primary control is placebo, ISA sample size will be 
evaluated through a test of superiority to placebo conducted for each of the intervention doses at 
2-sided significance levels of 
 using a 2-sample t-test. In other cases, the sample size 
justification may depend on a superiority or non-inferiority test to the primary control. 
Borrowing information from placebo or other active or investigational treatment arms from other 
ISAs will be justified and detailed within the respective ISA and SAP, as necessary. Sample size 
for control arms may vary by ISA, and an ISA that enters the CWMM master protocol later in 
calendar time may randomize fewer participants, since there may be a sufficient set of placebo or 
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active or investigational treatment participants from which information may be borrowed and 
used in the primary efficacy analysis. Operating characteristics may also vary for the ISAs that 
enter later in calendar time for the same reason. 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
 consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
 applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 International Organization for Standardization (ISO) 14155, and 
 applicable laws and regulations. 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents, 
for example, advertisements, must be submitted to an 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 
stablished by the IRB/IEC 
 notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 providing oversight of study conduct for participants under their responsibility and 
adherence to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations, and 
 reporting to the sponsor or designee significant issues related to participant safety, 
participant rights, or data integrity 
Investigator sites are compensated for participation in the study as detailed in the Clinical Trial 
Agreement. 
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10.1.2. 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process  
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the potential participant or the potential participant’s 
legally authorized representative and answer all questions regarding the CWMM master 
protocol and relevant ISAs. 
Potential participants must be informed that their participation is voluntary. Participants 
or their legally authorized representatives will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
privacy and data protection requirements, where applicable, and the IRB/IEC or study 
center. 
The medical record must include a statement that written informed consent was obtained 
before the participant was entered into the CWMM master protocol and any ISA, and the 
date the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative and is kept on file. 
A participant who is rescreened for the CWMM master protocol must sign a new ICF, along with 
ICFs for currently available ISAs. 
10.1.4. 
Data Protection  
Participants will be assigned a unique identifier by the sponsor. Any participant records, 
datasets, or tissue samples that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable 
will not be transferred. 
The participant must be informed that the participant’s personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant who will be required to give consent for their 
data to be used as described in the informed consent. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
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The sponsor has processes in place to ensure data protection, information security, and 
data integrity. These processes include appropriate contingency plan(s) for appropriate 
and timely response in the event of a data security breach. 
10.1.5. 
Committees Structure  
Internal Assessment Committee (IAC) 
In addition to the safety reviews routinely performed by the blinded study team as described in 
Section 8.2, an IAC may exist for the purpose of reviewing safety data in an unblinded fashion 
periodically or on an ad hoc basis if needed. The IAC may determine whether any changes to the 
study, for example, dose reductions or other protocol modifications, should be made (Section 
10.1.5.1). 
The IAC will be independent from the study team and include, at a minimum, a Lilly medical 
physician, a statistician, and a representative from the Lilly Global Patient Safety organization. 
Details about IAC membership, purpose, responsibilities, and operation will be described in an 
IAC charter, which will be approved prior to the first unblinding. 
If an efficacy interim analysis is conducted, the IAC will be responsible for review of the 
efficacy data. See Section 9.4 for general information about interim analyses. Details of interim 
analyses will be provided in the SAP. 
Investigator sites will receive information about interim analyses results only if such information 
is relevant regarding the safety of their study participants. 
Clinical Event Committee (CEC) 
An external (independent), blinded CEC may be used to adjudicate select clinical events in ISAs. 
If applicable, the CEC will be defined in the relevant ISA. 
10.1.5.1. Stopping Rules  
Each ISA may specify study stopping rules as appropriate for the study intervention. 
The IAC may convene periodically but also when the accumulated safety data triggers one of the 
stopping rules if specified in an ISA. Further enrollment in that ISA, or further dosing in that 
ISA, or both may be stopped, pending a decision of the IAC. 
10.1.6. 
Dissemination of Clinical Study Data  
Clinical study reports 
A clinical study report will be provided for each ISA. 
Reports 
The sponsor will disclose a summary of study information, including tabular study results, on 
publicly available websites where required by local law or regulation. 
The summary of results will be posted within the time frame specified by local law or regulation. 
If the study remains ongoing in some countries and a statistical analysis of an incomplete dataset 
would result in analyses lacking scientific rigor (for example, underpowered) or compromise the 
integrity of the overall analyses (for example, trial not yet unblinded), the summary of results 
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will be submitted within 1 year after the end of the study globally or as soon as available, 
whichever is earlier. 
Data 
The sponsor provides access to all individual participant data collected during the trial, after 
anonymization, with the exception of pharmacokinetic or genetic data. 
Data are available to request 6 months after the indication studied has been approved in the US 
and EU and after primary publication acceptance, whichever is later. No expiration date of data 
requests is currently set once data are made available. 
Access is provided after a proposal has been approved by an independent review committee 
identified for this purpose and after receipt of a signed data-sharing agreement. 
Data and documents, including the study protocol, SAP, clinical study report, and blank or 
annotated CRF, will be provided in a secure data-sharing environment for up to 2 years per 
proposal. 
For details on submitting a request, see the instructions provided at www.vivli.org. 
10.1.7. 
Data Quality Assurance  
All participant data relating to the study will be recorded on printed or electronic CRFs or 
electronic clinical outcome assessment (eCOA) unless transmitted to the sponsor or designee 
electronically, for example, laboratory data. The investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the CRF. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must review and confirm that data entries are accurate and complete throughout 
the duration of the study by physically or electronically signing the CRF, as instructed by the 
sponsor. All completed CRFs must be signed prior to archival. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
Data monitoring and management 
When applicable, quality tolerance limits may be predefined to identify systematic issues that 
can impact participant safety and/or reliability of study results. These predefined parameters may 
be monitored during the study and important excursions from the quality tolerance limits and 
remedial actions taken may be summarized in the clinical study report. 
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, 
CROs. 
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The sponsor or designee will perform monitoring to confirm that data transcribed into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; that 
the safety and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH GCP, and 
all applicable regulatory requirements. 
Records retention and audits 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for the time period outlined in the Clinical Trial Agreement unless 
local regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor. 
In addition, sponsor or its representatives will periodically check a sample of the participant data 
recorded against source documents at the study site. The study may be audited by sponsor or its 
representatives, and/or regulatory agencies at any time. Investigators will be given notice before 
an audit occurs. 
Data capture system 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor. 
Electronic data capture system 
An electronic data capture (EDC) system will be used in this study for the collection of CRF 
data. The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system. The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF. 
Clinical outcome assessments 
Clinical outcome assessment (COA) data (patient-focused outcome instrument) will be collected 
by authorized study personnel, via a paper source document or eCOA. 
Additionally, any eCOA data (patient-focused outcome instrument) will be directly recorded by 
the participant or investigator site personnel, into a device, for example, hand-held smart phone 
or tablet. The eCOA data will serve as the source documentation and the investigator will not 
maintain a separate written or electronic record of these data. 
Data storage and access 
Data collected via the sponsor-provided data capture systems will be stored at third parties. The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture systems. Prior to decommissioning, the investigator will receive or access an 
archival copy of pertinent data for retention. 
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports will be provided to the investigator for review 
and retention. Data will subsequently be transferred from the central vendor to the sponsor data 
warehouse. 
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Data from complaint forms submitted to the sponsor will be encoded and stored in the global PC 
management system. 
10.1.8. 
Source Documents  
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on or entered in the CRF and are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
Definition of what constitutes source data can be found in Section 10.1.7. 
10.1.9. 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
Study or site termination 
Either the CWMM master protocol as a whole or only a particular ISA may be discontinued at 
the discretion of the sponsor if the sponsor judges’ discontinuation to be necessary for medical, 
safety, regulatory, futility, lack of benefit/efficacy, or discontinuation of study intervention 
development, or other reasons consistent with applicable laws, regulations, and GCP. 
The sponsor or sponsor’s designee reserves the right to close the study site or terminate either the 
CWMM master protocol as a whole or an ISA, at any time for any reason at the sole discretion of 
the sponsor. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a study site closure visit 
has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to 
For study termination: 
● discontinuation of further study intervention development 
For site termination: 
● failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
● inadequate recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator, and 
● total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
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used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10. 
Publication Policy  
In accordance with the sponsor’s publication policy, the results of the ISAs conducted as part of 
this CWMM master protocol will be submitted for publication by a peer-reviewed journal. 
10.1.11. 
Investigator Information  
Researchers with appropriate education, training, and experience, as determined by the sponsor, 
will participate as investigators in this clinical trial. 
10.1.12. 
Sample Retention  
Sample retention enables use of new technologies, response to regulatory questions, and 
investigation of variable response that may not be observed until later in the development of the 
intervention or after the intervention becomes commercially available. 
This table describes the retention period for potential sample types collected for the CWMM 
master protocol and ISAs. 
Sample Type  
Custodian  
Retention Period After Last Patient Visita 
Nonpharmacogenomic Sponsor or Designee 
up to 15 years 
 
  
Pharmacokinetic  
Sponsor or Designee 
1 year  
Genetics/PD  
Sponsor or Designee 
up to 15 years  
Immunogenicity  
Sponsor or Designee 
15 years  
a Retention periods may differ locally. 
 
 
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10.3. 
Appendix 3: Adverse Events and Serious Adverse Events: Definitions 
and Procedures for Recording, Evaluating, Follow-up, and 
Reporting  
Information for ISAs having devices 
The definitions and procedures detailed in this appendix are in accordance with ISO 14155. 
Both the investigator and the sponsor will comply with all local medical device reporting 
requirements. 
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study. See Section 6.1.1 of the relevant ISA for the list of 
sponsor medical devices. 
10.3.1. 
Definition of AE  
AE definition 
 For drug-only clinical studies: 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. 
 For clinical studies that include a medical device: An AE is any untoward medical 
occurrence, unintended disease or injury, or untoward clinical signs (including abnormal 
laboratory finding) in study participants, users, or other persons, whether or not related to 
the investigational medical device used in an ISA. 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 condition detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Medication error, misuse, or abuse of IMP, including signs, symptoms, or clinical 
sequelae. 
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 Lack of efficacy or failure of expected pharmacological action per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, 
the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
 The disease or disorder being studied or expected progression, signs, or symptoms of the 
disease or disorder being studied, unless more severe than expected for the participant’s 
condition. 
 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  
An SAE is defined as any untoward medical occurrence that, at any dose, meets 1 or more 
of the criteria listed: 
 Results in death 
 Is life-threatening 
o The term life-threatening in the definition of serious refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
o In general, hospitalization signifies that the participant has been admitted to 
hospital or emergency ward (usually involving at least an overnight stay) for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered serious. 
o Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent disability or incapacity 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
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o This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma, for example, sprained ankle, which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
 Is a congenital anomaly or birth defect 
o Abnormal pregnancy outcomes, for example, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, and ectopic pregnancy, are considered SAEs. 
 Other situations 
o Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as important 
medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious. 
o Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
 Resulted in medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
10.3.3. 
Definition of Product Complaints  
Product complaint 
 A PC is any written, electronic, or oral communication that alleges deficiencies related to 
the identity, quality, durability, reliability, safety, effectiveness, or performance of a 
study intervention. When the ability to use the study intervention safely is impacted, the 
following are also PCs: 
o deficiencies in labeling information, and 
o use errors for device or drug-device combination products due to ergonomic 
design elements of the product. 
 PCs related to study interventions used in clinical trials are collected to ensure the safety 
of participants, monitor quality, and to facilitate process and product improvements. 
 Investigators will instruct participants to contact the site as soon as possible if he or she 
has a PC or problem with the study intervention so that the situation can be assessed. 
 An event may meet the definition of both a PC and an AE/SAE. In such cases, it should 
be reported as both a PC and as an AE/SAE. 
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10.3.4. 
Recording and Follow-Up of AE and/or SAE and Product Complaints  
AE, SAE, and product complaint recording 
 When an AE/SAE/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 CRF page, and PC information is reported on 
the Product Complaint Form. 
 Note: An event may meet the definition of both a PC and an AE/SAE. In such cases, it 
should be reported as both a PC and as an AE/SAE. 
 It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to sponsor or designee in lieu of completion of the CRF page for AE/SAE and the 
Product Complaint Form for PCs. 
 There may be instances when copies of medical records for certain cases are requested by 
sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to sponsor or designee. 
 The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/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 AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant. 
 Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event, and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 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. The investigator will use clinical judgment to 
determine the relationship. 
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 A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 The investigator will also consult the IB and/or Product Information, for marketed 
products, in their assessment. 
 For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to sponsor or designee. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to sponsor or designee. 
 The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
 The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor or 
designee to elucidate the nature and/or causality of the AE or SAE as fully as possible. 
This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor or designee with a copy of any postmortem 
findings, including histopathology. 
10.3.5. 
Reporting of SAEs  
SAE reporting via an electronic data collection tool 
 
 The primary mechanism for reporting an SAE will be the electronic data collection tool. 
 If the electronic system is unavailable, then the site will use the SAE paper form (see next 
section) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on an SAE paper form (see next section) or 
to the sponsor or designee by telephone. 
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 Contacts for SAE reporting can be found in the Global Patient Safety Clinical Trial SAE 
Transmission Cover Sheet and Form. 
SAE reporting via paper form 
 Facsimile transmission of the SAE paper form is the preferred method to transmit this 
information to the sponsor or designee. 
 Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames. 
 Contacts for SAE reporting can be found in Global Patient Safety Clinical Trial SAE 
Transmission Cover Sheet and Form. 
10.3.6. 
Regulatory Reporting Requirements  
SAE regulatory reporting 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators. 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information, for example, summary or listing of SAEs, from the sponsor 
will review and then file it along with the IB or state other documents and will notify the 
IRB/IEC, if appropriate according to local requirements. 
 
 
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10.5. 
Appendix 5: Genetics  
Use/analysis of DNA 
● Genetic or epigenetic 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 or epigenetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism 
of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
● DNA samples will be used for research related to primary intervention or obesity, 
diabetes mellitus, related traits or complications, including nonalcoholic 
steatohepatitis and related diseases. They may also be used to develop tests or 
assays, including diagnostic tests related to primary intervention or comparators, 
study interventions related to this drug class and/or obesity, diabetes mellitus, 
related traits or complications, including nonalcoholic steatohepatitis. Genetic or 
epigenetic research may consist of the analysis of 1 or more candidate genes or 
the analysis of genetic or epigenetic markers throughout the genome or analysis of 
the entire genome (as appropriate). 
● The samples may be analyzed as part of a multi-study assessment of genetic or 
epigenetic factors involved in the response to primary intervention or 
comparators, or study interventions related to this class to understand study 
disease or related conditions. 
● The results of genetic or epigenetic analyses may be reported in the clinical study 
report 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 the primary intervention or study 
interventions related to this class or research on obesity, diabetes mellitus, related 
traits or complications, including nonalcoholic steatohepatitis continues but no 
longer than 15 years or other period as per local requirements. 
 
 
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10.6. 
Appendix 6: Liver Safety: Suggested Actions and Follow-up 
Assessments  
Hepatic evaluation testing 
See CWMM master protocol Section 8.2.10 for guidance on appropriate test selection. 
The Lilly-designated central laboratory should complete the analysis of all selected testing 
except for testing listed in the investigator-designated local laboratory table. The central 
laboratory will report results if a validated test or calculation is available. 
Local testing may be performed in addition to central testing when necessary for immediate 
participant management. 
The local laboratory must be qualified in accordance with applicable local regulations. 
Tests assayed by Lilly-designated central laboratory 
Hepatic Hematology Panel 
Hepatitis A virus (HAV) testing: 
   Hemoglobin 
    HAV total antibody 
   Hematocrit 
    HAV IgM antibody 
   Erythrocytes (RBCs - red blood cells) 
Hepatitis B virus (HBV) testing: 
   Leukocytes (WBCs - white blood cells) 
    Hepatitis B surface antigen (HBsAg) 
   Differential: 
    Hepatitis B surface antibody (anti-HBs) 
       Neutrophils, segmented 
    Hepatitis B core total antibody (anti-HBc) 
       Lymphocytes 
    Hepatitis B core IgM antibody 
       Monocytes 
    HBV DNAb 
       Basophils 
Hepatitis C virus (HCV) testing: 
       Eosinophils 
    HCV antibody 
   Platelets 
    HCV RNAb 
   Cell morphology (RBC and WBC) 
Hepatitis D virus (HDV) testing: 
Hepatic Clinical Chemistry Panel 
    HDV antibody 
   Total bilirubin 
    HDV IgM antibody 
   Direct bilirubin 
Hepatitis E virus (HEV) testing: 
   Alkaline phosphatase (ALP) 
    HEV IgG antibody 
   Alanine aminotransferase (ALT) 
    HEV IgM antibody 
   Aspartate aminotransferase (AST) 
    HEV RNAb 
   Gamma-glutamyl transferase (GGT) 
Anti-nuclear antibody (ANA) 
   Creatine kinase (CK) 
Anti-smooth muscle antibody (ASMA)a 
Hepatic Coagulation Panel 
Anti-actin antibodyc 
   Prothrombin time, INR (PT-INR) 
Immunoglobulin IgA (quantitative) 
Urine Chemistry 
Immunoglobulin IgG (quantitative) 
   Drug screen 
Immunoglobulin IgM (quantitative) 
Haptoglobin 
  
 
 
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Tests assayed ONLY by investigator-designated local laboratory  
Acetaminophen 
Cytomegalovirus (CMV) testing: 
Acetaminophen protein adducts 
    CMV antibody 
Alkaline phosphatase isoenzymes 
    CMV DNAb 
Ceruloplasmin 
Herpes simplex virus (HSV) testing: 
Copper 
    HSV (Type 1 and 2) antibody 
Ethyl alcohol (EtOH) 
    HSV (Type 1 and 2) DNAb 
Phosphatidylethanol (PEth) 
Liver kidney microsomal type 1 (LKM-1) antibody 
Urine Chemistry 
Microbiology Culture: 
    Ethyl glucuronide (EtG) 
    Blood 
Epstein-Barr virus (EBV) testing: 
    Urine 
    EBV antibody 
 
    EBV DNAb 
 
a 
Not required if anti-actin antibody is tested. 
b 
Reflex/confirmation dependent on regulatory requirements, testing availability, or both. 
c 
Not required if anti-smooth muscle antibody (ASMA) is tested. 
 
 
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10.8. 
Appendix 8: Standardized Protocols for the Measurement of Height, 
Weight, Waist Circumference, and Vital Signs  
The following information has been adapted from standardized physical measurement protocols 
for the WHO’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 the participant’s height in 
centimeters, and measure and record 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 kilogram. 
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 non-stretchable 
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 CRF. 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, garments 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 (BP and HR, measured by pulse) should be taken before 
obtaining an ECG tracing and before collection of blood samples for laboratory testing. 
 The participant should sit quietly for 5 minutes before vital sign measurements are taken. 
 For each parameter, 2 measurements will be taken using the same arm, preferably the 
nondominant arm. 
 The recordings should be taken at least 1 minute apart. Each measurement of sitting pulse 
and BP needs to be recorded in the CRF. 
 BP must be taken with an automated BP instrument. 
 If BP and pulse measurements are taken separately, pulse should be taken prior to BP. 
Note: In the event pulse measurement cannot be taken via an automated BP instrument, the 
preferred location for measurement of pulse is the radial artery. 
 
 
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10.9. 
Appendix 9: Diet and Physical Activity Suggestions for Sites without 
Programs  
10.9.1. 
Diet  
Diet recommendations are based on the World Health Organization (WHO 2020a) for everyone 
which is based on a Mediterranean eating pattern. 
The Mediterranean eating pattern for a healthy diet consists of 
 legumes (for example, lentils and beans) 
 nuts 
 whole grains (for example, unprocessed wheat, maize, millet, oats, and brown rice) 
 at least 5 portions of fruit and vegetables per day (excluding potatoes, sweet potatoes, 
cassava, and other starchy roots) 
 less than 10% of total energy intake from free sugars (equivalent to 50 g or 12 level 
teaspoons), but ideally less than 5% of total energy intake. Free sugars are sugars 
added to foods and drinks, as well as sugars present in honey, syrups, fruit juices, and 
fruit juice concentrates 
 less than 30% of total energy intake from fats. Unsaturated fats are preferred over 
saturated fats. Unsaturated fats are found in fish, avocado, nuts, sunflower, canola, 
and olive oils. Consumption of saturated fats, which are fats in fatty meat, butter, 
palm and coconut oil, cream cheese, ghee, and lard, should be reduced to less than 
10% of total energy intake. Trans fats, which are found in industrially produced 
foods, should be avoided, and 
 salt intake should not be more than 5 g (about 1 teaspoon) per day and should be 
iodized. 
10.9.2. 
Physical Activity  
Regular physical activity can improve a participant’s health. Moving more and sitting less 
benefits everyone, regardless of age, sex, race, ethnicity, or current fitness level. Benefits 
accumulate with even small amounts and start immediately. 
To safely engage in physical activity, types of physical activity appropriate for the participant’s 
current fitness should be chosen. Furthermore, the amount and duration of physical activity 
should be gradually increased over time. Participants with chronic conditions and symptoms 
should be under the care of a health care provider about the types and amounts of physical 
activity that are appropriate for the participant. 
Physical activity recommendations are based on WHO recommendations (WHO 2020b) and 
with the US Health and Human Services (HHS 2020) recommendations. 
 Any physical activity is better than none. Adults should move more and sit less. 
 Adults should do 150 minutes (2 hours 30 minutes) to 300 minutes (5 hours) of 
moderate-intensity aerobic physical activity throughout the week or 75 minutes (1 hour 
15 minutes) to 150 minutes (2 hours and 30 minutes) a week of vigorous-intensity 
aerobic physical activity, or an equivalent combination of moderate- and 
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vigorous-intensity aerobic activity. Preferably, aerobic activity should be spread 
throughout the week. 
 Aerobic activity should be performed in bouts of at least 10 minutes duration. 
 For additional health benefits, adults should increase their moderate-intensity aerobic 
physical activity to 300 minutes per week or engage in 150 minutes of vigorous-intensity 
aerobic physical activity per week, or an equivalent combination of moderate- and 
vigorous-intensity activity. Additional health benefits are gained by engaging in physical 
activity beyond the equivalent of 300 minutes (5 hours) of moderate-intensity physical 
activity a week. 
 Muscle-strengthening activities should be done involving major muscle groups on 2 or 
more days a week. 
 Older adults, with poor mobility, should perform physical activity to enhance balance and 
prevent falls on 3 or more days per week, as well as aerobic and muscle-strengthening 
activities. They should be as physically active as their abilities and conditions allow. 
When older adults cannot do 150 minutes of moderate-intensity aerobic activity a week 
because of chronic conditions, they should be as physically active as their abilities and 
conditions allow. 
 
 
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10.10. 
Appendix 10: Medical Device Adverse Events (AEs), Adverse Device 
Effects (ADEs), Serious Adverse Events (SAEs), and Device 
Deficiencies: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting  
Refer to Appendix 3 (Section 10.3) for definitions and procedures for recording, evaluating, 
follow-up, and reporting of all events. 
 
 
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10.11. 
Appendix 11: Country-Specific Requirements  
For sites in EU Member States 
Sponsor has processes that are compliant with General Data Protection Regulation (GDPR) data 
privacy regulations and the European Clinical Trial Regulation (CTR) (Articles 56, 57, 58). 
For sites outside of EU Member States 
Country-specific requirements, if any, will be described in a separate protocol addendum or an 
ISA. 
 
 
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10.12. 
Appendix 12: Provisions for Changes in Study Conduct during 
Exceptional circumstances  
The following provisions are applicable to all ISAs unless otherwise specified. 
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 or 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” 
 a change in the method of study intervention administration 
 dispensation of additional study intervention during an extended treatment period 
 alternate delivery of study intervention and ancillary supplies, and 
 provision of their personal or medical information required prior to implementation of 
these activities. 
See the relevant ISA for the additional informed consent requirements, if any, specific to that 
ISA. 
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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. 
Remote visits 
Types of remote visits for Visit 401 (CWMM master protocol screening period) 
Telemedicine:  
Telephone or technology-assisted virtual visits, or both, are acceptable to complete 
appropriate assessments. Assessments to be completed in this manner may include, but 
are not limited to 
1. medical history 
2. concomitant medications 
3. AEs 
4. explain diet and physical activity plan, and 
5. mental health questionnaires, for example, PHQ-9. 
Mobile healthcare: 
Healthcare visits may be performed by a mobile healthcare provider at locations other 
than the study site when participants cannot travel to the site due to an exceptional 
circumstance if written approval is provided by the sponsor. Procedures performed at 
such visits may include, but are not limited to 
 height, weight, and waist measurements 
 vital signs 
 symptom-directed physical assessments 
 ECGs 
 administration of patient-reported outcomes 
 collection of blood and urine samples, and 
 collection of health information. 
Other alternative locations: 
During exceptional circumstances, laboratory samples, and ECGs may be collected 
locally, if needed outside of mobile healthcare visits. 
Types of remote visits for Visit 402 and thereafter 
See the relevant ISA. 
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. 
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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 for Visit 401 (CWMM master protocol screening period) 
Local laboratory testing may be conducted in lieu of central laboratory testing. The local 
laboratory must be qualified in accordance with applicable local regulations. 
Local laboratory testing option for Visit 402 and thereafter 
See the relevant ISA. A 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 
 arranging delivery of study supplies, and 
 if applicable, working with the sponsor to determine how study intervention that is 
typically administered on site will be administered to the participant; for example, 
during a mobile healthcare visit or at an alternate location such as an infusion center. 
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 or 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. 
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If study intervention will be administered to the participant during a mobile healthcare visit 
or at an alternate location, these additional requirements must be met: 
 Only authorized study personnel may supply, prepare, or administer study 
intervention. 
 See the relevant ISA for any intervention-specific instructions. 
Screening period guidance 
To ensure safety of study participants, laboratory values and other eligibility assessments taken 
at screening visits are valid for a maximum of 
 weeks. The following rules will be applied for 
active, nonrandomly assigned participants whose participation in the study must be paused due to 
exceptional circumstances: 
 If screening is paused for less than  weeks from screening to randomization, the 
participant will proceed to the next study visit per the usual SoA, provided that 
randomization visit must be conducted within  weeks from first screening visit. 
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  weeks from screening to randomization, the 
participant may be discontinued because of screening interruption due to an 
exceptional circumstance. This is documented as a screen failure in the CRF. The 
participant can reconsent and be rescreened as a new participant. This rescreen is in 
addition to the one allowed by the main protocol. The screening procedures per the 
usual SoA should be followed, starting at screening Visit 401 to ensure participant 
eligibility at randomization Visit 0. 
Adjustments to visit window for Visit 401 
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
This table describes the allowed adjustments to visit windows. 
Screening (SoA) 
For this visit… 
Visit Interval Tolerance 
Screening (Visit 401) 
The visit window “Weeks” are described in the SoA, and there is no specific visit 
interval tolerance stated, but flexibility can be considered following consultation 
with, and with prior approval by, the sponsor. 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study. 
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Adjustments to visit windows for Visit 402 and thereafter 
See relevant ISA. 
Documentation 
Changes to study conduct will be documented 
Sites will identify and document the details of how participants, visit 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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Vital signs (includes 2 
measurements for pulse rate, 
blood pressure) 
All onsite visits 
Vital sign measurements (includes 2 
measurements for pulse rate, blood 
pressure) should be taken before 
obtaining an ECG tracing and before 
collection of blood samples for 
laboratory testing, per the instruction in 
Section 8.2.1 and Section 10.8 
Symptom-directed physical 
assessment 
As needed 
Symptom-directed physical assessment 
may be conducted at the discretion of the 
PI or qualified personnel as indicated per 
local regulations based on participant 
status and standard of care 
ECG 12-lead (central) – see 
comments 
As specified in ISA 
Single or Triplicate 
ECG measurements should be obtained 
per the instructions in Section 8.2.3. 
ECGs should be obtained prior to 
collection of blood samples for 
laboratory testing 
Dispense participant diary 
At frequency as listed in the ISA 
IF dosing occurs outside of the 
site 
 
Diary review 
At frequency as listed in the ISA 
IF dosing occurs outside of the 
site 
 
Diary return 
At frequency as listed in the ISA 
IF dosing occurs outside of the 
site 
 
Bioelectrical Impendence 
Analysis (BIA)  
At Weeks  
 and 
 
 
Patient Health Questionnaire-9 
(PHQ-9) 
At Weeks  
 and 
 
 
C-SSRS Since Last Assessed 
(Category Version) 
At Weeks  
 
 and 
 
AE collection should occur prior to the 
collection of the C-SSRS. For this study, 
the C-SSRS is adapted for the 
assessment of the ideation and behavior 
categories only. The Intensity of Ideation 
and Lethality of Behavior sections are 
removed 
Explain diet and physical 
activity plan 
At frequency as listed in the ISA 
IF dosing occurs outside of the 
site 
 
Review diet and physical 
activity 
Goals 
At frequency as listed in the ISA 
IF dosing occurs outside of the 
site 
 
Hematology 
At Weeks  
 
 and 
 
 
Hemoglobin A1c (HbA1c) 
At Weeks  
 
 and 
 
 
Clinical chemistry 
At Weeks  
 
 and 
 
 
Urinalysis 
At Weeks  
 and 
 
 
Lipids 
At Weeks  
 
 and 
  
 
Cystatin-C 
At Weeks  
 
 and 
 
 
Calcitonin  
At Weeks  
 
 and 
 
 
Pancreatic amylase  
At Weeks  
 and 
 
 
Lipase 
At Weeks  
 and 
 
 
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Urinary albumin/creatinine Ratio 
(UACR) 
At Weeks , 
 and 
 
 
EGFR 
 
 
At Weeks  
 and 
 
 
Genetic sample 
(pharmacogenetic storage 
sample) 
At treatment randomization visit 
 
Exploratory biomarker samples 
(Non-pharmacogenetic stored 
sample) 
At Weeks  
 
 and 
 
 
Register visit with IWRS 
All onsite visits 
 
Randomization via IWRS 
At treatment randomization visit 
 
Dispense study intervention via 
IWRS 
At Weeks  
 and 
 
Other dispensing time points will be 
called out in the relevant ISA 
Participant returns unused study 
intervention 
At Weeks 
 
 and 
 
 
Assess study intervention 
compliance 
At frequency as listed in the ISA 
IF dosing occurs outside of the 
site 
 
Abbreviations: AE = adverse event; 
; C-SSRS = 
Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EGFR = estimated glomerular filtration rate; 
HIV = human immunodeficiency virus; ICF = informed consent form; ISA = intervention-specific appendix; 
IWRS = interactive web-response system; PK = pharmacokinetics.  
Dispensing and dosing frequency is specific to the study intervention and will be described in the ISAs. 
 
 
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10.14. 
Appendix 14: Abbreviations and Definitions  
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
AE 
adverse event 
ALT 
alanine aminotransferase 
ALP 
alkaline phosphatase 
AST 
aspartate aminotransferase 
authorized IMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004 or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labeling of the medicinal product, 
which is used as an investigational medicinal product 
authorized AxMP 
Applicable to the EU only: a medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member State concerned in accordance with 
Directive 2001/83/EC, irrespective of changes to the labeling of the medicinal product, 
which is used as an auxiliary medicinal product 
AxMP 
auxiliary medicinal product. See also NIMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment. AxMP does not include investigational medicinal product (IMP) or 
concomitant medications. Concomitant medications are medications unrelated to the 
clinical trial and not relevant for the design of the clinical trial 
blinding/masking 
A single-blind study is one in which the investigator and/or the investigator’s staff are 
aware of the treatment but the participant is not, or vice versa, or when the sponsor is 
aware of the treatment but the investigator and/the investigator’s staff and the 
participant are not. 
A double-blind study is one in which neither the participant nor any of the investigator 
or sponsor staff who are involved in the treatment or clinical evaluation of the subjects 
are aware of the treatment received 
BMI 
body mass index 
BP 
blood pressure 
CBC 
complete blood count 
C-SSRS 
Columbia Suicide-Severity Rating Scale 
CEC 
Clinical Event Committee 
CFR 
Code of Federal Regulations 
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CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
COA 
clinical outcome assessment 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system 
Compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
case report form; a printed, optical, or electronic document designed to record all of 
the protocol-required information to be reported to the sponsor for each trial 
participant 
CRP 
clinical research physician: Individual responsible for the medical conduct of the 
study. Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer 
CV 
cardiovascular 
D. Bil 
direct bilirubin 
Device deficiencies 
equivalent to product complaint 
eCOA 
electronic clinical outcome assessment 
EDC 
electronic data capture system 
ECG 
electrocardiogram 
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 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyltransferase 
GI 
gastrointestinal 
HbcAb 
hepatitis B core antibody 
HbsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
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HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committees 
IMP 
Investigational Medicinal Product (see also “investigational product”) 
A medicinal product which is being tested or used as a reference, including as a 
placebo, in a clinical trial 
IND 
Investigational New Drug 
informed consent 
A process by which a participant voluntarily confirms their willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the participant’s decision to participate. Informed consent is documented by 
means of a written, signed, and dated informed consent form. 
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. See also “IMP.” 
IRB 
Institutional Review Boards 
ISA 
intervention-specific appendix 
ISO 
International Organization for Standardization 
IWRS 
interactive web-response system 
LDL 
low-density lipoprotein 
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medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involves a failure to uphold 1 or more 
of the 5 “rights” of medication use: the right participant, the right drug, the right dose, 
right route, at the right time. 
In addition to the core 5 rights, the following may also represent medication errors: 
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication’s labeling, for example, Summary of Product Characteristics, IB, local 
label, and protocol, or 
• shared use of cartridges or prefilled pens, or both 
Misuse 
Use of a study intervention for self-treatment that either is inconsistent with the 
prescribed dosing regimen or indication, or both, or is obtained without a prescription 
NIMP 
Non-investigational medicinal product. See AxMP. 
A medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product. Examples include rescue medication, 
challenge agents, agents to assess endpoints in the clinical trial, or background 
treatment 
Participant 
Equivalent to CDISC term “subject”: an individual who participates in a clinical trial, 
either as recipient of an investigational medicinal product or as a control 
PC 
product complaint 
PHQ-9 
Patient Health Questionnaire-9 
PK/PD 
pharmacokinetics/pharmacodynamics 
PR 
pulse rate 
PRO/ePRO 
patient-reported outcomes/electronic patient-reported outcomes 
PT-INR 
prothrombin time 
QTc 
corrected QT interval 
QTcF 
corrected QT interval (Fridericia) 
QTL 
quality tolerance limit 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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screen 
The act of determining if an individual meets minimum requirements to become part 
of a pool of potential candidates for participation in a clinical study  
SoA 
schedule of activities 
TBL 
total bilirubin 
TEAE 
Treatment-emergent adverse event: An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment 
ULN 
upper limit of normal 
 
 
 
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10.15. 
Appendix 15: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [c]: 04-Feb-2025 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The main purpose of this amendment is to provide clarification and expand on specified 
components that will apply across future ISAs. 
Section # and Name 
Description of Change 
Brief Rationale 
5.1. Inclusion Criteria 
The inclusion criterion 2 has been modified, 
reinstating the requirement for participants 
with overweight (a BMI of ≥27 to <30 kg/m2) 
to have a weight-related comorbidity.  
In response to feedback from the 
FDA, Lilly has reinstated the 
requirement for participants with 
overweight to have a weight-
related comorbidity. 
 
 
Amendment [b]: 18-July-2024 
This amendment is considered to be nonsubstantial. 
Overall Rationale for the Amendment: 
The main purpose of this amendment is to provide clarification and expand on specified 
components that will apply across future ISAs. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis 
Objectives and Endpoints subheader revised to 
remove estimands. 
Correction. 
Revised secondary endpoint from 
“proportion” to “incidence” of participants 
achieving ≥5% or ≥10% body weight 
reduction. 
Description updated. 
Study population: removed comorbidity (high 
blood pressure, dyslipidemia, cardiovascular 
disease, OSA) requirement for participants 
with obesity or overweight 
FDA expectations for CWM 
populations have changed. 
Specified that an upper limit of approximately 
% of participants will be female. 
To ensure sufficient 
representation of both sexes. 
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Section # and Name 
Description of Change 
Brief Rationale 
Data Monitoring Committee revised to “No.” 
There is no DMC for CWMM; 
there is an IAC and Clinical 
Events Committee. 
1.3.2. Visit 401 - 
Screening 
Indicated master protocol and relevant ISA 
ICFs are signed at V401 in left column. 
Clarification. 
Removed “report any procedure related events 
prior to V401” from adverse event row 
Clarification 
Indicated that PHQ-9 is collected 
electronically via eCOA device. 
To clarify PHQ-9 collection after 
identifying sites completing PHQ-
9 on paper. All scales (except C-
SSRS) are to be completed 
electronically via eCOA. 
3. Objective, Endpoints, 
and Estimands 
Clarified primary objective estimand to align 
with current definition 
Clarification and correct 
description for accuracy. 
Revised secondary endpoint from 
“proportion” to “incidence” of participants 
achieving ≥5% or ≥10% body weight 
reduction. 
Description updated. 
Revised exploratory endpoint from 
“
” to “
” 
 
 
Description updated. 
Revised exploratory BMI endpoint from 
“
” to “
” and 
 
 
 
 
 
 
 
 
Correction. 
Aligned description for secondary objective 
from “percentage” to “incidence” of 
participants achieving ≥5% or ≥10% body 
weight reduction. 
Description updated. 
4.2. Scientific Rationale 
for Study Design 
Redefined study population to include adults 
who have a BMI ≥27 kg/m2 without weight-
related diseases (hypertension, dyslipidemia, 
cardiovascular disease, or obstructive sleep 
apnea). . 
FDA expectations for CWM 
populations have changed. 
5.1. Inclusion Criteria 
IC 2: removed weight-related comorbidities 
requirement for participants with a BMI 
≥27 kg/m2. 
FDA expectations for CWM 
populations have changed. 
5.2. Exclusion Criteria 
EC 5: revised to better indicate that prior 
liposuction or abdominoplasty is permitted if 
performed >1 year before screening. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
EC 15: revised as follows: 
Have an elevated resting pulse rate (PR) 
(mean >100 bpm) or reduced resting pulse rate 
(mean <50 bpm) at screening and baseline. 
Expansion of the exclusion 
criteria. 
EC 18: revised as follows: 
Have ongoing or a history of 
bradyarrhythmias other than sinus 
bradycardia. 
To provide clarification. 
EC 40: addition of tirzepatide (Zepbound®, 
Mounjaro®) and Ozempic® to medications 
prohibited within 3 months prior to screening. 
Clarification. 
7.1.1. Hepatic Criteria for 
Study Drug Interruption or 
Discontinuation 
Revised header from “Liver Chemistry 
Stopping Criteria” and removed section 
content as this is addressed in section 8.2.10. 
Update per Lilly Safety 
guidelines. 
8.1.1. Bioelectrical 
Impedance Analysis 
Added BIA section to efficacy assessments. 
New CWM assessment tool. 
8.2.3. Electrocardiograms 
Added bullet indicating that all V401 
screening ECGs are to be collected locally. 
Clarification. 
Revised to indicate that changes from baseline 
in QT/QTc should be identified by the 
investigator. 
Clarification. 
8.2.10.1. Close Hepatic 
Monitoring 
8.2.10.2 Comprehensive 
Hepatic Evaluation  
8.2.10.3. Study Drug 
Interruption or 
Discontinuation 
Revised section and added updated content 
based on Lilly Safety guidelines. 
Changes in criteria affecting the following 
sections: 
 close hepatic monitoring 
 comprehensive hepatic 
evaluation 
 study intervention interruption 
or discontinuation 
Update per Lilly Safety 
guidelines. 
8.2.11. Hepatitis B Testing 
and Monitoring 
Added hepatitis B safety monitoring section. 
Update per Lilly Safety 
guidelines. 
8.2.12. Mood Changes, 
Suicidal Ideation, and 
Suicidal Behavior Risk 
Monitoring 
Revised section header to include mood 
changes. 
The wording of the header needed 
to be corrected. 
9.2. Analysis Sets 
In the data point set table, DPS1 description 
revised to indicate data obtained up to the date 
of discontinuation of any study drug or 
intercurrent events (ICEs) specified in 
respective ISAs. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
In the data point set table, DPS2 description 
revised to include during treatment period at 
or after randomization regardless of adherence 
to study drug. 
Clarification. 
9.3.3.1. Efficacy Analysis 
Aligned description for secondary efficacy 
analysis from “proportion” to “incidence” of 
participants achieving ≥5% or ≥10% body 
weight reduction. 
Alignment with secondary 
endpoint. 
9.5. Sample Size 
Determination 
Specified that an upper limit of approximately 
% of participants will be female. 
Reflecting decision for limits on 
enrollment. 
10.2.1. Clinical Laboratory 
Tests 
In hematology section of table removed 
“segmented” from differential neutrophils. 
Clarification. 
In additional testing section of table, comment 
added to HbA1c indicating testing may be 
performed locally for V601 and all other visits 
assay by Lilly-designated laboratory. 
Clarification. 
10.8. Appendix 8:  
Standardized Protocols for  
the Measurement of  
Height, Weight, Waist  
Circumference, and Vital  
Signs 
Measuring height section Step 4 revised to  
clarify the participant’s height must be  
directly measured in centimeters 
To provide clarification and  
ensure accuracy in measurements 
captured. 
10.13.1. Activities during  
an ISA Treatment Period 
Addition of BIA at Weeks  
 and 
 
Alignment with secondary 
endpoint. 
Throughout 
Minor editorial corrections/clarifications. 
Clarification. 
Amendment [a]: 13-August-2023 
Overall Rationale for the Amendment: 
The main purpose of this protocol amendment is to clarify placebo borrowing as partial across 
ISAs in response to regulatory feedback.  
Changes specific to certain protocol sections and a brief rationale are provided in this table.  
Section # and Name 
Description of Change 
Brief Rationale 
1.2. Schema 
Revised the schema to change “randomize to 
an ISA” to “randomize to one ISA” and 
removed “option to add ISAs for other 
intervention” 
Clarification 
2.2.1. Intervention 
Selection: Adding or 
Stopping 
Added the following: 
To address regulatory feedback 
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Section # and Name 
Description of Change 
Brief Rationale 
Intervention-Specific 
Appendices 
“Future ISAs with new investigational drugs 
will cross-reference the IND for that 
investigational drug. 
The platform design is not an adaptive design, 
therefore, there is no plan to discontinue ISAs 
based on interim analyses or external new 
data.” 
4.2. Scientific Rationale 
for Study Design 
Added the following: 
 each ISA will have a concurrent 
control arm. 
 ‘partial’ next to placebo borrowing 
To specify that only a specified 
proportion of placebo participants 
would be borrowed across ISAs 
9.3.1. General 
Considerations 
Added “any partial” next to borrowing of 
placebo information 
9.2. Analysis Sets 
Added the following to DPS2 description, 
“Data points also includes those collected 
after the discontinuation likely due to efficacy 
and safety reason.” 
Clarification 
10.13.1. Activities during 
an ISA Treatment Period 
Revised ECG requirement to state “as 
specified in ISA” and added “single” in 
comment 
Removed ECG 12-lead (central) for postdose 
Alignment with ISA 
Throughout 
Minor editorial and formatting changes 
Minor, therefore, not detailed 
 
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11. 
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