A Phase 2, Parallel-Group, Double-Blind, 4-Arm Study to Investigate Weight Management With LY3305677 Compared With Placebo and in Adult Participants With Obesity or Overweight
Phase: PHASE2
Conditions: Obesity, Overweight and Obesity
Sponsor: Eli Lilly and Company

 
Protocol: W8M-MC-OXA1 (b) 
 
A Phase 2, Parallel-Group, Double-Blind, 4-Arm Study to Investigate Weight Management 
with LY3305677 Compared with Placebo in Adult Participants with Obesity or 
Overweight 
 
 
NCT06124807 
 
Approval Date: 28-Oct-2024 

CONFIDENTIAL Master Protocol W8M-MC-CWMM 
ISA: W8M-MC-OXA1(b) 
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Title Page  
Confidential Information 
The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of 
Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical 
investigation of LY3305677, 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 
ISA Title: A Phase 2, Parallel-Group, Double-Blind, 4-Arm Study to Investigate Weight 
Management with LY3305677 Compared with Placebo in Adult Participants with Obesity or 
Overweight 
ISA Number: W8M-MC-OXA1  
ISA Amendment Number: b 
Compound: Mazdutide (LY3305677)  
ISA Brief Title:  
A Study to Investigate Weight Management with LY3305677 Compared with Placebo in Adult 
Participants with Obesity or Overweight 
Study Phase: 2 
Sponsor Name: Eli Lilly and Company 
Legal Registered Address: Indianapolis, Indiana, USA 46285 
Regulatory Agency Identifier Numbers: 
IND for CWMM master protocol: 163848 
EU trial number: 2022-502816-35-00 
Document ID: VV-CLIN-117989 
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Approval Date: Protocol Amendment (b) Electronically Signed and Approved by Lilly on date 
provided below.  
Medical monitor name and contact information will be provided separately. 
 
 
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Protocol Amendment Summary of Changes Table  
DOCUMENT HISTORY 
Document 
Date 
Amendment a 
13-Aug-2023 
Original Protocol 
30-May-2023 
Amendment [b]  
Overall Rationale for the Amendment: 
The main objective of this ISA amendment is to incorporate changes to the objectives as it 
relates to treatment effects on liver fat. The population of interest in secondary endpoint was 
specified to be those with elevated liver fat at baseline, and additional endpoints evaluating 
change in liver fat were added. 
Changes specific to certain ISA sections and a brief rationale are provided in the table below.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
3. Objectives, Endpoints and 
Estimands 
 
 
 
 
Secondary and exploratory endpoints 
related to liver fat content (LFC): 
Modified population in secondary 
endpoint related to liver fat content to 
subset the population to include 
participants with baseline LFC ≥5% 
and baseline LFC .  
Added the following secondary and 
exploratory endpoints for participants 
with baseline LFC ≥5% and baseline 
LFC ≥10% as measured by MRI-
PDFF at Weeks 32 and 48: 
 
Incidence of ≥30% relative 
reduction in LFC 
(secondary) 
 
Incidence of LFC<5% 
(exploratory) 
 
Incidence of ≥50% relative 
reduction in LFC 
(exploratory) 
Additional liver fat analyses added for 
comparison with similar endpoints from 
other studies.  
 
 
Added “24-hour mean” to each 
ABPM endpoint. 
Clarification 
Added time points of “Week 32” and 
“Week 48” to HRQoL, function, and 
appetite objective 
Clarification 
Added “Change from baseline in:” to 
body composition endpoints 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Liver fat objective: specified MRI 
measurement as MRI-PDFF 
Clarification   
1.1 Synopsis 
Data monitoring committee changed 
from “Yes” to “Not applicable; refer 
to CWMM master protocol.” 
Correction 
1.3 Schedule of Activities 
(SoA) for OXA1 ISA and 
CWMM Master Protocol 
Subsection “Early discontinuation 
(ED) visits”: removed “from study 
intervention or” 
Correction 
Removed “intervention” from Visit 
801 description 
Correction 
Added return of actigraphy device 
(AX6) row (V0, V40, and V48) 
Clarification 
Specified EGC 12-lead (central) is 
triplicate for all applicable visits 
Correction 
Added “2 to 6 hours postdose at Visits 
1, 12, and 24” and “as applicable” to 
postdose ECG row comments 
Clarification 
Removed “paper or” from PRO 
section  
Correction 
2.2 Background 
Added summary of Phase 1 study 
OXAG data 
Provide clinically relevant information 
to investigators 
4.1.1 Overview of Study 
Periods 
Subsection “Prescreening”: removed 
“via the central laboratory” regarding 
HBA1c measurement 
Correction 
5.2 Exclusion Criteria 
Added new exclusion criterion #126; 
mean resting pulse rate >100 bpm or 
<60 bpm 
Correction 
7.1 Discontinuation of Study 
Intervention 
BMI discontinuation criterion revised 
from “18 kg/m2” to “18.5 kg/m2.” 
Correction 
8.1 Efficacy Assessments 
Exploratory endpoint “MRI”: revised 
to “Body composition (assessed by 
MRI)” 
Correction 
Added new exploratory endpoint: 
“Liver fat content (assessed by MRI-
PDFF)”  
Alignment with additional endpoint 
8.1.1.1 PROMIS Short Form 
Pain Interference 4a v1.1 
Added, “; higher scores indicate better 
levels of function and/or better 
health” 
Clarification 
8.1.3 Magnetic Resonance 
Imaging (MRI) 
Subsection “MRI procedures”: Added 
that local MRI over-reads should be 
completed 
To ensure participant safety 
9.1 Statistical Hypotheses 
Added “at Week 32” to null 
hypotheses and modified subscripts 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
9.3.1 General 
Considerations 
Additional considerations for OXA1: 
added secondary endpoint analyses 
for TE ADA, pharmacokinetics of the 
primary intervention, and liver fat 
content 
To align with changes in 
Objectives/endpoints 
Added exploratory endpoint analyses 
for body composition and liver fat 
content 
To align with changes in 
Objectives/endpoints 
10.8 Appendix 8: 
Abbreviations and 
Definitions 
Addition of LFC and WC 
Editorial 
Throughout 
Minor editorial clarifications 
Clarification 
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Table of Contents  
1. 
Protocol Summary ..........................................................................................................9 
1.1. 
Synopsis ............................................................................................................................9 
1.2. 
Schema ............................................................................................................................13 
1.3. 
Schedule of Activities (SoA) for OXA1 ISA and CWMM Master 
Protocol ...........................................................................................................................14 
2. 
Introduction ...................................................................................................................28 
2.1. 
Study Rationale ...............................................................................................................28 
2.2. 
Background .....................................................................................................................28 
2.3. 
Benefit/Risk Assessment ................................................................................................29 
2.3.1. 
Risk Assessment .............................................................................................................29 
2.3.2. 
Benefit Assessment .........................................................................................................30 
2.3.3. 
Overall Benefit Risk Conclusion ....................................................................................30 
3. 
Objectives, Endpoints, and Estimands .......................................................................31 
4. 
Study Design ..................................................................................................................34 
4.1. 
Overall Design ................................................................................................................34 
4.1.1. 
Overview of Study Periods .............................................................................................34 
4.2. 
Scientific Rationale for Study Design ............................................................................39 
4.3. 
Justification for Dose ......................................................................................................40 
4.3.1. 
LY3305677 .....................................................................................................................40 
4.4. 
End of Study Definition ..................................................................................................41 
5. 
Study Population ...........................................................................................................42 
5.1. 
Inclusion Criteria ............................................................................................................42 
5.2. 
Exclusion Criteria ...........................................................................................................42 
5.3. 
Lifestyle Considerations .................................................................................................44 
5.4. 
Screen Failures ................................................................................................................44 
5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant .....................................45 
6. 
Study Intervention(s) and Concomitant Therapy .....................................................46 
6.1. 
Study Intervention(s) Administered................................................................................46 
6.2. 
Preparation, Handling, Storage, and Accountability ......................................................47 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................47 
6.4. 
Study Intervention Compliance ......................................................................................48 
6.5. 
Dose Modification ..........................................................................................................48 
6.5.1. 
Dose Escalations .............................................................................................................48 
6.5.2. 
Temporary Interruption and Restarting of Study Intervention .......................................49 
6.5.3. 
Dose Reductions and Re-escalations ..............................................................................49 
6.5.4. 
Starting Doses and First Dose Escalation .......................................................................50 
6.5.5. 
Subsequent Dose Modifications .....................................................................................50 
6.6. 
Continued Access to Study Intervention after the End of the 
Study ...............................................................................................................................51 
6.7. 
Treatment of Overdose ...................................................................................................51 
6.8. 
Prior and Concomitant Therapy ......................................................................................52 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................53 
7.1. 
Discontinuation of Study Intervention ............................................................................53 
7.1.1. 
Liver Chemistry Stopping Criteria ..................................................................................53 
7.1.2. 
Cardiac Arrhythmia and QTc Stopping Criteria .............................................................53 
7.1.3. 
Temporary Interruption of Study Intervention ...............................................................53 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................54 
7.3. 
Lost to Follow up ............................................................................................................54 
8. 
Study Assessments and Procedures.............................................................................55 
8.1. 
Efficacy Assessments .....................................................................................................55 
8.1.1. 
Patient-Reported Outcomes ............................................................................................56 
8.1.2. 
Actigraphy.......................................................................................................................58 
8.1.3. 
Magnetic Resonance Imaging (MRI) ..............................................................................58 
8.2. 
Safety Assessments .........................................................................................................59 
8.2.1. 
Vital Signs .......................................................................................................................59 
8.2.2. 
Physical Examinations ....................................................................................................59 
8.2.3. 
Electrocardiograms .........................................................................................................59 
8.2.4. 
Clinical Safety Laboratory Tests ....................................................................................59 
8.2.5. 
Major Adverse Cardiovascular Events ...........................................................................59 
8.2.6. 
Deaths .............................................................................................................................59 
8.2.7. 
Hepatobiliary Disorders ..................................................................................................59 
8.2.8. 
Acute Renal Events .........................................................................................................59 
8.2.9. 
Pregnancy Testing ...........................................................................................................60 
8.2.10. Hepatic Monitoring .........................................................................................................60 
8.2.11. Suicidal Ideation and Behavior Risk Monitoring ...........................................................60 
8.2.12. Additional Safety Data and Sample Collections .............................................................60 
8.3. 
Adverse Events, Serious Adverse Events, and Product 
Complaints ......................................................................................................................65 
8.3.1. 
Timing and Mechanism for Collecting Events ...............................................................65 
8.3.2. 
Pregnancy ........................................................................................................................65 
8.3.3. 
Adverse Events of Special Interest .................................................................................65 
8.3.4. 
Incident Diabetes ............................................................................................................66 
8.3.5. 
Safety Topics for Monitoring..........................................................................................66 
8.4. 
Pharmacokinetics ............................................................................................................67 
8.4.1. 
Bioanalysis ......................................................................................................................67 
8.5. 
Pharmacodynamics .........................................................................................................67 
8.6. 
Genetics ..........................................................................................................................67 
8.7. 
Biomarkers ......................................................................................................................68 
8.8. 
Immunogenicity Assessments.........................................................................................69 
8.9. 
Health Economics ...........................................................................................................69 
9. 
Statistical Considerations .............................................................................................70 
9.1. 
Statistical Hypotheses .....................................................................................................70 
9.2. 
Analyses Sets ..................................................................................................................70 
9.3. 
Statistical Analyses .........................................................................................................70 
9.3.1. 
General Considerations ...................................................................................................70 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis ....................................................................71 
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9.3.3. 
Secondary Endpoint(s) Analysis .....................................................................................71 
9.3.4. 
Exploratory Endpoint(s) Analysis...................................................................................71 
9.3.5. 
Safety Analyses ...............................................................................................................71 
9.3.6. 
Other Analyses ................................................................................................................71 
9.4. 
Interim Analysis ..............................................................................................................72 
9.5. 
Sample Size Determination ............................................................................................73 
10. 
Supporting Documentation and Operational Considerations ..................................74 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................74 
10.1.1. Committees Structure......................................................................................................74 
10.2. 
Appendix 2: Clinical Laboratory Tests ...........................................................................75 
10.2.1. Clinical Laboratory Tests ................................................................................................75 
10.2.2. Laboratory Samples to be Obtained at Time of Systemic 
Hypersensitivity Event ....................................................................................................77 
10.3. 
Appendix 3: Contraceptive and Barrier Guidance ..........................................................78 
10.3.1. Definitions.......................................................................................................................78 
10.3.2. Contraception Guidance for Females Participating in OXA1 ........................................79 
10.3.3. Contraception Guidance for Males Participating in OXA1 ............................................80 
10.4. 
Appendix 4: Genetics......................................................................................................82 
10.5. 
Appendix 5: Mechanistic Biomarkers ............................................................................83 
10.6. 
Appendix 6: Country-specific Requirements .................................................................85 
10.6.1. Brazil ...............................................................................................................................85 
10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances .............................................................................................87 
10.8. 
Appendix 8: Abbreviations and Definitions ...................................................................89 
10.9. 
Appendix 9: Protocol Amendment History ....................................................................94 
11. 
References ......................................................................................................................97 
 
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1. 
Protocol Summary  
1.1. 
Synopsis  
ISA Title:  
A Phase 2, Parallel-Group, Double-Blind, 4-Arm Study to Investigate Weight Management with 
LY3305677 Compared with Placebo in Adult Participants with Obesity or Overweight  
ISA Brief Title:  
A Study to Investigate Weight Management with LY3305677 Compared with Placebo in Adult 
Participants with Obesity or Overweight 
Regulatory Agency Identifier Numbers:  
IND for CWMM master protocol: 163848 
EU trial number: 2022-502816-35-00 
Rationale: 
LY3305677 is an oxyntomodulin analog that has demonstrated acceptable safety and the 
possibility of weight loss efficacy in early phase trials. It is being developed as a potential once-
weekly injection treatment for chronic weight management. The current study is the first Phase 2 
trial testing LY3305677, aimed at evaluating safety and efficacy across a wide dose range in the 
target population. This study will inform the further clinical development of LY3305677. 
Objectives, Endpoints, and Estimands: 
The CWMM master protocol contains objectives and endpoints that will be evaluated for all 
study interventions evaluated under the CWMM master protocol. 
OXA1 includes the following LY3305677-specific features:  
 Primary analysis time point occurs at Week 32 
 Intervention is LY3305677 
 Control is placebo 
In addition to the objectives and endpoints stated in the CWMM master protocol, the secondary 
objectives and endpoints specific to OXA1 are listed in this table. Exploratory objectives are 
listed in the main body of OXA1.   
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 every 4 weeks - Visit 24 to Visit 48 (Visits 28, 36 and 44 are telephone visits). 
Study Population: 
In addition to meeting the entry criteria specified in the CWMM master protocol, participants are 
adult males and females who have not been diagnosed with diabetes mellitus, that is T2DM, or 
rare forms of diabetes mellitus, except gestational diabetes. Participants also agree to abide by 
the reproductive and contraceptive requirements provided in OXA1.  
Number of Participants: 
Approximately 165 participants will be randomly assigned in a 3:2:3:3 ratio with  
 45 participants allocated to placebo 
 30 participants to LY3305677 3/6 mg 
 45 participants to LY3305677 10 mg and 
 45 participants to LY3305677 16 mg 
 
Assuming a 20% dropout rate, this results in approximately 132 total completers with 24 
completers on the LY3305677 3/6 mg arm and 36 completers for placebo, and each of the 10 mg 
and 16 mg LY3305677 arms. 
Intervention Groups and Duration: 
This study includes a 6-week screening/lead-in period, a 48-week double-blind treatment period, 
and an 8-week posttreatment follow-up period. 
Participants will self-administer study intervention subcutaneously once weekly. 
 
Intervention Name 
LY3305677 
LY3305677 Placebo 
Dosage Level(s) 
1.5 mg 
3 mg (target dose) 
6 mg (target dose) 
8 mg 
9 mg 
10 mg (target dose) 
12 mg 
16 mg (target dose) 
Matched  
Route of Administration 
Subcutaneous using a syringe 
Subcutaneous using a syringe 
Frequency of Administration 
Once weekly 
Once weekly 
Authorized as defined by EU 
Clinical Trial Regulation 
Not authorized in EU 
Not authorized in EU 
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Abbreviation: EU = European Union. 
Ethical Considerations of Benefit/Risk: 
LY3305677 is being investigated as a subcutaneously administered, once weekly therapy as an 
adjunct to diet and physical activity to improve weight management in participants with obesity, 
or overweight if accompanied by weight-related comorbidities. At this time, no safety or efficacy 
issues have been identified which would constitute undue risk to study participants. The safety 
profile continues to be refined as more clinical safety data become available. The overall 
benefit–risk profile supports further development of LY3305677. 
Data Monitoring Committee: Not applicable; refer to CWMM master protocol.  
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1.2. 
Schema  
Abbreviation: LY = LY3305677. 
 
Screening starts
Posttreatment 
Follow-up 
(8 weeks)
Placebo
Week
-6 
-5
0      1      2  
3
4      5  
6      7      8   9 
10 11 12 13    14    15   16    17   18    19 20 22 24    28        32  
36        40   
44   
48        
Visit
401  402 0      1      2             4              6      
8       
10         12         14      
16 
18        
20  22 24      28     32    
36        40    
44  
48                            801                                                    
Randomization 
to Treatment
Primary Endpoint
End of Treatment
Treatment
LY 6 mg
LY 1.5 mg
LY 3 mg
LY 1.5 mg
LY 3 mg
LY 6 mg
LY 9 mg
LY 12 mg
LY 16 mg 
Lead-in
LY 1.5 mg
LY 3 mg
LY 6 mg
LY 8 mg
LY 10 mg
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1.3. 
Schedule of Activities (SoA) for OXA1 ISA and CWMM Master 
Protocol  
In addition to activities required by the CWMM master protocol, this SoA shows visits and 
procedures unique to the intervention-specific appendix (ISA), which is Study W8M-MC-OXA1 
(OXA1) for the study intervention, LY3305677. Please refer to the CWMM master protocol SoA 
Section 1.3 for information pertaining to screening (Visit 401). 
Visit 402 (Lead-in) 
Visit 402 may be used to accomplish OXA1-specific activities (such as magnetic resonance 
imaging [MRI]) requiring significant time to schedule and/or perform. If this visit takes shorter 
or longer than 5 weeks, it will not be considered a protocol deviation. 
Visit 0 (Randomization to treatment) 
Participants will be randomly assigned to an OXA1 treatment arm at Visit 0 and will receive 
their first dose of study intervention. 
Unscheduled visits 
Unscheduled visits may occur as needed. The SoA reflects some of the procedures that may 
occur during these visits. Perform additional procedures per investigator’s discretion. 
Early discontinuation (ED) visits 
ED visits will be completed by participants permanently discontinuing early from the study. 
These participants should also complete posttreatment follow-up. The SoA reflects the 
procedures that may occur during these visits. 
Visit 801 (Posttreatment follow-up) 
Visit 801 occurs approximately 8 weeks after a participant’s last dose of study intervention. The 
SoA reflects the procedures that may occur during these visits. 
Fasting visits 
Participants should not eat or drink anything but water for a minimum of 8 hours before a fasting 
visit. 
If a participant attends these visits in a non-fasting state, they should return in a fasting state for 
body weight measurement and sample collection. If they return within the visit interval tolerance 
specified in the SoA, it is not a protocol deviation. 
Telephone/Telemedicine visits 
Visits 2, 6, 10, 14, 18, 22, 28, 36, and 44 may occur remotely via telephone and/or telemedicine. 
An onsite visit is also acceptable. 
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2. 
Introduction  
LY3305677 (mazdutide) is a long-acting, synthetic peptide oxyntomodulin (OXM) analog 
currently being developed as a once-weekly, subcutaneously administered injection for use as an 
adjunct to diet and physical activity for weight management in participants who have a BMI ≥30 
kg/m2 or ≥27 kg/m2 if accompanied by weight-related comorbidities. 
2.1. 
Study Rationale  
LY3305677 is an OXM analog that has demonstrated acceptable safety and weight loss efficacy 
in early phase trials. It is being developed as a potential once-weekly injection treatment for 
chronic weight management. The current study is the first Phase 2 trial testing LY3305677, 
aimed at evaluating safety and efficacy across a wide dose range in the target population. This 
study will inform the further clinical development of LY3305677. 
2.2. 
Background  
OXM is a gut-derived peptide hormone released in response to food intake. OXM activates both 
glucagon-like peptide-1 (GLP-1) and glucagon receptors resulting in reduced food intake, 
improved glucose and lipid metabolism, increased energy expenditure, and body weight loss. 
When administered exogenously, OXM can improve glucose control and increase weight loss 
(Pocai 2013). 
LY3305677 is a long-acting, synthetic peptide analog of OXM and contains a fatty acyl side 
chain to extend time of action, allowing once-weekly dosing. 
Phase 1 data from the LY3305677 multiple-ascending dose study I8P-MC-OXAD (OXAD) in 
patients with type 2 diabetes mellitus (T2DM) demonstrated significant decreases in body weight 
in all treatment groups (up to a mean of 10.73 kg [-12.7%] in the high-dose group at 
approximately 4 months). LY3305677 significantly reduced HbA1c in all treatment groups and 
improved insulin sensitivity in mixed-meal tolerance tests, as demonstrated by Matsuda index 
increases of approximately 2-fold in the high-dose group. Treatment with LY3305677 
significantly reduced fasting cholesterol, LDL cholesterol, and triglyceride levels, with 
reductions in triglycerides of approximately 50% and in LDL cholesterol of approximately 30% 
in the high-dose group at approximately 4 months. 
Phase 1 data from the LY3305677 multiple dose titration study I8P-MC-OXAG (OXAG) in 
participants with obesity or overweight demonstrated the maximum LS mean difference of 
weight loss was approximately 19 kg or 20% of body weight compared to placebo. The LS mean 
difference in absolute decrease and percent decrease from baseline in WC were approximately 
12 cm or 11% of WC compared to placebo in Cohort 1 and 16 cm or 16% of WC compared to 
placebo in Cohort 2. 
A detailed description of the chemistry, pharmacology, safety, and efficacy of LY3305677 is 
provided in the Investigator’s Brochure (IB). 
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2.3. 
Benefit/Risk Assessment  
This section summarizes the key observations from the completed or ongoing Phase 1 trials with 
LY3305677. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs/SAEs with LY3305677 may be found in the IB. 
Information on serious adverse events (SAEs) that are expected in the study population 
independent of drug exposure will be assessed by the sponsor in aggregate, periodically during 
the course of the study, and may be found in Section 7 (Reference Safety Information for 
Assessment of Expectedness of Serious Adverse Reactions) of the IB. 
2.3.1. 
Risk Assessment  
Study intervention 
LY3305677 
The most common AEs observed in the LY3305677 clinical trials in healthy participants and 
participants with T2DM have been GI effects. These GI AEs have been mild to moderate in 
severity and none was severe. 
Based on preclinical and clinical observations with LY3305677, with GLP-1 receptor agonists, 
and with GLP-1 containing multifunctional agonists, potential risks associated with LY3305677 
include   
 acute pancreatitis 
 cardiovascular effects 
 GI effects 
 hypoglycemia 
 hypersensitivity 
 thyroid C-cell tumors  
 liver and biliary effects, and  
 developmental effects. 
As LY3305677 actions include GLP-1 agonism, these will be safety topics for LY3305677. 
Refer to Section 8.3.5 for further details about safety topics for monitoring in the current 
development program in Phase 2. Please refer to the IB, Section 6 for more details. 
Management of risks for the study 
All identified risks from preclinical and clinical studies to date are associated with on-target 
pharmacology and are considered monitorable and manageable at the planned dose range of 3 to 
16 mg of LY3305677. These risks are similar to those noted during development of marketed 
GLP-1 RAs. 
OXA1 Sections 5.1, 5.2, and 8.3 address known potential risks associated with LY3305677. 
After signing the ICF, participants will be educated about signs and symptoms of hypoglycemia 
and how to treat hypoglycemia. Hypoglycemia may be identified by spontaneous reporting of 
symptoms from participants or by blood glucose (BG) samples collected during study visits.  
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Study site PI will provide education on signs and symptoms of low blood pressure and when to 
seek medical care. Hypotension events may be identified by spontaneous reporting of symptoms 
(for example, dizziness, blurred vision, and fainting) and blood pressure levels. If systolic blood 
pressure persisted below 90 mmHg or diastolic blood pressure persisted below 60 mmHg or 
recurrent symptomatic hypotension has occurred, the PI should consider reducing 
antihypertensive medication dose level or inform participants to consult with their physician. 
Changes of antihypertensive medication will be recorded in CRF.    
Participants will be closely monitored with scheduled medical assessments, vital signs, 
laboratory evaluations, and triplicate electrocardiogram (ECG) measurements. 
Section 6.5 addresses dose modification based on participant safety and tolerability. 
2.3.2. Benefit Assessment  
LY3305677 is a dual agonist of the GLP-1 and glucagon receptors that is currently in early 
clinical development. Full assessment of its potential benefits has not been completed. The 
purpose of this Phase 2 trial is to provide an initial efficacy assessment in participants who have 
a BMI ≥30 kg/m2 or ≥27 kg/m2 if accompanied by weight-related comorbidities, in addition to 
safety and pharmacokinetics/pharmacodynamics (PK/PD) assessments. 
Participants may benefit by receiving personal health information, routine safety assessments, 
and frequent engagement with health care providers during the study, which provide 
opportunities for coaching and support. 
Once-weekly administration of LY3305677 has the potential to offer improved weight 
management. 
2.3.3. Overall Benefit Risk Conclusion  
LY3305677 is being investigated as a subcutaneously administered, once-weekly therapy as an 
adjunct to diet and physical activity to improve weight management in participants with BMI 
≥30 kg/m2 or ≥27 kg/m2 if accompanied by comorbidities. At this time, no safety or efficacy 
issues have been identified which would constitute undue risk to study participants. The safety 
profile continues to be refined as more clinical safety data become available. The overall 
benefit–risk profile supports further development of LY3305677. 
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To compare the effect of LY3305677 versus 
placebo on physical activity at Week 32 and Week 
48 
Change from baseline in physical 
activity measured by: 
 Daily steps count 
 M10 (activity intensity of most 
active 10 hours during 24-hour 
period) 
 MVPA (moderate to vigorous 
physical activity in minutes 
during 24-hour period) 
 
To compare the effects of LY3305677 versus 
placebo on HRQoL, function, and appetite at Week 
32 and Week 48 
Change from baseline in: 
 PROMIS SF Pain Interference 4a 
v1.1 
 PGIS - Physical Function due to 
Weight 
 PGIC - Physical Function due to 
Weight 
 Domains of SF-36 v2, Acute 
 Appetite VAS 
 
To compare the effect of LY3305677 versus 
placebo on glucose regulation at Week 32 and 
Week 48 
Change from baseline in: 
 Fasting insulin 
 Fasting glucose 
 HbA1c 
 HOMA2-IR 
 HOMA2-B 
To compare the effect of LY3305677 versus 
placebo on biomarkers at longitudinal time points 
and at Week 32 and Week 48 
Change from baseline in longitudinal and 
endpoint biomarkers  
To assess the relationships between LY3305677 
dose and/or exposure and key safety and efficacy 
measures, as applicable 
Dose-response or exposure-response 
analyses for key safety and efficacy 
endpoints, as applicable 
To compare the effect of LY3305677 versus 
placebo on body composition as measured by MRI 
at Week 32 and Week 48  
Change from baseline in: 
 Adipose tissue volumes 
 Muscle volumes 
 Additional MRI-derived measures 
may be explored 
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To compare the effect of LY3305677 versus 
placebo on liver fat content (LFC) as measured by 
MRI-PDFF at Week 32 and Week 48 
For participants with baseline LFC ≥5% 
and baseline LFC ≥10%: 
 Incidence of LFC< 5%  
 Incidence of ≥50% relative 
reduction in LFC 
Abbreviations: ABPM = ambulatory blood pressure monitoring; BP = blood pressure; HbA1c = hemoglobin A1c; 
HOMA2-B = homeostasis model of beta-cell function; HOMA2-IR = homeostasis model assessment of insulin 
resistance; HRQoL = health-related quality of life; PGIC = Patient’s Global Impression of Change; 
PGIS = Patient’s Global Impression of Severity; PROMIS = Patient-Reported Outcome Measurement 
Information System; SF-36 = Short Form 36; VAS = visual analog scale. 
 
Primary and additional estimands 
Please refer to the CWMM master protocol for a description of the primary estimand and 
additional estimands that will be used for the primary and secondary efficacy objectives for 
comparisons between LY3305677 and placebo. 
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4. 
Study Design  
4.1. 
Overall Design  
OXA1 is a Phase 2, parallel-group, double-blind, 4-arm study to investigate weight management 
with LY3305677 subcutaneously administered once weekly compared with placebo. For 
convenience, the functional combination of the CWMM master protocol plus the OXA1 ISA will 
be simply described as “the study”. 
The study consists of a 6-week screening/lead-in period, a 48-week treatment period, and a 
posttreatment follow-up period of approximately 8 weeks after the last visit in the treatment 
period.  
The primary endpoint will be at Week 32. 
The study schema is presented in Section 1.2. 
4.1.1. 
Overview of Study Periods  
Prescreening 
An optional prescreening Visit 601 which includes assessment of abbreviated eligibility criteria 
as outlined in the SoA may be conducted at a traditional investigator site or other location 
associated with the investigator. 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 8 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. 
Screening period 
The screening period consists of Visit 401 (screening) and Visit 402 (lead-in) and is split across 
the CWMM master protocol and OXA1; Visit 401 occurs as part of the CWMM master protocol 
and Visit 402 occurs as part of OXA1. Signing informed consent forms (ICFs), completing 
screening procedures, and randomization to the ISA all take place during Visit 401. 
Visit 402 will be used to complete any OXA1-specific baseline procedures including baseline 
procedures for OXA1 appendices. 
If the time between Visit 401 and randomization (Visit 0) takes more or less time than 6 weeks, 
it is not a protocol deviation. 
Visit 401 
Participant screening for the CWMM master protocol and OXA1 occurs during CWMM master 
protocol Visit 401 and is described in CWMM master protocol Sections 1.3 (SoA) and 4.1. 
Participants who successfully pass screening procedures and are assigned to participate in OXA1 
will proceed with Visit 402 as detailed below. 
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Participants who have not fasted for Visit 401 will need to return to the site for collection of 
fasting parameters. This visit will be considered part of Visit 401. 
Visit 402 (Start of OXA1 procedures) 
Prior to Visit 402, all screening results, including laboratory results, will be reviewed to confirm 
participant eligibility for CWMM master protocol and OXA1.  
Participants will complete procedures as indicated in the SoA (Section 1.3). 
Participants will receive education on recognizing the symptoms of hypoglycemic events. 
Participant diaries will be dispensed and their use explained. 
Participants will meet with site personnel to discuss diet and physical activity goals (see Section 
5.3 of CWMM master protocol). 
Participants will be registered in interactive web-response system (IWRS). 
Ambulatory blood pressure monitoring (ABPM) 
At Visit 402, participants will begin to undergo a baseline 24-hour ABPM session. Upon return 
of the ABPM device, the recordings must be transmitted to the core laboratory and analyzed 
before the participant leaves the site. 
If the session provides technically satisfactory results (≥70% of readings are valid), this 
measurement will serve as the baseline value. 
If a technically satisfactory result is not achieved, the investigator should review the device 
settings and placement and the participant’s ABPM device in attempt to correct any user error or 
device malfunctions. Then another 24-hour ambulatory monitoring session should be conducted 
prior to Visit 0, and this measurement will serve as the baseline value. 
If the second session also provides technically unsatisfactory results, the participant should not 
participate in additional ABPM collections. 
See Section 8.2.12.1 for addition information on ABPM. 
Actigraphy  
A wrist worn AX6 device will be dispensed to participants and placed on the non-dominant wrist 
at Visit 402 to collect activity data for at least 2 weeks before being returned to the site at Visit 0. 
See Section 8.1.2 for addition information on actigraphy. 
Magnetic Resonance Imaging 
After the participant has given consent, and meets all ISA eligibility requirements, MRI 
measurements at baseline should be performed between Visit 402 and Visit 0 (randomization) in 
OXA1, before the participant receives the first dose of study intervention. 
Participants are required to report for the MRI after approximately 8 hours without eating, 
drinking (except water), and without performing any significant physical activity. Participants 
can take normal maintenance medications with water if medications are not required to be 
administered with food. 
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Treatment period 
Visit 0 (randomization to treatment arm) 
Study participants are required to report to the study site after approximately 8 hours without 
eating or drinking (except water) and should not have performed any significant physical 
activity. 
At Visit 0, eligible participants, those who meet all applicable inclusion criteria and none of the 
applicable exclusion criteria for the CWMM master protocol and for OXA1, will perform all 
required study procedures prior to randomization to a treatment arm (see SoA). 
Participant diaries will be reviewed. 
Patient-reported outcomes questionnaires should be administered according to the SoA. The 
preferred administration order of these questionnaires is 
1. PROMIS SF Pain Interference 4a v1.1 
2. PGIS – Physical Function due to Weight 
3. SF-36 v2 acute form, and 
4. Appetite visual analog scale (VAS). 
The mental health questionnaires (PHQ-9 and C-SSRS [since last assessed]) should be 
completed after the assessment for AEs. 
Participants will return wrist worn AX6 device at this visit. 
All study Visit 0 baseline measurements and assessments must be completed prior to the first 
dose of study intervention. Furthermore, triplicate ECGs should be collected prior to blood 
sample collection. 
Study intervention dispensing and dosing 
Beginning at randomization, all participants will receive study intervention according to the 
randomized treatment arm for the duration of the 48-week treatment period (primary endpoint at 
32 weeks) as per the SoA (Section 1.3). 
Following randomization, study site personnel will discuss the treatment group assignment with 
the participant and explain the dose escalation process and change in dose volume for the 
LY3305677 dose. Site personnel should distribute the treatment group dosing handout to the 
participant and explain that study intervention should be administered in the abdomen in 
different quadrants, rotating over time. Participants should be instructed to not inject in the same 
place every time. 
Study site personnel will either demonstrate LY3305677 (or matching placebo) study 
intervention preparation and injection technique using a vial and syringe or coach the participant 
through study intervention preparation. They will then coach and observe the study participant 
inject the first dose of LY3305677 or matching placebo. 
The date and time of the first dose of study intervention will be recorded on eCOA device (either 
provisioned or participant’s own device).  
Visits 1 to 20 (dose escalation) 
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Visits 2, 6, 10, 14, and 18 will be telephone visits; onsite visits are permitted at these times if 
necessary or preferred. 
For all onsite visits (except PK specific visits), study participants are required to report to the 
study site after approximately 8 hours without eating or drinking (except water) and should not 
have performed any significant physical activity within that same period. 
Study procedures will be performed according to the SoA (Section 1.3). 
ECGs should be performed in triplicate during these visits as indicated in the SoA. 
Appetite VAS should be completed after the assessment for AEs during visits as indicated in the 
SoA. 
The mental health questionnaires (PHQ-9 and C-SSRS [since last assessed]) should be 
completed after the assessment for AEs during visits as indicated in the SoA. 
Safety and efficacy assessments and laboratory sample collections will be performed as specified 
in the SoA and as described in the CWMM master protocol. 
Study intervention dosing 
Injections of the study intervention on study visit days should only occur after all other site 
procedures have been completed. Dose escalation will occur in certain treatment groups up 
through Week 20 of treatment. See Section 6.5.1 for detailed dose escalation information. 
After the initial study visits to acquaint participants with dilution and self-administration of 
LY3305677, visits are every 2 weeks from Visits 2 to 24; after Visit 24, visits are every 4 weeks. 
Site personnel should observe the participant to check the participant is correctly diluting and 
injecting LY3305677. Sites may have participants return to the site for unscheduled visits to 
assist participants with study intervention dilution and injections as needed. 
The date and time of the doses of study intervention will be recorded on the eCOA device.  
Visits 22 to 48 (maintenance) 
After Visit 24 during the maintenance period, visits will occur approximately every 4 weeks until 
Week 48 visit procedures should be conducted according to the SoA (Section 1.3).  
Visits 22, 28, 36 and 44 will be telephone visits; onsite visits are permitted at these times if 
necessary or preferred. 
 
 
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Actigraphy 
At Visit 32 the AX6 device will be dispensed to participants, placed on the non-dominant wrist, 
wear device continuously for at least 2 weeks, and return to site at Visit 40.  At Visit 40, the AX6 
device will be dispensed to participants, they will be instructed to begin wearing the device on 
their non-dominant wrist at Visit 44, wear continuously for at least 2 weeks, and return to site at 
Visit 48.   
See Section 8.1.2 for addition information on actigraphy. 
Ambulatory blood pressure monitoring 
Within 1 week of Visit 32 (Week 32) and Visit 48 (Week 48), the participant will undergo one 
24-hour ambulatory monitoring session. Upon return of the ABPM device, the recordings must 
be transmitted to the core laboratory and analyzed before the participant leaves the site. If the 
session provides technically satisfactory results (≥70% of readings are valid), this measurement 
will serve as the final value. If a technically satisfactory result is not achieved, the investigator 
should review the device settings and placement and the participant’s ABPM device in an 
attempt to correct any user error or device malfunctions. Another 24-hour ambulatory monitoring 
session should be conducted (within 7 days after the previous collection), and this measurement 
will serve as the final value. If the second session also provides technically unsatisfactory results, 
the data will be considered missing but will not be considered a protocol deviation. 
See Section 8.2.12.1 for addition information on ABPM. 
Magnetic Resonance Imaging 
The postbaseline MRI measurements at Visit 32 should occur within ± 2 weeks.  MRI 
measurement Visit 44 may be performed anytime between Visits 44 and 48. Both MRI 
measurements should be performed after a fast of at least 8 hours. 
Patient-reported outcomes 
Patient-reported outcomes questionnaires should be administered according to the SoA.  
1. PROMIS SF Pain Interference 4a v1.1 
2. PGIS – Physical Function due to Weight 
3. PGIC – Physical Function due to Weight 
4. SF-36 v2 acute form, and 
5. Appetite VAS. 
The mental health questionnaires (PHQ-9 and C-SSRS [since last assessed]) should be 
completed after the assessment for AEs. 
The date and time of the doses of study intervention will be recorded on the eCOA device.  
Safety and efficacy assessments and laboratory sample collections will be performed as specified 
in the SoA (Section 1.3) and as described in the CWMM master protocol. 
Participants are also required to return any remaining diaries to the study site at Week 48. 
Early discontinuation (ED) visit 
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Participants who discontinue study intervention but remain in the study do not need to undergo 
ED procedures, but rather should continue to follow regularly scheduled visit procedures. 
Participants unable or unwilling to continue the study for any reason will perform an ED of 
treatment visit (Section 7.1 of the CWMM master protocol). If the participant is discontinuing 
during an unscheduled visit or a scheduled visit, that visit should be performed as an ED visit. 
Procedures should be completed according to the SoA (Section 1.3). 
Participants who withdraw from the study after signing the informed consent but who have not 
taken a dose of study intervention prior to randomization do not need to complete ED 
procedures. 
Magnetic Resonance Imaging 
The postbaseline MRI measurements at ED may be performed within ±7 days of the date of the 
study visit. MRI measurements should be performed after a fast of at least 8 hours. 
Patient-Reported Outcomes 
Patient-reported outcomes questionnaires should be administered according to the SoA.  
1. PROMIS SF Pain Interference 4a v1.1 
2. PGIS – Physical Function due to Weight 
3. PGIC – Physical Function due to Weight 
4. SF-36 v2 acute form. 
The mental health questionnaires (PHQ-9 and [C-SSRS since last assessed]) should be 
completed after the assessment for AEs. 
Posttreatment follow-up period 
Visit 801 
Visit 801, a posttreatment follow-up visit, will occur approximately 8 weeks following the last 
treatment period visit. All participants who have taken at least 1 dose of study intervention 
should complete Visit 801, according to the SoA (Section 1.3). 
For participants who discontinue from the study early (regardless of whether they discontinue 
study intervention at the same time they discontinue from the study, or if they have discontinued 
study intervention at an earlier visit), an ED visit followed by the posttreatment follow-up visit 
(Visit 801) should be completed as per the SoA. 
4.2. 
Scientific Rationale for Study Design  
OXA1 is a Phase 2 study designed to examine the body weight-lowering efficacy and safety of 
LY3305677 QW (planned dose range: 3 mg to 16 mg) compared with placebo during the 48-
week treatment period (with the primary endpoint at Week 32), in participants who have a BMI 
≥30 kg/m2 or ≥27 kg/m2 if accompanied by overweight associated comorbidities. 
Phase 1 data in healthy participants, and participants with obesity and overweight or T2DM 
demonstrated that LY3305677 has potential to produce clinically meaningful weight loss and 
improve glycemic control with an acceptable safety and tolerability profile consistent with other 
incretin classes such as GLP-1 RAs and dual GLP-1/GIP RAs. 
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In OXA1, a placebo arm is included to determine if any LY3305677 safety or efficacy effects are 
different from no treatment.  
A primary study endpoint at Week 32 is considered sufficient duration for an early understanding 
of drug effect on body weight. The study will continue for an additional 16 weeks, for a total 
treatment duration of 48 weeks, to collect additional data on weight loss.    
At the higher LY3305677 target doses of 10 mg QW and 16 mg QW, each study arm is further 
randomly assigned into 2 different dose-escalation strategies to investigate the impact on GI 
tolerability. These data will be used to optimize dose-escalation strategies for future clinical 
development.  
Consistent with current guidelines for weight management, all participants will receive diet and 
physical activity counseling throughout the study. Clinical sites that have their own diet and 
physical activity programs may use those programs. However, for sites without specific diet and 
physical activity programs, a suggested diet and physical activity program is provided in 
CWMM master protocol Section 10.9.   
In CWMM master protocol Section 10.9.1, the diet recommendations are based on the World 
Health Organization (WHO 2020a) diet for everyone and are based on a Mediterranean Diet 
eating pattern. In CWMM master protocol Section 10.9.2, physical activity recommendations are 
based on WHO recommendations (WHO 2020b) and with the US Health and Human Services 
(HHS 2020) recommendations. 
The primary efficacy measure, mean percent change in body weight, is an accepted Phase 2 
endpoint for investigational drugs being developed for weight management (FDA 2007). 
In addition, the study includes other parameters relevant to assessment of the effects of 
LY3305677 on safety, BP, lipids, PK and PD parameters, and patient-reported outcomes. 
Further, safety and tolerability over a wide dose range of LY3305677 versus placebo will be 
assessed to enable robust benefit–risk characterizations in treatment of participants who have a 
BMI ≥30 kg/m2 or ≥27 kg/m2 if accompanied by weight-related comorbidities. 
4.3. 
Justification for Dose  
4.3.1. 
LY3305677  
The LY3305677 planned target doses of 3, 6, 10, and 16 mg, administered subcutaneously QW, 
were selected for OXA1 based on the following: 
 Safety and tolerability of LY3305677 in healthy participants and T2DM participants in 
the Phase 1 single ascending dose study I8P-MC-OXAA (0.03 to 5 mg dose range), 
multiple ascending dose studies I8P-MC-OXAB (0.05 to 1.5 mg QW dose range) and 
I8P-MC-OXAD (4.5 to 10 mg QW dose range). Preliminary safety, tolerability, and 
weight loss data from the multiple ascending dose study OXAG provide the additional 
clinical data to support dosing for the top dose of 16 mg QW.  
 PK/PD modeling of dose-exposure-response data from Study OXAD. 
 Acceptable margin of safety for the 16 mg maximum dose in this study relative to the no 
observed adverse-effect level in monkeys in the 6-month toxicology studies. 
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 The lowest maintenance dose of 3 mg QW is anticipated to provide modest weight loss 
benefit but will be necessary for robust characterization of the LY3305677 dose-
exposure-response relationship for weight change. For participants randomly assigned to 
the 3 mg dose, a dose-escalation to 6 mg is planned after the primary endpoint (Week 32) 
and will be maintained at 6 mg until the end of the study. 
 Maintenance doses of 6 mg, 10 mg, and 16 mg QW are expected to provide clinically 
meaningful weight loss relative to placebo in a dose-related manner. To reach these 
higher doses, a starting dose not exceeding 2 mg QW will be used for initiation of 
treatment, followed by gradual dose escalation to reach the targeted higher doses to 
mitigate any GI tolerability issues. 
 The selected dose range is anticipated to be wide enough to support robust dose-
exposure-response analyses of multiple key safety, tolerability, and efficacy endpoints to 
provide a comprehensive benefit-risk assessment and dose selection rationale for further 
clinical development of LY3305677 in weight management. 
4.4. 
End of Study Definition  
A participant is considered to have completed OXA1 if the participant has completed all periods 
of the study including the last scheduled procedure shown in the SoA. 
The end of OXA1 is defined as the date of the last visit of the last participant in OXA1 or last 
scheduled procedure shown in the SoA for the last participant in OXA1 globally. 
 
 
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5. 
Study Population  
Eligibility for participation is based on inclusion and exclusion criteria specified in the CWMM 
master protocol, with additional criteria specific to the OXA1 as detailed below. Participants 
must first meet all criteria for the CWMM master protocol, and then must meet all criteria for 
OXA1 to be eligible to participate in OXA1.  
5.1. 
Inclusion Criteria  
In addition to meeting the inclusion criteria specified in the CWMM master protocol, OXA1 
participants must meet the following inclusion criteria at the time of screening: 
Sex and contraceptive/barrier requirements 
100. 
Are males and females who agree to abide by the reproductive and contraceptive 
requirements provided in OXA1, Section 10.3. 
5.2. 
Exclusion Criteria  
In addition to meeting the exclusion criteria specified in the CWMM master protocol, OXA1 
participants will be excluded if any of the following apply at the time of screening:  
Medical conditions 
Diabetes related 
101. 
Have any prior diagnosis of diabetes mellitus, that is T2DM, or rare forms of diabetes 
mellitus, except gestational diabetes. 
102. 
Have at least 1 laboratory value suggestive of diabetes during screening, including 1 
or more of HbA1c ≥6.5% (48 mmol/mol), fasting serum glucose ≥126 mg/dL 
(7.0 mmol/L), or random glucose ≥200 mg/dL (11.1 mmol/L). 
Other medical 
103. 
Have any of the following cardiovascular conditions within 6 months prior to 
screening: 
 acute myocardial infarction 
 cerebrovascular accident (stroke) 
 unstable angina, or 
 hospitalization due to congestive heart failure (CHF). 
Note: This supersedes CWMM master protocol Section 5.2, exclusion criterion 15. 
104. 
Have a history of New York Heart Association (NYHA) Functional Classification 
I-IV CHF. 
Note: This supersedes CWMM master protocol Section 5.1, inclusion criterion 2. 
105. 
Have renal impairment measured as estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73 m2, calculated per Chronic Kidney Disease Epidemiology 
Consortium (CKD-EPI) as determined by the central laboratory during screening. 
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106. 
Have a known clinically significant gastric emptying abnormality (for example, 
severe gastroparesis or gastric outlet obstruction), or chronically take drugs that 
directly affect GI motility. 
107. 
Have a history of acute or chronic pancreatitis. A participant with a history of acute 
pancreatitis caused by gallstones may be included in the study if the participant has 
had a cholecystectomy. 
108. 
Have a known self or family history (first-degree relative) of multiple endocrine 
neoplasia type 2A or type 2B, thyroid C-cell hyperplasia, or medullary thyroid 
carcinoma. 
109. 
Have a serum calcitonin level (at screening) of 
 ≥20 ng/L, if eGFR ≥60 mL/min/1.73 m2, or 
 ≥35 ng/L if eGFR <60 mL/min/1.73 m2, as determined by central laboratory at 
screening. 
110. 
Have fasting triglycerides >500 mg/dL (5.7 mmol/L).  
111. 
Have had any exposure to GLP-1 analogs, or other incretin receptor agonist 
compounds within the prior 3 months or any prior history of hypersensitivity/allergies 
to these medications.  
112. 
Have contraindications for MRI scanning, such as persons with cardiac pacemaker 
and implants made out of metal (for example, cochlea implant, nerve stimulators, 
magnetic vascular clips, and metallic heart valve) or other contraindications for MRI.  
113. 
Have claustrophobia precluding completion of an MRI examination.  
114. 
Any condition or circumstance that, in the opinion of the investigator, would interfere 
with completion of the MRI examination, such as, but not limited to, body weight or 
girth that exceeds the MRI scanner capabilities.  
Prior/concomitant therapy 
115. 
Have discontinued a GLP-1 receptor agonist treatment due to lack of efficacy or 
intolerability. 
116. 
Use of metformin, or any other glucose-lowering medication such as an SGLT 2 
inhibitor, for example, prescribed for polycystic ovarian syndrome, diabetes 
prevention, or heart failure, is not permitted. 
Prior/concurrent clinical study experience 
117. 
Have participated within the last 6 months, whether on active drug or placebo, in a 
clinical study that contained a selective GLP-1 RA or GIP/GLP-1 or GLP-1/Gcg dual 
receptor agonists or GLP-1/Gcg/GIP tri-receptor agonists. 
118. 
Have known or suspected hypersensitivity to trial product(s), to selective GLP-1 RAs 
or GIP/GLP-1 or GLP-1/Gcg dual receptor agonists or GLP-1/Gcg/GIP tri-receptor 
agonists. 
 
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Exclusion criteria specifically for Ambulatory Blood Pressure Monitoring  
The following additional exclusions apply only to participation in ABPM collections. A 
participant who qualifies for the study based on both the CWMM master protocol and the above 
inclusion/exclusion parameters but does not qualify for ABPM may still participate in the study. 
Not being able to participate in ABPM procedures is not considered a protocol deviation.  
119. 
Participants with hypertension who do not have well-controlled blood pressure (BP) 
(>140/90 mmHg), regardless of antihypertensive treatment. Participants receiving 
treatment for hypertension should be on a stable antihypertensive regimen for at least 
3 months prior to screening. 
Note: If the investigator anticipates a need to add antihypertensive medication during 
the course of the study, the participant should not be included in the ABPM 
procedures. 
120. 
Participant works in rotation shifts or works during the hours of 2200 to 0700. 
121. 
Participant performs strenuous manual labor that cannot be avoided during the 
monitoring period. 
122. 
Participant has a nondominant arm circumference of >55 cm at screening. 
123. 
Participant is unable to obtain a valid baseline ABPM reading. 
124. 
Chronic use of nonsteroidal anti-inflammatory agents or cyclooxygenase-2 (COX-2) 
inhibitors, as well as other agents, prescription or over-the-counter, known to affect 
BP, are permitted; however, use of these agents on an as-needed basis during the 48-
hour period immediately prior to or during each 24-hour ABPM recording is 
prohibited. Examples include, but are not limited to, decongestants (pseudoephedrine, 
ephedrine, phenylephrine, naphazoline, and oxymetazoline) and multi-symptom cold 
remedies. 
125. 
Male participants must abstain from use of phosphodiesterase type 5 (PDE-5) 
inhibitors (that is, tadalafil, vardenafil, and sildenafil) or yohimbine (herbal 
aphrodisiac) during the 48-hour period immediately prior to or during each 24-hour 
ABPM recording, since these medications may confound the BP measurements. 
Additional exclusion criteria 
126. 
Have an elevated resting pulse rate (mean >100 bpm) or reduced resting pulse rate 
(mean <60 bpm) at screening. Note: This supersedes CWMM master protocol Section 
5.2, exclusion criterion 15. 
 
5.3. 
Lifestyle Considerations  
See CWMM master protocol, Section 5.3. 
5.4. 
Screen Failures  
See CWMM master protocol, Section 5.4. 
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5.5. 
Criteria for Temporarily Delaying Enrollment of a Participant  
This section is not applicable to this study.  
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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/used by a study participant 
according to the study protocol. 
6.1. 
Study Intervention(s) Administered  
Study intervention will be dispensed at the study visits summarized in the SoA (Section 1.3). 
Returned study intervention should not be re-dispensed to the participants. 
Detailed dosing instructions for all treatment arms in this study can be found in Section 6.5.1. 
This table lists the interventions used in this clinical study. 
Intervention Name 
LY3305677 
LY3305677 Placebo 
Dosage Level(s) 
1.5 mg 
3 mg (target dose) 
6 mg (target dose) 
8 mg 
9 mg 
10 mg (target dose) 
12 mg 
16 mg (target dose) 
Matched  
Route of Administration 
Subcutaneous using a syringe 
Subcutaneous using a syringe 
Frequency of Administration 
Once weekly 
Once weekly 
Authorized as defined by EU 
Clinical Trial Regulation 
Not authorized in EU 
Not authorized in EU 
Abbreviation: EU = European Union. 
 
The first injections of study intervention should occur at Visit 0 after the participant has 
undergone all other study procedures and assessments. Subsequent study intervention 
administrations should be scheduled on the same day of the week and approximately the same 
time of the day if possible. If a dose of study intervention is missed, the participant should take it 
as soon as possible, unless it is within 72 hours of the next dose. If less than 72 hours remains, 
that dose should be skipped, and the next dose should be taken at the scheduled day and time. 
The day of weekly administration can be changed, if necessary, as long as the last dose was 
administered 72 or more hours before. 
Participants will inject study intervention SC into the abdominal wall, alternating between 4 sites 
weekly, that is right and left upper quadrants and right and left lower quadrants, using the 
injection supplies provided. Furthermore, participants should dilute LY3305677 and inject 
themselves in the presence of site personnel at each visit to check the participant is correctly 
diluting and injecting LY3305677.  
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A caregiver may administer the injection after appropriate training. A new syringe will be used 
for each injection of LY3305677 study intervention. The actual date and time of all dose 
administrations will be recorded in the study intervention administration diary by the participant. 
Packaging and labeling 
Study intervention will be supplied by the sponsor or its designee in accordance with current 
Good Manufacturing Practice. Study interventions will be labeled as appropriate for country 
requirements. 
6.2. 
Preparation, Handling, Storage, and Accountability  
The investigator or designee must confirm appropriate storage conditions have been maintained 
during transit for all study intervention received and any discrepancies are reported and resolved 
before use of the study intervention. 
Only participants enrolled in the study may receive study intervention. Only authorized study 
personnel may supply, prepare, or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized study personnel. 
The investigator or authorized study personnel are responsible for study intervention 
accountability, reconciliation, and record maintenance (that is, receipt, reconciliation, and final 
disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided by the sponsor. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding  
This is a double-blind study.  
At Visit 0, participants who meet all criteria for enrollment will be randomly assigned to one of 
the study treatment arms (placebo, LY 3/6 mg, LY 10 mg and LY 16 mg) in a 3:2:3:3 ratio. 
Participants randomized to placebo will be assigned to follow the injection dose schedule with 
matching injection volume for 1 of the LY3305677 treatment arms. Although the participant and 
the investigator will know the injection volume of study drug, they will not know whether the 
participant is receiving LY3305677 or placebo. Assignment to treatment arms will be determined 
by a computer-generated random sequence using an IWRS with the following stratification 
variables: 
 BMI (≤30, >30 kg/m2 at screening) 
 Sex (male or female) 
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete. 
See the CWMM master protocol Section 6.3 for emergency unblinding and additional 
information on minimizing bias. 
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6.4. 
Study Intervention Compliance  
Study intervention administration data (date and time of each dose administered) will be 
recorded in the diary by the participant and reviewed by the investigator at each study 
visit. 
The participants will be instructed to return any unused study intervention and/or empty 
cartons at the next visit to the study site for the purpose of performing study intervention 
accountability. 
Also, see the CWMM master protocol (Section 6.4) for measures to assure or assess compliance. 
6.5. 
Dose Modification  
Study intervention administration in OXA1 should follow the schedule summarized in Section 
1.3 (SoA) and detailed in the dose escalation table in Section 6.5.1. 
Adjustment in study intervention dose level will be allowed for participants assigned to each of 
the treatment groups. 
Dose modifications of LY3305677 or placebo, will be conducted in a blinded fashion as depicted 
in the dose escalation table in Section 6.5.1.  
Dose modification is allowed for: 
 dose escalations 
 adverse events 
 temporary dose interruption, or 
 dose reductions, without dosing interruptions, and 
 when appropriate to ensure participant safety or to address tolerability issues. 
Dose reductions may occur at unscheduled visits. 
See CWMM master protocol Section 7.1 for detailed information about discontinuation of study 
intervention. 
6.5.1. 
Dose Escalations  
This table provides dose escalation schemes for LY treatment arms in OXA1. Patients in placebo 
arm will be split to sub-groups that match the dosing volume and escalation plan of each LY 
treatment arms. 
 
 
 
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LY 9 mg is not tolerated 
Reduce dose to LY 6 mg and re-
escalate. 
 
If LY 9 mg is not tolerated a second 
time 
Maintain at LY 6 mg. 
 
LY 12 mg is not tolerated 
Reduce dose to LY 9 mg and re-
escalate. 
 
If LY 12 mg is not tolerated a second 
time 
Maintain at LY 9 mg. 
 
LY 16 mg is not tolerated 
Reduce the LY dose to 12 mg and re-
escalate.  
 
If LY 16 mg is not tolerated a second 
time  
Maintain at LY 12 mg. 
Abbreviation: LY = LY3305677. 
 
6.6. 
Continued Access to Study Intervention after the End of the Study  
LY3305677 will not be made available after conclusion of the study. 
6.7. 
Treatment of Overdose  
For this study, any total dose of study intervention within a 72-hour time period over 16 mg will 
be considered an overdose and should be reported as per criteria described in Section 10.3 of the 
CWMM master protocol. The amount of study intervention taken will be estimated from the 
participants scheduled dose at the time of the overdose.   
In the event of an overdose, the investigator or treating physician should: 
 Contact the Lilly-designated medical monitor immediately. 
 Evaluate the participant to determine, in consultation with the Lilly-designated 
medical monitor, whether study intervention should be interrupted or whether the 
dose should be reduced. 
 Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate. Based on the known AE profile of LY3305677, the 
following are the possible AEs related to an overdose: 
o severe GI events that lead to dehydration and require medical intervention 
o CV abnormalities, such as increase in heart rate (HR), decrease in BP, and 
supraventricular arrhythmias/cardiac conduction disorders, and 
o hypoglycemia 
 Implement medical intervention/monitoring according to the clinical presentation. 
 Obtain a plasma sample for PK analysis as soon as possible. 
 Document the event of overdose in the CRF. 
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6.8. 
Prior and Concomitant Therapy  
See the CWMM master protocol (Section 6.8). 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
See the CWMM master protocol (Section 7). 
7.1. 
Discontinuation of Study Intervention  
In addition to the reasons stated in the CWMM master protocol Section 7.1, participants in 
OXA1 should be permanently discontinued from study intervention if 
 the participant is diagnosed with pancreatitis 
 the participant is diagnosed with multiple endocrine neoplasia type 2 syndrome, or 
 the participant’s BMI reduces below 18.5 kg/m2. 
7.1.1. 
Liver Chemistry Stopping Criteria  
See CWMM master protocol (Section 7.1.1). 
7.1.2. 
Cardiac Arrhythmia and QTc Stopping Criteria  
Discontinuation of study intervention should be considered by the investigator and sponsor if any 
of the following occurs in a participant: 
 QTc ≥ 500 msec or change in QTc ≥ 60 msec from baseline 
 Clinically significant arrhythmia (i.e., atrial fibrillation) 
See CWMM master protocol (Section 7.1.2). 
7.1.3. 
Temporary Interruption of Study Intervention  
In certain situations, after randomization, study intervention may need to be temporarily 
interrupted. Every effort should be made by the investigator to maintain participants on study 
intervention and to restart study intervention after any temporary interruption, as soon as it is 
appropriate to do so. A participant may experience multiple events that require dosing 
interruption; each event should be addressed individually per guidance provided in this section. 
For example, participants may need to temporarily interrupt study intervention due to 
 occurrence of intolerable GI AEs 
 other AEs that warrant dosing interruption determined by the investigator, or 
 reasons unrelated to AEs. 
If the reason for temporary dosing interruption is related to poor participant tolerability, for 
example, when protracted GI events of vomiting and/or diarrhea trigger a request from the 
participant and/or from the investigator for temporary discontinuation of dosing, 1 weekly dose 
of study intervention may be omitted. A longer interruption may be needed at the discretion of 
the investigator.  
In other situations when participant safety is compromised, for example due to an SAE, more 
than 1 dose may need to be skipped. 
The decision to interrupt dosing in any of these situations will not be considered a protocol 
deviation. 
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If the participant interrupts dosing for other reasons that are not related to the tolerability or 
safety of the participant, dosing interruption will be considered a protocol deviation. 
The dates and number of skipped doses related to temporary interruption of study treatment will 
be documented. 
Other situations of study intervention interruption that are not described in this section should be 
discussed between the primary investigator or designee and Lilly study physician/research 
scientist to decide on an appropriate dosing plan for any participant with such events. 
7.1.3.1. 
Restarting Study Intervention after a Temporary Interruption  
If the number of consecutive missed doses of study intervention is ≤2, the treatment can be 
restarted at the same dose if the drug was well tolerated prior to discontinuation. 
If the number of consecutive missed doses is ≥3 (or fewer doses if the study intervention was not 
well tolerated) when the dose interruption occurred, then the treatment should be restarted as 
described below.  
If the dose interruption occurs during the first 4 weeks of dosing (that is, the starting dose level), 
the participant should be restarted on the first dose level.  
If the participant has a dose interruption after the first 4 weeks, restart LY3305677 at 3 mg and 
stay on 3 mg for 2-4 weeks before continuing to dose escalate every 4 weeks according to the 
escalation schedule assigned to the participant.   
See Section 6.5.3 for guidance on dose escalation/maintenance for participants who do not 
tolerate a dose level of study intervention. 
7.2. 
Participant Discontinuation/Withdrawal from the Study  
See CWMM master protocol (Section 7.2). 
7.3. 
Lost to Follow up  
See CWMM master protocol (Section 7.3). 
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8. 
Study Assessments and Procedures  
See CWMM master protocol (Section 8). 
8.1. 
Efficacy Assessments  
Primary 
The primary efficacy measure is percent change in body weight from baseline at Week 32. Body 
weight measurements will be collected at specific clinic visits as summarized in the SoA 
(Section 1.3). Methods for measuring body weight are described in Section 10.8 of the CWMM 
master protocol. 
Secondary 
The following secondary efficacy measures will be collected or calculated at the times shown in 
the SoA: 
 body weight, 
 BMI, and 
 liver fat (assessed by MRI-PDFF). 
Exploratory 
See Section 3 of the CWMM master protocol and Section 3 of OXA1 for specific efficacy 
endpoints. The following exploratory efficacy measures will be collected or calculated at the 
times shown in the SoA: 
 Waist circumference 
 Body weight 
 BMI 
 Fasting lipid profile, consisting of total cholesterol, LDL cholesterol, VLDL cholesterol, 
HDL cholesterol triglycerides, non-HDL cholesterol. 
 Systolic and diastolic blood pressure (included in vital signs) 
 HbA1c 
 Fasting insulin 
 Fasting glucose (included in clinical chemistry panel) 
 Mechanistic biomarkers: to explore potential mechanism of action modifying glucose, 
lipid, or nutrient metabolism, markers will be assessed (see Section 10.5 for detailed list 
of biomarkers) related to 
o insulin sensitivity 
o pancreatic beta or alpha cell function 
o glucagon receptor target engagement 
o lipid metabolism 
o liver fat, inflammation, or fibrosis 
o purine metabolism 
o cardiovascular risk, and 
o inflammation. 
 Patient-reported outcomes 
o PROMIS SF Pain Interference 4a v1.1  
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o PGIS – Physical Function due to Weight 
o PGIC – Physical Function due to Weight 
o SF-36 v2, acute form, and 
o Appetite VAS. 
 Physical activity (assessed with Axivity AX6 actigraphy device) 
 Body composition (assessed by MRI) 
 Liver fat content (assessed by MRI-PDFF) 
8.1.1. 
Patient-Reported Outcomes  
The self-administered questionnaires will be translated into the primary languages of the region 
and administered at the site during the designated visits in the OXA1 SoA. At these visits, the 
questionnaires should be completed after AE collection but before the participant has discussed 
their medical condition or progress in the study with the investigator and/or site staff, if the 
participant is not adversely affected by their fasting condition. 
Preferred administration order of these questionnaires is 
1. PROMIS SF Pain Interference 4a v1.1 
2. PGIS – Physical Function due to Weight 
3. PGIC – Physical Function due to Weight  
4. SF-36 v2 acute form, and 
5. Appetite VAS. 
8.1.1.1. 
PROMIS Short Form Pain Interference 4a v1.1  
The Patient-Reported Outcome Measurement Information System (PROMIS) (Health Measures 
[WWW]) is a set of patient-completed measures that evaluates and monitors physical, mental, 
and social health in adults and children. It can be used with the general population and with 
individuals living with chronic conditions.    
The PROMIS Short Form Pain Interference 4a assesses consequences of pain on relevant aspects 
of one’s life. This includes the extent to which pain interferes with day-to-day, social, and 
household activities. The PROMIS Short Form Pain Interference 4a consists of 4 items that asks 
participants to rate their pain interference over the past 7 days on a 5-point scale ranging from “1 
– not at all” to “5 – very much.” Individual item scores are totaled to obtain a raw score, with 
higher scores indicating more interference. Raw scores can be converted to a t-score, which is 
standardized with a mean of 50 and a standard deviation (SD) of 10; higher scores indicate better 
levels of function and/or better health. Patient Global Impression of Severity - Physical Function 
due to Weight  
The Patient Global Impression of Severity - Physical Function due to Weight (PGIS - physical 
function weight) questionnaire is designed to assess the participants’ overall perception of their 
condition. This is a single global item that asks participants to rate how their weight limited their 
ability to perform physical activities in the past 7 days on a 5-point scale ranging from “not at all 
limited” to “extremely limited.” 
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8.1.1.2. Patient Global Impression of Change - Physical Function due to Weight  
The Patient Global Impression of Change – Physical Function due to Weight (PGIC - physical 
function weight) questionnaire is designed to assess the participant’s overall perception of the 
efficacy of treatment. This is a single global item that asks participants to rate the overall change 
in their ability to perform physical activities due to their weight since starting the study 
medication. The responses are based on a 5-point scale ranging from “much better” to “much 
worse”. 
8.1.1.3. 
SF-36 v2, Acute Form  
The Short Form-36 version 2 Health Survey acute form (SF-36 v2 acute), 1-week recall version 
is a 36-item generic, participant-completed measure designed to assess the following 8 domains:  
  
 
Physical functioning 
 
Role-physical 
 
Bodily pain 
 
General health 
 
Vitality 
 
Social functioning 
 
Role-emotional, and 
 
Mental health. 
The Physical Functioning domain assesses limitations due to health “now” while the remaining 
domains assess functioning “in the past week.” Each domain is scored individually and 
information from these 8 domains are further aggregated into 2 health component summary 
scores: Physical Component Summary and Mental Component Summary. Items are answered on 
Likert scales of varying lengths (3-point, 5-point, or 6-point scales). Scoring of each domain and 
both summary scores are norm based and presented in the form of t-scores, with a mean of 50 
and SD of 10; higher scores indicate better levels of function and/or better health (Maruish 
2011).  
8.1.1.4. Appetite Visual Analog Scale  
To explore the effects of LY3305677 on meal intake and appetite sensation, participants will be 
asked to rate their appetite sensations using a 100-mm VAS for parameters of hunger, fullness, 
satiety, and prospective food consumption in the fasted state (refer to the SoA in Section 1.3).   
The VAS is a validated tool to assess appetite sensation parameters (Flint et al. 2000). The VAS 
is presented as a 10-cm (100-mm) line, anchored by verbal descriptors, usually “extremely” and 
“not at all.” Participants are required to rate their subjective sensations on four 100-mm scales 
combined with questions similar to the following:   
Overall appetite score is calculated as the average of the 4 individual scores: satiety + fullness + 
(100-prospective food consumption) + (100-hunger) / 4 (van Can et al. 2014). The higher overall 
appetite score indicates less appetite, and the lower score indicates more appetite. 
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8.1.2. 
Actigraphy   
An actigraphy device (Axivity AX6) will be utilized in OXA1 to objectively evaluate the effect 
of study intervention on physical activity parameters. 
This actigraphy device is a data capture tool capable of recording raw data from a suite of 
integrated sensors and can be configured to collect movement-relevant data in an uninterrupted 
fashion for up to 2 months, thus is ideal for collecting longitudinal movement data, for example, 
physical activity and sleep, in real-world health research and well-defined clinical trials. 
This actigraphy device meets the CE (Conformitè Europëenne) mark requirements. Participants 
should wear the actigraphy device for at least 2 weeks, at 3 separate times during the study, per 
the SoA.  
Lack of participation in actigraphy collections at any time is not considered a protocol deviation. 
8.1.3. 
Magnetic Resonance Imaging (MRI)  
Purpose 
The collected MRI and biomarker data will be used to explore the effect of study intervention on 
liver fat content and additional MRI derived measurements. 
Collection visits 
Collection visits are specified in the SoA (Section 1.3). MRI procedures will be performed and 
specific circulating biomarkers to be collected. 
Participants are required to report for the MRI after approximately 8 hours without eating, 
drinking (except water), and without performing any significant physical activity. Participants 
can take normal maintenance medications with water if medications are not required to be 
administered with food. 
MRI procedures 
MRI measurements at baseline should be performed between Visit 402 and Visit 0 
(randomization) in OXA1, before the participant receives the first dose of study intervention. 
The postbaseline MRI measurements at Week 32 should occur within ±2 weeks. Week 48 
measurements should be scheduled and performed anytime between Visits 44 and 48 and ED 
measurements may be performed within ±7 days of the date of the study visit. Both MRI 
measurements should be performed after a fast of at least 8 hours.  
To obtain consistent and quality data for central review, investigators will be provided with 
detailed instructions on the MRI acquisition protocol to be used.  
Scans will be performed at 1.5 Tesla (T) or 3 T. The same scanner and imaging acquisition 
sequence or procedure should be used for all participant time points. Any exceptions must be 
approved in advance of scanning by the imaging core laboratory. A standardized imaging 
acquisition sequence or procedure will be utilized at all MRI centers and details will be provided 
in MRI Site instructions. 
MRI images are transmitted to a central reader for evaluation of the MRI-based efficacy 
endpoints. To ensure participant’s safety, images should also be over-read locally to exclude 
underlying liver pathologies.   
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8.2. 
Safety Assessments  
Planned time points for safety assessments are provided in the OXA1 SoA (Section 1.3). 
Lilly will periodically review evolving aggregate safety data within the study. The study team 
will review safety reports in a blinded fashion (for applicable blinded study period) according to 
the schedule provided in the Trial-Level Safety Review plan. Lilly will also review SAEs within 
time frames mandated by company procedures. The Lilly-designated medical monitor will, as 
appropriate, consult with the functionally independent Global Patient Safety therapeutic area 
physician or clinical scientist. 
See the CWMM master protocol Section 8.2 for safety assessments and safety monitoring 
activities required for all ISAs. 
Procedures specified in the following subsections of OXA1 must be followed in addition to those 
described in the CWMM master protocol. 
8.2.1. 
Vital Signs  
See the CWMM master protocol, Section 8.2.1. 
8.2.2. 
Physical Examinations  
See the CWMM master protocol, Section 8.2.2. 
8.2.3. 
Electrocardiograms  
See CWMM master protocol, Section 8.2.3. 
8.2.4. 
Clinical Safety Laboratory Tests  
Perform laboratory assessments per the SoA (Section 1.3). See CWMM master protocol, 
Section 8.2.4 for information on reporting, review and recording, and repeating 
laboratory tests. 
See OXA1, Section 10.2 and CWMM master protocol, Section 10.2 for the list of clinical 
laboratory tests. 
8.2.5. 
Major Adverse Cardiovascular Events  
See the CWMM master protocol, Section 8.2.5. 
8.2.6. 
Deaths  
See CWMM master protocol, Section 8.2.6. 
8.2.7. 
Hepatobiliary Disorders  
See CWMM master protocol, Section 8.2.7. 
8.2.8. 
Acute Renal Events  
See CWMM master protocol, Section 8.2.8. 
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8.2.9. 
Pregnancy Testing  
See CWMM master protocol, Section 8.2.9. 
8.2.10. 
Hepatic Monitoring  
See CWMM master protocol, Section 8.2.10. 
8.2.11. 
Suicidal Ideation and Behavior Risk Monitoring  
8.2.11.1. Columbia-Suicide Severity Rating Scale  
See CWMM master protocol, Section 8.2.11.1. 
8.2.11.2. Patient Health Questionnaire-9  
See CWMM master protocol, Section 8.2.11.2. 
8.2.12. 
Additional Safety Data and Sample Collections  
8.2.12.1. Ambulatory Blood Pressure Monitoring (ABPM)  
Ambulatory monitoring device 
An ambulatory monitoring device that uses an inflatable cuff attached to a portable device worn 
around the waist will be used to collect multiple BP and HR readings over a 24-hour period, 
during both sleep and wake cycles. The multiple readings collected by the ABPM device can be 
averaged to obtain mean BP and HR values, to detect variations over time, and to compute other 
distribution patterns. 
Study procedures 
Participants who give consent and meet all eligibility requirements will receive education about 
ABPM and will be trained in its use at Visit 402. Ambulatory monitoring of HR and BP will be 
performed prior to Visit 0 and initiated at Visit 402, in the week prior to Visit 32 (Week 32: 
primary endpoint), and again in the week prior to Visit 48. It will not be considered a protocol 
deviation if a participant does not meet all ABPM eligibility requirements to participate in 
ABPM procedures. Participants that do not have a baseline ABPM measure should not have any 
subsequent ABPM collections. 
Use of the ABPM device 
The ABPM device will be attached to the nondominant arm, and participants will be instructed to 
wear the monitor for a 24- to 27-hour period. Participants will also be instructed to keep track of 
daily activities throughout the testing period and not to engage in strenuous activity. 
Ambulatory blood pressure measurements: 
 Should be collected on a typical workday, not on a non-working day 
 Will be recorded every 30 minutes during daytime hours (0700 to 2200 hours) 
 Will be recorded every 60 minutes during nighttime hours (2200 to 0700 hours). 
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A 24-hour session of ambulatory monitoring produces technically acceptable measurements if 
≥70% of the readings are valid. 
If a technically satisfactory result is not achieved, the investigator should review the device 
settings and placement and the participant’s activity track in an attempt to correct any user error 
or device malfunctions. Another 24-hour ambulatory monitoring session should be conducted 
prior to Visit 0, and this measurement will serve as the baseline value. If the second session also 
provides technically unsatisfactory results, the participant should not undergo any further ABPM 
measures. 
8.2.12.2. Hypoglycemia  
Upon ICF signing, all participants will be educated about signs and symptoms of hypoglycemia 
and how to treat hypoglycemia.  
Hypoglycemia may be identified by spontaneous reporting of symptoms from participants 
(whether confirmed or unconfirmed by simultaneous glucose values) or by blood glucose (BG) 
samples collected during study visits. 
All participants who develop incident diabetes during the study will be provided with 
glucometers (Section 8.3.4). Participants without diabetes may, at the investigator’s discretion, 
be given glucometers to assist in the evaluation of reported symptoms consistent with persistent 
hypoglycemia. Participants receiving glucometers should be instructed to record relevant 
information (for example, glucose values and symptoms). 
Participants who develop incident diabetes during the study may be started on allowed glucose-
lowering medications (Section 6.8). In the event that participants subsequently develop persistent 
or recurrent unexplained hypoglycemia during the treatment period, participants will be asked to 
reduce the dose or discontinue any concomitant glucose-lowering medication commonly 
associated with hypoglycemia (for example, sulfonylurea or insulin).   
If a hypoglycemic event meets severe criteria (see definition below), it should be recorded as 
serious on the AE and SAE CRFs and reported to Lilly as an SAE. 
Investigators should use the following definitions and criteria when diagnosing and categorizing 
an episode considered to be related to hypoglycemia (the BG values in this section refer to values 
determined by a laboratory or International Federation of Clinical Chemistry and Laboratory 
Medicine blood-equivalent glucose meters and strips) in accordance with the 2020 American 
Diabetes Association position statement on glycemic targets (ADA 2020). Level 2 and Level 3 
hypoglycemia events are considered as safety topics of special interest: 
Level 1 hypoglycemia:  
Glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L): Level 1 hypoglycemia can 
alert a person to take action such as treatment with fast-acting carbohydrates. Providers should 
continue to counsel participants to treat hypoglycemia at this glucose alert value. 
Level 2 hypoglycemia:   
Glucose <54 mg/dL (3.0 mmol/L): Level 2 hypoglycemia is also referred to as documented 
or BG-confirmed hypoglycemia with glucose <54 mg/dL (3.0 mmol/L). This glucose 
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threshold is clinically relevant regardless of the presence or absence of symptoms of 
hypoglycemia.  
Level 3 hypoglycemia:   
Severe hypoglycemia (in adults): A severe event characterized by altered mental and/or 
physical status requiring assistance for treatment of hypoglycemia. For example, participants 
had altered mental status and could not assist in their own care, or were semiconscious or 
unconscious, or experienced coma with or without seizures, and the assistance of another 
person was needed to actively administer carbohydrate, glucagon, or other resuscitative 
actions. Glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of glucose concentration to normal is considered 
sufficient evidence that the event was induced by a low glucose concentration. 
 The determination of a hypoglycemic event as an episode of severe hypoglycemia, as 
defined above, is made by the investigator based on the medical need of the 
participant to have required assistance and is not predicated on the report of a 
participant simply having received assistance. 
 If a hypoglycemic event meets the criteria of severe hypoglycemia, the investigator 
must record the event as serious on the AE CRF and report it to Lilly as an SAE. 
Nocturnal hypoglycemia: 
Nocturnal hypoglycemia is a hypoglycemia event (including severe hypoglycemia) that 
occurs at night and presumably during sleep.   
To avoid duplicate reporting, all consecutive BG values <70 mg/dL (3.9 mmol/L) occurring 
within a 1-hour period may be considered to be a single hypoglycemic event 
(Weinberg et al. 2010; Danne et al. 2013). 
8.2.12.3. Pancreatitis  
Diagnosis of acute pancreatitis 
Acute pancreatitis is safety topic of interest in all studies with LY3305677, including this study. 
The diagnosis of acute pancreatitis requires 2 of the following 3 features (Banks and Freeman 
2006; Koizumi et al. 2006):  
 abdominal pain, characteristic of acute pancreatitis (that is, epigastric pain radiating 
to the back, often associated with nausea and vomiting) 
 serum amylase (total, pancreatic, or both) and/or lipase ≥3X ULN, and 
 characteristic findings of acute pancreatitis on CT scan or MRI. 
If acute pancreatitis is suspected, the investigator should ensure that the following steps are 
taken: 
 obtain appropriate laboratory tests, including pancreatic amylase (p-amylase) and 
lipase, and 
 perform imaging studies, such as abdominal CT scan with or without contrast, or 
abdominal MRI. 
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Note: Abdominal ultrasound may be used as an alternative method only if CT and MRI 
cannot be performed. 
 evaluate for possible causes of acute pancreatitis, including alcohol use, gallstone/gall 
bladder disease, hypertriglyceridemia, and concomitant medications. 
Discontinuation for acute pancreatitis 
If acute pancreatitis is suspected by the investigator, the participant must temporarily discontinue 
use of the study intervention. Afterwards, if the case is confirmed as acute pancreatitis by the 
adjudication committee, study intervention must be permanently discontinued; the participant 
may continue in the study. If the case is not confirmed, then the participant can restart study 
intervention, if the investigator deems as clinically appropriate, as described in the 
Section 7.1.3.1. 
Case adjudication and data entry 
An independent Clinical Endpoint Committee (CEC) will adjudicate all suspected cases of acute 
pancreatitis. Relevant data from participants with acute pancreatitis will be entered into a 
specifically designed CRF page. The adjudication committee representative will enter the results 
of adjudication in a corresponding CRF page. 
Asymptomatic elevation of pancreatic amylase and/or lipase 
Serial measures of pancreatic enzymes have limited clinical value for predicting episodes of 
acute pancreatitis in asymptomatic participants (Nauck et al. 2017; Steinberg et al. 2017a, 
2017b). Therefore, further diagnostic follow-up of cases of asymptomatic elevation of pancreatic 
enzymes (lipase and/or pancreatic amylase ≥3X ULN) is not mandated but may be performed 
based on the investigator’s clinical judgment and assessment of the participant’s overall clinical 
condition.   
8.2.12.4. Thyroid Malignancies and C-Cell Hyperplasia  
Individuals with personal or family history of MTC and/or MEN-2 will be excluded from the 
study. Participants who are diagnosed with MTC and/or MEN-2 during the study will have study 
intervention stopped and should continue follow-up with an endocrinologist. 
The assessment of thyroid safety during the trial will include reporting of any case of thyroid 
malignancy (including MTC, papillary carcinoma, and others) and measurements of calcitonin. 
These data will be captured in specific CRFs. The purpose of calcitonin measurements is to 
assess the potential of LY3305677 to affect thyroid C-cell function, which may indicate 
development of C-cell hyperplasia and neoplasms.  
8.2.12.4.1. Calcitonin Measurements  
If an increased calcitonin value (see definitions below) is observed in a participant who has been 
administered a medication that is known to increase serum calcitonin, then this medication 
should be stopped, and calcitonin levels should be measured after an appropriate washout period. 
For participants who require additional endocrine assessment because of increased calcitonin 
concentration as defined in this section, data from the follow-up assessment will be collected in 
the specific section of the CRF. 
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Calcitonin measurements in participants with eGFR ≥60 mL/min/1.73 m2  
A significant increase in calcitonin for participants with eGFR ≥60 mL/min/1.73 m2 is defined 
below. If a participant’s laboratory results meet these criteria, these clinically significant 
laboratory results should be recorded as an AE.   
 Serum calcitonin value ≥20 ng/L and <35 ng/L AND ≥50% increase from the 
screening value. These participants will be asked to repeat the measurement within 
1 month. If this repeat value is increasing (≥10% increase), the study intervention should 
be stopped, and the participants encouraged to undergo additional endocrine assessment 
and longer-term follow-up by an endocrinologist to exclude any serious adverse effects 
on the thyroid. 
 Serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. In these 
participants, study intervention should be stopped, and the participants recommended to 
immediately undergo additional endocrine assessments and longer-term follow-up by an 
endocrinologist.   
Calcitonin measurement in participants with eGFR <60 mL/min/1.73 m2  
A significant increase in calcitonin for participants with eGFR <60 mL/min/1.73 m2 is defined as 
a serum calcitonin value ≥35 ng/L AND ≥50% over the screening value. If a participant’s labs 
meet these criteria, these clinically significant labs should be recorded as an AE.   
In these participants, study intervention should be discontinued (after first confirming the value) 
and the participants recommended to immediately undergo additional endocrine assessments and 
longer-term follow-up by an endocrinologist to exclude any serious adverse effect on the thyroid.   
8.2.12.5. Supraventricular Arrhythmias and Cardiac Conduction Disorders  
Treatment-emergent cardiac conduction disorders will be further evaluated. Participants who 
develop any event from these groups of disorders should undergo an ECG, which should be 
submitted to the central reading center. Additional diagnostic tests to determine exact diagnosis 
should be performed, as needed. The specific diagnosis will be recorded as an AE. Events that 
meet criteria for serious conditions as described in CWMM master protocol, Section 10.3 must 
be reported as SAEs. 
8.2.12.6. Hypersensitivity Reactions  
Many drugs, including oral agents and biologic agents, carry the risk of systemic hypersensitivity 
reactions. If such a reaction occurs, additional data should be provided to the sponsor in the 
designated CRFs. 
Sites should have appropriately trained medical staff and appropriate medical equipment 
available when study participants are receiving study intervention. It is recommended that 
participants who experience a systemic hypersensitivity reaction be treated per national and 
international guidelines. 
In the case of a suspected systemic hypersensitivity event, additional blood samples should be 
collected as described in Section 10.2.2. Laboratory results are provided to the sponsor via the 
central laboratory. 
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8.2.12.7. Injection Site Reactions  
Symptoms of a local injection site reaction may include erythema, induration, pain, pruritus, and 
edema. If an injection site event is reported, the AE will be recorded, and additional data will be 
provided to the sponsor in the CRF. At the time of AE occurrence of severe or serious types, 
samples will be collected for measurement of LY3305677 antidrug antibodies (ADAs) and 
LY3305677 concentration. 
8.2.12.8. Antidrug Antibodies  
The occurrence of ADA formation will be assessed as outlined in Section 8.8. 
8.2.12.9. Severe Gastrointestinal Adverse Events  
LY3305677 may cause severe GI AEs, such as nausea, vomiting, and diarrhea. Information 
about severe GI AEs as well as antiemetic/antidiarrheal use will be collected in the CRF/AE and 
Concomitant Medications forms, respectively. 
8.3. 
Adverse Events, Serious Adverse Events, and Product Complaints  
See the CWMM master protocol, Section 10.3 for AE, SAE, and product complaint definitions.  
8.3.1. 
Timing and Mechanism for Collecting Events  
See CWMM master protocol, Section 8.3.1. 
8.3.2. 
Pregnancy  
See CWMM master protocol, Section 8.3.2. 
8.3.3. 
Adverse Events of Special Interest  
8.3.3.1. 
Hypotension and Related Neurological Signs and Symptoms  
Hypotension, orthostatic hypotension, and related neurological events will be identified by 
spontaneous reporting of symptoms (for example dizziness, blurred vision, and syncope) and 
blood pressure levels. See Section 2.3.1 for hypotension assessment.  
8.3.3.2. 
Acute Renal Failure  
As hypotension may lead to renal impairment, 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 kidney disease. LY3305677 may cause severe GI AEs, such as 
nausea, vomiting, and diarrhea, consistent with other GLP-1R agonists (Aroda and Ratner 2011). 
These events may lead to dehydration, which could cause a deterioration in renal function, 
including acute renal failure. To date no cases have been observed related to acute renal failure. 
Participants should notify investigators in case of severe nausea, frequent vomiting or diarrhea, 
or symptoms of dehydration. 
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8.3.3.3. 
Skin Burning Sensation and Related Adverse Events  
If skin burning sensation and related AEs, for example, hyperesthesia and sensitive skin, are 
reported, it should be recorded as an AE and a skin assessment CRF should be used to capture 
additional information about these events. 
See Section 8.3.5 for Safety Topic for Monitoring. 
8.3.4. 
Incident Diabetes  
Participants may be diagnosed with T2DM in a healthcare setting during the time of their 
participation in the study. This will be recorded as an AE. Newly added pharmacologic 
treatments will be recorded as new concomitant medications. Data collected within the course of 
the study (scheduled HbA1c measurements, concomitant medication records) will be used to 
provide confirmatory evidence of the diabetes diagnosis but failure to confirm in this way is not 
required to record the diabetes diagnosis event.  
8.3.5. Safety Topics for Monitoring  
The following safety topics of interest are specific to OXA1: 
These are safety topics of interest that may be anticipated based on published information, 
potential findings based on drug class even if not observed with the specific investigational 
molecule (LY3305677), preclinical results, or early clinical results. They can also be events that 
regulatory bodies recommend be monitored. Such topics would not be recorded as notable, 
unless fitting one of the notable criteria as defined by the ICH Guidance (E3) on “Structure and 
Content of Clinical Study Reports”: deaths, SAEs, and AEs leading to permanent discontinuation 
of the investigational drug. 
Based on this definition, safety topics for monitoring include the following: 
 Hypoglycemia  
 Severe/serious gastrointestinal adverse reactions 
 Acute kidney injury 
 Pancreatitis events (will be adjudicated by CEC) 
 Hepatic disorders 
 Biliary disorders 
 MACE3 (MI, stroke, CV death) (will be adjudicated by CEC) 
 Supraventricular arrhythmias and cardiac conduction disorders  
 Malignancies (including medullary and papillary thyroid carcinoma) 
 Major depressive disorder/suicidal ideation or behavior  
 Abuse/liability potential 
 Hypotension and related neurological signs and symptoms 
 Hypersensitivity reactions, and 
 Injection site reactions. 
See Section 8.2.12 for any additional samples and data collections when certain AEs occur. 
The details of analysis will be provided in the statistical analysis plan (SAP). 
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8.4. 
Pharmacokinetics  
See the OXA1 (Section 1.3) for the visits and times of PK sample collection. 
The actual date and time (24-hour clock time) of every dose and sample collection must be 
recorded accurately on the appropriate forms. 
Plasma samples will be collected for measurement of plasma concentrations of LY3305677 as 
specified in the SoA.  
A maximum of 3 samples may be collected at additional time points during the study if 
warranted and agreed upon between the investigator and the sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (for example, to 
obtain data closer to the time of peak plasma concentrations) to ensure appropriate monitoring.  
Instructions for the collection and handling of biological samples will be provided by the 
sponsor.   
Samples will be used to evaluate the PK of LY3305677. Samples collected for analyses of 
LY3305677 plasma concentration may also be used to evaluate safety or efficacy aspects related 
to concerns arising during or after the study. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.4.1. 
Bioanalysis  
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor. 
Concentrations of LY3305677 will be assayed using a validated liquid chromatography mass 
spectrometry method. Analyses of samples collected during placebo treatment are not planned. 
Bioanalytical samples collected to measure LY3305677 concentrations will be retained for a 
maximum of 1 year following last participant visit for the study. During this time, samples 
remaining after the bioanalyses may be used for exploratory analyses such as metabolism work, 
protein binding, or bioanalytical method cross-validation. 
8.5. 
Pharmacodynamics  
Pharmacodynamic assessments are evaluated as part of the efficacy measures (Section 8.1) and 
biomarkers (Section 8.7) in this study and will be collected in accordance with the SoA (Section 
1.3). 
8.6. 
Genetics  
Whole-blood samples will be collected from participants to enable DNA isolation for exploratory 
pharmacogenetic and/or epigenetic analyses as specified in the SoA (Section 1.3), where local 
regulations allow. 
Samples will not be used to conduct unspecified disease or population genetic or epigenetic 
research either now or in the future. Samples may be used to investigate variable exposure or 
response to LY3305677 or to investigate genetic variants or epigenetic modifications thought to 
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play a role in obesity, diabetes mellitus, or related traits or complications including nonalcoholic 
steatohepatitis. Assessment of variable response may include evaluation of AEs or differences in 
pharmacodynamic, mechanistic, safety, or efficacy measures.  
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last participant visit for the study, 
or for a shorter period if local regulations and/or the Ethical Review Board impose shorter time 
limits, at a facility selected by Lilly or its designee. This retention period enables use of new 
technologies, response to regulatory questions, and investigation of variable response that may 
not be observed until later in the development of LY3305677 or after LY3305677 is 
commercially available. 
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named. However, existing approaches include whole-genome or exome 
sequencing, genome-wide association studies, multiplex assays, epigenetic assays, and candidate 
gene studies. Regardless of technology utilized, data generated will be used only for the specific 
research scope described in this section. 
See CWMM master protocol, Section 10.5 for information regarding genetic research and 
CWMM master protocol, Section 10.1.12 for details about sample retention and custody.  
8.7. 
Biomarkers  
In addition to the planned biomarker research as indicated in the SoA and Sections 8.1 and 10.5, 
biomarker research on stored nonpharmacogenetic samples may be performed to address 
questions of relevance to drug disposition, target engagement, pharmacodynamics, mechanism of 
action, variability of participant response (including safety) and clinical outcome. Sample 
collection is incorporated into clinical studies to enable examination of these questions through 
measurement of biomolecules, including, proteins, lipids, and other cellular elements.  
Serum and plasma samples for nonpharmacogenetic biomarker research will be collected at the 
times specified in the SoA (Section 1.3) where local regulations allow. 
Samples will be used for research on the drug targets, disease process, variable response to 
LY3305677, pathways associated with obesity, diabetes mellitus, related clinical traits or 
complications including nonalcoholic steatohepatitis, mechanism of action of LY3305677, 
and/or research methods, or for validating diagnostic tools or assay(s) related to obesity, diabetes 
mellitus, related traits or complications. 
All samples will be coded with the participant number. These samples and any data generated 
can be linked back to the participant only by the investigative site personnel. 
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last participant visit for the study, or for a shorter period if local regulations and ethical 
review boards (ERBs) impose shorter time limits. This retention period enables use of new 
technologies, response to regulatory questions, and investigation of variable response that may 
not be observed until later in the development of LY3305677 or after LY3305677 becomes 
commercially available.  
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8.8. 
Immunogenicity Assessments  
At the visits and times specified in the SoA (Section 1.3), venous blood samples will be collected 
and stored for future analysis to determine antibody production against LY3305677. Antibodies 
may be further characterized for cross-reactive binding to oxyntomodulin and/or their ability to 
neutralize the activity of the LY3305677 (Section 9.3.6.6). 
To interpret the results of immunogenicity, a venous blood sample will be collected at the same 
time points to determine the serum concentrations of LY3305677. All samples for 
immunogenicity should be taken predose when applicable and possible. 
If the immunogenicity sample at the last scheduled assessment or discontinuation visit indicates 
TE ADA, additional samples may be taken until the signal returns to baseline, that is, no longer 
indicates TE ADA, or for up to 1 year after last dose.     
Immunogenicity will be assessed by a validated assay designed to detect ADAs in the presence 
of LY3305677 at a laboratory approved by the sponsor. Samples may be stored for a maximum 
of 15 years (or according to local regulations). Samples may also be used for development and 
control of an immunogenicity assay.  
8.9. 
Health Economics  
Health economics parameters are not evaluated in this study. 
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9. 
Statistical Considerations  
The SAP for OXA1 will be finalized prior to the first unblinding. The OXA1 SAP will include a 
more technical and detailed description of the statistical analyses described in this section. This 
section is a summary of the planned statistical analyses of the most important endpoints, 
including primary and key secondary endpoints.  
The LY3305677 ISA-specific components related to objectives, endpoints, and estimands are 
included below:  
 Primary analysis time point occurs at Week 32 
 Intervention is LY3305677 
 Control is placebo 
9.1. 
Statistical Hypotheses  
The primary objective is to demonstrate that LY3305677 3 mg, 10 mg, or 16 mg QW 
administered subcutaneously is superior to placebo with regard to percent change in body weight 
from baseline to primary time point, in participants with obesity, or overweight plus weight-
related comorbidities. Thus, the null hypotheses to be tested in relation to the primary objective 
are as follows:  
 H30: QW LY3305677 3 mg is not different from placebo with respect to percent change 
in body weight from baseline at Week 32.  
 H10,0: QW LY3305677 10 mg is not different from placebo with respect percent change 
in body weight from baseline at Week 32. 
 H16,0: QW LY3305677 16 mg is not different from placebo with percent change in body 
weight from baseline at Week 32. 
9.2. 
Analyses Sets  
The analysis sets are defined in Section 9.2 of the CWMM master protocol. 
9.3. 
Statistical Analyses  
The following subsections are to be read as supplement to the statistical considerations specified 
in Section 9 of the CWMM master protocol. 
9.3.1. General Considerations  
Statistical analyses of this study will be the responsibility of Eli Lilly and Company or its 
designee. 
See the CWMM master protocol (Section 9.3.1) for primary and secondary estimands as well as 
primary and secondary endpoint analyses. 
Additional considerations specific to OXA1 include the following: 
 Secondary endpoint analyses for TE ADA, PK of the primary intervention, and LFC. 
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 Exploratory endpoint analyses for patient-reported outcomes, glucose regulation, 
biomarkers, dose/exposure-response relationships with safety and efficacy, body 
composition, and LFC. 
Any change to the data analysis method described in OXA1 will require an amendment to this 
protocol only if it changes a principal feature of OXA1. Any other change to the data analysis 
methods described in the ISA, and the justification for making the change, will be described in 
the SAP and the clinical study report. Additional exploratory analyses of the data will be 
conducted as deemed appropriate. 
9.3.2. 
Primary Endpoint(s)/Estimand(s) Analysis  
See the CWMM master protocol (Section 9.3.2) for an outline of the primary endpoint analyses. 
Details of the analyses will be provided in the OXA1 SAP. 
9.3.3. 
Secondary Endpoint(s) Analysis  
The following secondary analyses are to be read as supplementary to those outlined in the 
CWMM master protocol. Details of the analyses will be provided in the OXA1 SAP.  
Refer to Evaluation of Immunogenicity (Section 9.3.6.6) for an outline of TE ADA analysis. 
9.3.4. 
Exploratory Endpoint(s) Analysis  
Details of the analyses will be provided in the OXA1 SAP. 
9.3.5. 
Safety Analyses  
See CWMM master protocol, Section 9.3.5 for a description of safety analyses. 
9.3.5.1. 
Central Laboratory Measures, Vitals, and Electrocardiograms  
See the CWMM master protocol for a description of central laboratory measures, vitals, and 
ECG data analysis. 
9.3.5.2. 
Analysis of C-SSRS Data  
See the CWMM master protocol for a description of C-SSRS data analysis. 
9.3.6. 
Other Analyses  
9.3.6.1. 
Participant Disposition  
See the CWMM master protocol for a description of participant disposition analyses. 
9.3.6.2. 
Participant Characteristics  
See the CWMM master protocol for a list of participant characteristics to be summarized for 
OXA1. 
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9.3.6.3. 
Concomitant Therapy  
See the CWMM master protocol for a description of concomitant therapy data summary for 
OXA1. 
9.3.6.4. 
Treatment Compliance  
Frequency counts and percentages of participants compliant to study intervention will be 
summarized by treatment group and dose escalation subgroup using the full analysis set. Detailed 
analyses are described in the SAP. 
9.3.6.5. 
Pharmacokinetic/Pharmacodynamic Analyses  
LY3305677 concentration data will be analyzed using a population PK approach via nonlinear 
mixed-effects modeling with the NONMEM software. The relationships between LY3305677 
dose and/or concentration and selected efficacy, tolerability, and safety endpoints will be 
characterized, where applicable.  
Additionally, the impact of intrinsic and extrinsic participant factors such as age, weight, gender, 
and renal function on PK and/or PD parameters may be examined as needed. If antidrug antibody 
titers are detected from immunogenicity testing, then the impact of immunogenicity on 
LY3305677 PK or any relevant PD parameters may also be evaluated via PK/PD analysis or 
graphically. Additional analyses may also be conducted if they are deemed appropriate. Further 
details on PK and PK/PD analyses will be provided in the PK/PD analysis plan. 
9.3.6.6. 
Evaluation of Immunogenicity  
Upon assay validation, the frequency and percentage of participants with preexisting ADA and 
with TE ADA may be tabulated. TE ADAs are defined as those with a titer 2-fold (1 dilution) 
greater than the minimum required dilution, if no ADAs were detected at baseline (treatment-
induced ADA) or those with a 4-fold (2 dilutions) increase in titer compared with baseline, if 
ADAs were detected at baseline (treatment-boosted ADA).  
The frequency of cross-reactive binding to endogenous oxyntomodulin and/or neutralizing 
antibodies may also be tabulated in TE-ADA+ participants, when available.  
The relationship between the presence of ADA and the PK parameters and PD response 
including safety and efficacy may be assessed.  
9.4. 
Interim Analysis  
An interim efficacy and safety assessment may occur after 100% of participants complete either 
Visit 20 (Week 20) or Visit 24 (Week 24) of the treatment period to support planning activities 
associated with the clinical development program and to aid in the development of PK/PD 
modeling. An internal assessment committee (IAC) will be formed to review the interim analyses 
for the safety and efficacy reports in an unblinded manner. 
Additional interim analyses may be conducted to monitor safety of study participants. Details on 
the exact timing of the interim analyses, operational support, and unblinding will be specified in 
the assessment committee (AC) charter and in the study unblinding plan.  
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If there are unplanned interim analyses, an IAC will be formed to review the interim analyses in 
an unblinded manner. The details regarding number of committee members and type(s) of 
analysis to be undertaken will be provided in the AC charter. 
Study team members who have potential contact with the sites will remain blinded throughout 
the study. Information that may unblind the study during the analyses will not be reported to 
study sites or blinded study team members before the study has been unblinded. Study sites will 
receive information about interim results only if deemed necessary for the safety of the 
participants. 
The primary database lock and primary data analysis for OXA1 will occur when all participants 
have completed 32 weeks of treatment. The final database lock and final analyses for this study 
will be performed after all randomly assigned participants have completed the study. Unblinded 
data and results (including primary study results at 32 weeks) will not be shared with the study 
sites to maintain blinding at the sites while the study is still ongoing. Details will be specified in 
the unified master blinding/unblinding plan and in the AC charter.  
Early access to the PK and PD data for OXA1 before the primary database lock may be 
conducted to allow population PK/PD analysis and model development. If applicable, this early 
access will be detailed in the Unblinding Plan and the Population PK/PD Analysis Plan. 
 
9.5. 
Sample Size Determination  
Approximately 165 participants will be randomly assigned in a 3:2:3:3 ratio with  
 45 participants allocated to placebo 
 30 to LY3305677 3/6 mg 
 45 to LY3305677 10 mg, and  
 45 to LY3305677 16 mg. 
Assuming a 20% dropout rate, this results in approximately 132 total completers with 24 
completers on the LY3305677 3/6 mg arm and 36 completers for the placebo, each of 10 mg and 
16 mg LY3305677 arms. 
An upper limit of 60% enrollment of women will be used to ensure a sufficiently large sample of 
men.  
Sample size determination is based on the evaluation of superiority to placebo that will be 
conducted for each of the 3 LY3305677 doses at a 2-sided significance level of 0.05 using a 2-
sample t-test. 
The LY3305677 group mean percentage change in body weight from baseline at Week 32 
compared to placebo is assumed to be -8% assuming a common SD of 10%.  
The chosen sample size provides at least 91% power to establish superiority of at least one of the 
LY3305677 doses compared to placebo. No adjustment for multiplicity will be performed. 
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10. 
Supporting Documentation and Operational Considerations  
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations  
10.1.1. 
Committees Structure  
10.1.1.1. Internal Assessment Committee  
See CWMM master protocol, Section 10.1.5 for information on the IAC. 
See Section 9.4 of OXA1 for information on efficacy interim analyses and the IAC. 
10.1.1.2. Clinical Endpoint Committee  
An independent, blinded CEC with membership external to the sponsor will be responsible for 
case adjudication in a blinded fashion. 
The independent CEC will adjudicate cases noted in Section 8.3.5. The CEC charter will contain 
the final detailed event definitions used for adjudication. 
 
 
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10.4. 
Appendix 4: Genetics  
See CWMM master protocol, Section 10.5. 
 
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10.6. 
Appendix 6: Country-specific Requirements  
10.6.1. 
Brazil  
This section describes protocol changes applicable to adult participants at study sites in Brazil. 
This table describes the changes and provides a rationale for the changes. 
Master Protocol or ISA Section Number 
and Name 
Description of the Change 
Brief Rationale 
CWMM master protocol, Section 5.2. 
Exclusion Criteria 
Exclusion criterion #44, 
regarding previous clinical 
trial participation, has been 
replaced with exclusion 
criterion #49 in which “last 3 
months” is changed to “1 
year”. 
Resolution No. 251 (Brazil 1997). 
The National ERB Brazil 
recommends not having a 
participant enter a new clinical 
study if less than 1 year has 
elapsed since participation in 
another clinical study of an 
investigational drug or device 
unless there is a direct benefit to 
the research participant. 
CWMM master protocol, Section 10.1.12. 
Appendix 1: Sample Retention 
Addition specific to Brazil - 
biological samples will be 
stored for up to 10 years. 
Compliance with Brazilian 
regulation applicable to sample 
storage, resolution CNS 441 
(Brazil 2011). 
OXA1 ISA, Section 10.4. Appendix 4: 
Genetics 
Addition specific to Brazil. 
Biological samples obtained 
to evaluate genetic material 
(DNA/RNA) will follow the 
Brazilian laws and 
regulations. 
Compliance with Brazilian laws 
and regulations (CNS 340/2004 
and CNS 441/2011). 
Patient Access to Project Benefits 
New section specific to 
Brazil. 
Clarifies the sponsor 
responsibilities to comply with 
Resolution CNS 466 (Brazil 
2012) and RDC 38 (Brazil 2013). 
OXA1 ISA, Section 11. References 
Addition of Brazil-specific 
references. 
The references are specific to the 
Brazil-specific requirements. 
The revised text described below shows the changes applicable to adult participants at study sites 
in Brazil. Deletions are identified by strikethrough format and additions by underlined text. 
CWMM master protocol 
5.2. 
Exclusion Criteria 
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.  
 
50. Are currently enrolled in, discontinued, or completed within a period of 1 year, before 
inclusion, from a clinical study involving an investigational intervention or nonapproved 
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use of a drug or device, or concurrently enrolled in any other type of medical research 
judged not to be scientifically or medically compatible with this study unless there is direct 
benefit to the research subject. A time period of at least 5 elimination half-lives or 90 days, 
whichever is longer, as indicated by the protocol, must still be followed if a direct benefit 
to the research participant is identified. 
CWMM master protocol 
10.1.12. 
Sample Retention 
In Brazil, the biological samples obtained within this study will be stored for up to 10 years, with 
possibility of renewal under request, followed by appropriate justification and a report with all 
activities developed with the biological samples (CNS 441/2011). The sample and any data 
generated from it can be linked back to the participant only by investigator site personnel. The 
duration allows the sponsor to respond to regulatory requests related to the study intervention. 
OXA1 ISA 
10.4. Appendix 4: Genetics 
In Brazil, the biological samples from this study used to evaluate genetic material (DNA/RNA) 
will follow the Brazilian laws and regulations (CNS 340/2004 and CNS 441/2011). The sample 
and any data generated from it can be linked back to the participant only by investigator site 
personnel. The duration allows the sponsor to respond to regulatory requests related to the study 
drug. 
Patient Access to the Project Benefits 
In Brazil, at the end of their participation in the study, all participants must have assured access 
to the best proven prophylactic, diagnostic, and therapeutic methods, which may include 
LY3305677, identified through the study (CNS 466/2012 and RDC 38/2013). 
11. 
References 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 251/1997 do Conselho Nacional de Saúde/MS: 
Normas de Pesquisa com Novos Fármacos, Medicamentos, Vacinas e Testes Diagnósticos 
Envolvendo Seres Humanos. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 466/2012 do Conselho Nacional da Saúde / 
MS: Diretrizes e Normas Regulamentadoras de Pesquisas Envolvendo Seres Humanos. 
Publicado no Diário Oficial da União em 13 de junho, 2013. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 340/2004 do Conselho Nacional da Saúde/MS: 
Diretrizes para Análise Ética e Tramitação dos Projetos de Pesquisa da Área Temática 
Especial de Genética Humana. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução 441/2011 do Conselho Nacional da Saúde / 
MS: Diretrizes para análise ética de projetos de pesquisas que envolvam armazenamento de 
material biológico humano ou uso de material armazenado em pesquisas anteriores. 
BRASIL, MINISTÉRIO DA SAÚDE. Resolução-RDC 38/2013 da Agência Nacional 
deVigilância Sanitária/MS: Aprova o regulamento para os programas de acesso expandido, 
usocompassivo e fornecimento de medicamento pós-estudo. 
 
 
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10.7. 
Appendix 7: Provisions for Changes in Study Conduct During 
Exceptional Circumstances  
Section 10.12 of the CWMM master protocol, which describes provisions for changes in study 
conducting during exception circumstances, is applicable to OXA1. 
In addition, the changes described in this appendix are applicable. These are temporary measures 
intended to be used only during specific time periods as directed by the sponsor in partnership 
with the investigator. 
See Section 10.12 of the CWMM master protocol for these topics. 
 Exceptional circumstances  
 Implementing changes under exceptional circumstances  
 Considerations for making a change  
 Informed consent 
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 402 and thereafter 
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 
 concomitant medications 
 AEs 
 review diet and exercise goals 
 review of study participant diary (including study intervention compliance) 
 administration of PROs, and 
 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 
 weight and waist measurements 
 vital signs 
 symptom-directed physical assessments 
 ECGs 
 administration of PROs 
 collection of blood and urine samples, and 
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 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.  
See Section 10.12 of the CWMM master protocol for additional information on data capture, 
safety reporting, and return to on-site visits. 
Local laboratory testing option 
Local laboratory testing may be conducted in lieu of central laboratory testing after agreement 
with the Lilly-designated medical monitor. The local laboratory must be qualified in accordance 
with applicable local regulations. 
Study intervention and ancillary supplies (including participant diaries) 
See Section 10.12 of the CWMM master protocol. 
Screening period guidance  
See Section 10.12 of the CWMM master protocol. 
Adjustments to visit windows  
Whenever possible and safe to do so, as determined by the investigator’s discretion, participants 
should complete the usual SoA. To maximize the possibility that these visits can be conducted as 
on-site visits, the windows for visits may be adjusted, upon further guidance from the sponsor. 
This minimizes missing data and preserves the intended conduct of the study. 
 
This table describes the allowed adjustments to visit windows from Visit 402 through Visit 801. 
 
Visit Number 
Tolerance 
Visit 402 
No adjustment to the visit window described SoA 
Visit 0 through Visit 
10 
Within 7 days before the intended date, or up to 7 days after the intended date 
Visit 12 through Visit 
48 
Within 14 days from the intended date, or up to 14 days after the intended date (can be 
up to 28 days after the intended date for Visit 48) 
Visit 801 
Within 14 days from the intended date, or up to 14 days after the intended date 
For participants whose visits have extended windows, additional study intervention may need to 
be provided to avoid interruption and maintain overall integrity of the study.  
Documentation 
See Section 10.12 of the CWMM master protocol.  
 
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10.8. 
Appendix 8: Abbreviations and Definitions  
 
Term 
Definition 
abuse 
Use of a study intervention for recreational purposes or to maintain an addiction or 
dependence 
ADAs 
antidrug antibodies 
AE 
adverse event 
ALT 
alanine aminotransferase 
ApoA1 
apolipoprotein A1 
ApoB 
apolipoprotein B 
ApoC3 
apolipoprotein C3 
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 labelling 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 labelling of the medicinal product, 
which is used as an auxiliary medicinal product 
AX6 
Axivity 6 
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 
BG 
blood glucose 
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 
participants are aware of the treatment received. 
BMI 
body mass index 
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CHF 
congestive heart failure 
complaint 
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system. 
compliance 
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements. 
CRF 
case report form; a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor for each trial participant. 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CT 
computed tomography 
Device deficiencies 
Equivalent to product complaint 
ECG 
electrocardiogram 
eCOA 
electronic clinical outcome assessment 
ED 
early discontinuation 
eGFR 
estimated glomerular filtration rate  
enroll 
The act of assigning a participant to a treatment. Participants who are enrolled in the 
study are those who have been assigned to a treatment. 
enter 
Participants entered into a study are those who sign the informed consent form directly 
or through their legally acceptable representatives. 
FGF21 
fibroblast growth factor 21 
FIB-4 
Fibrosis-4 
FLI 
fatty liver index 
Gcg 
glucagon 
GCP 
good clinical practice 
GIP 
glucose-dependent insulinotropic peptide 
GIP-1 
glucose-dependent insulinotropic peptide-1 
GI 
gastrointestinal  
GLP-1 
glucagon-like peptide-1 
GLP-1 RA 
glucagon-like peptide-1 receptor agonist 
HOMA2-B 
homeostasis model assessment of beta-cell function 
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HOMA2-IR 
homeostasis model assessment of insulin resistance 
hsCRP 
high-sensitivity C-reactive protein 
IAC 
internal assessment committee 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IGFBP-2 
insulin-like growth factor binding protein-2 
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. 
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/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.” 
IWRS 
interactive web-response system 
LDL 
low-density lipoprotein 
LFC 
liver fat content 
MACE3 
3-point major adverse cardiovascular events: cardiovascular death, nonfatal myocardial 
infarction, or nonfatal stroke 
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medication error 
Errors in the prescribing, dispensing, or administration of a study intervention, 
regardless of whether or not the medication is administered to the participant or the 
error leads to an AE. Medication error generally involve a failure to uphold one or more 
of the five “rights” of medication use: the right participant, the right drug, the right 
dose, right route, at the right time. 
In addition to the core five rights, the following may also represent medication errors:  
• dose omission associated with an AE or a product complaint 
• dispensing or use of expired medication 
• use of medication past the recommended in-use date 
• dispensing or use of an improperly stored medication 
• use of an adulterated dosage form or administration technique inconsistent with the 
medication's labeling (for example, Summary of Product Characteristics, IB, local 
label, protocol), or 
• shared use of cartridges, prefilled pens, or both. 
MRI 
magnetic resonance imaging 
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 
PGIC 
Patient’s Global Impression of Change 
PGIS 
Patient’s Global Impression of Severity 
PHQ-9 
Patient Health Questionnaire-9 
PI 
principal investigator 
PK/PD 
pharmacokinetics/pharmacodynamics 
PRO 
patient-reported outcomes 
PROMIS 
Patient-Reported Outcome Measurement Information System 
QTc 
corrected QT interval 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
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.  
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SF-36 
Short-Form-36 
SGLT2 
sodium-glucose cotransporter-2 
T2DM 
Type 2 diabetes mellitus 
TE ADA 
treatment-emergent antidrug antibodies 
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 
VAS 
visual analog scale 
VLDL 
WC 
very low-density lipoprotein 
waist circumference 
 
 
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10.9. 
Appendix 9: Protocol Amendment History  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment [a]: 13 August 2023 
Overall Rationale for the Amendment: 
The main purpose of this ISA amendment is to incorporate additional measurements to better 
characterize the effects of LY3305677 (mazdutide) and to provide guidance on safety monitoring 
in response to regulatory feedback.  
Changes specific to certain ISA sections and a brief rationale are provided in the below table.  
Section # and Name 
Description of Change 
Brief Rationale 
1.1. Synopsis  
Added change in liver fat as a secondary 
objective and endpoint 
To clarify liver fat as an important 
readout of this trial 
1.2. Schedule of Activities 
(SoA) for OXA1 ISA and 
CWMM Master Protocol 
ECG 12-lead (central) for postdose 
assessment added at Visit 1 and aligned 
in the comment. 
Added “hypotension” to the assessment  
“Explain symptoms of hypoglycemic and 
hypotension events” 
Updated urinalysis assessment to occur 
at the same time points as clinical 
chemistry testing 
Revised time point assessment for urine 
pregnancy (local) 
Added and increased frequency of serum 
beta-hydroxybutyrate as an assessment 
and will be assessed at the same time 
points as clinical chemistry testing. 
To address regulatory feedback 
2.3.1. Risk Assessment 
Added information regarding education 
on signs and symptoms of low blood 
pressure. 
To address regulatory feedback 
3. Objectives, Endpoints, 
and Estimands 
Added change in liver fat as a secondary 
objective and endpoint and removed it 
from exploratory objectives and 
endpoints. 
Revised the endpoint for body 
composition from  
 
“Absolute change and percent 
change from baseline: liver fat 
content by MRI-PDFF 
 
additional MRI-derived measures 
may be explored” 
to  
 
“Adipose tissue volumes 
 
Muscle volumes”  
To clarify liver fat as an important 
readout and to provide more details on 
other body composition endpoints of 
this trial  
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Section # and Name 
Description of Change 
Brief Rationale 
4.1.1. Overview of Study 
Periods 
Removed “Lack of participation in 
ABPM collections at any time is not 
considered a protocol deviation.” 
To clarify protocol language and 
ensure sufficient participants will be 
enrolled for ABPM assessment 
5.2. Exclusion Criteria 
Removed “or willing” from participation 
in Ambulatory Blood Pressure 
Monitoring (ABPM) procedures from 
exclusion criteria  
To clarify protocol language and 
ensure sufficient participants will be 
enrolled for ABPM assessment 
6.5.3. Dose Reductions 
and Re-escalations 
Added information for excessive body 
weight loss and discontinuation criterion 
To ensure participant’s safety 
7.1. Discontinuation of 
Study Intervention 
Added “diagnosis with multiple 
endocrine neoplasia type 2 syndrome” 
and “the participant’s BMI reduces 
below 18 kg/m2” 
To ensure participant’s safety 
7.1.2. Cardiac Arrhythmia 
and QTc Stopping Criteria 
Updated the section heading to include 
“Cardiac Arrhythmia” and added criteria 
leading to discontinuation of study 
intervention 
To ensure participant’s safety 
8.1. Efficacy Assessments 
Added “liver fat” to secondary 
assessments 
Alignment with Section 3 
8.1.3. Magnetic Resonance 
Imaging (MRI) 
Removed the following, 
“After the participant has given consent, 
and meets all ISA eligibility 
requirements” 
“Participants that do not have a baseline 
MRI performed, should not have a Week 
32 MRI or Week-44 MRI performed.” 
To clarify protocol language  
8.2.12.1. Ambulatory 
Blood Pressure Monitoring 
(ABPM) 
Removed “or refuses”  
To clarify protocol language and 
ensure sufficient participants will be 
enrolled for ABPM assessment 
8.3.3. Adverse Events of 
Special Interest 
Added the following sections: 
8.3.3.1. Hypotension and Related 
Neurological Signs and Symptoms  
8.3.3.2. Acute Renal Failure 
8.3.3.3. Skin Burning Sensation and 
Related Adverse Events   
Removed “There are no AESIs defined 
for LY3305677 in OXA1” 
To address regulatory feedback 
8.3.5. Safety Topics for 
Monitoring 
Added “Hypotension and related 
neurological signs and symptoms” 
To address regulatory feedback 
10.2.1. Clinical Laboratory 
Tests  
Revised the heading to remove 
“Performed Starting at Visit 0” 
Clarified measurement of beta-
hydroxybutyrate 
Clarification and to address regulatory 
feedback 
10.3.2. Contraception 
Guidance for Females 
Participating in OXA1 
Updated contraceptive and barrier 
guidance 
To align with emerging information 
and to address regulatory feedback 
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Section # and Name 
Description of Change 
Brief Rationale 
Revised examples of different forms of 
contraception 
10.3.3.1. Guidance for 
All Male Participants 
Updated contraceptive and barrier 
guidance 
Revised examples of highly effective, 
and effective methods of contraception 
To align with emerging information 
and to address regulatory feedback 
10.5. Appendix 5: 
Mechanistic Biomarkers 
Added footnote b for Beta-
hydroxybutyrate, which states the 
following: 
b Beta-hydroxybutyrate will be measured 
with increased frequency in conjunction 
with the clinical chemistry panel. 
To address regulatory feedback 
Throughout 
Minor editorial and formatting changes 
Minor, therefore, not detailed 
 
 
 
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11. 
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[ADA] American Diabetes Association. 6. Glycemic targets: standards of medical care in 
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Banks PA, Freeman ML; Practice Parameters Committee of the American College of 
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with type 1 diabetes treated with insulin glargine or NPH insulin (the PRESCHOOL study). 
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[FDA] Food and Drug Administration. Guidance for Industry. Developing products for weight 
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scales in assessment of appetite sensations in single test meal studies. Int J Obes Relat Metab 
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[HHS] Human and Health Services. Physical Activity Guidelines for Americans. Published 
September 16, 2020. Accessed May 24, 2021. https://www.hhs.gov/fitness/be-active/physical-
activity-guidelines-for-americans/index.html 
Health Measures. Patient-Reported Outcome Measurement Information System (PROMIS®) 
website. http://www.healthmeasures.net/explore-measurement-systems/promis 
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pancreatitis: diagnostic criteria for acute pancreatitis. J Hepatobiliary Pancreat Surg. 
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Maruish ME, editor. User’s Manual for the SF36v2 Health Survey. 3rd ed. Lincoln, RI: Quality 
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Nauck MA, Meier JJ, Schmidt WE. Incretin-based glucose-lowering medications and the risk of 
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Steinberg WM, Buse JB, Ghorbani MLM, et al.; LEADER Steering Committee; LEADER Trial 
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with liraglutide: Results from the LEADER randomized trial. Diabetes Care. 
2017a;40(7):966-972. https://doi.org/10.2337/dc16-2747 
Steinberg WM, Rosenstock J, Wadden TA, et al. Impact of liraglutide on amylase, lipase, and 
acute pancreatitis in participants with overweight/obesity and normoglycemia, prediabetes, or 
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type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development 
program. Diabetes Care. 2017b;40(7):830-848. https://doi.org/10.2337/dc16-2684 
van Can J, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on 
gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic 
adults. Int J Obes (Lond). 2014;38(6):784-793. https://doi.org/10.1038/ijo.2013.162  
Weinberg ME, Bacchetti P, Rushakoff RJ. Frequently repeated glucose measurements 
overestimate the incidence of inpatient hypoglycemia and severe hyperglycemia. J Diabetes 
Sci Technol. 2010;4(3):577-582. https://doi.org/10.1177/193229681000400311 
[WHO] World Health Organization. Healthy diet. Published 29 April, 2020a. Accessed May 24, 
2021. https://www.who.int/news-room/fact-sheets/detail/healthy-diet 
[WHO] World Health Organization. Physical activity and adults. Published 26 November, 
2020b. Accessed May 24, 2021. https://www.who.int/news-room/fact-sheets/detail/physical-
activity 
 
 
 
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