Clinical trial NCT03496298
Conditions: Type 2 Diabetes Mellitus
Sponsor: Sanofi
Start date: 2018-04-27; Completion date: 2020-12-10
Enrollment: 4076 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate that efpeglenatide 4 and 6 mg was noninferior to placebo on 3-point major adverse cardiac events (MACE) in Type 2 diabetes mellitus (T2DM) participants at high cardiovascular (CV) risk.

Secondary Objectives:

To demonstrate that efpeglenatide 4 and 6 mg was superior to placebo in T2DM participants with high CV risk on the following parameters:

* 3-point MACE.
* Expanded CV outcome.
* Composite outcome of new or worsening nephropathy.

To assess the safety and tolerability of efpeglenatide 4 and 6 mg, both added to standard of care in T2DM participants at high CV risk.

Detailed description:
The study duration per participant was up to approximately 36 months.

Arms: arm 1: Participants received placebo (matched to Efpeglenatide) as subcutaneous (SC) injection once weekly up to end of treatment. arm 2: Participants received Efpeglenatide as SC injection 2 milligrams (mg) per week for 4 weeks then 4 mg per week up to end of treatment. arm 3: Participants received Efpeglenatide as SC injection 2 mg per week for 4 weeks, then 4 mg per week for 4 weeks and then 6 mg per week up to end of treatment.
Interventions: intervention 1: Efpeglenatide (SAR439977) intervention 2: Placebo
Intervention descriptions: intervention 1: Pharmaceutical form: Solution for injection,

Route of administration: SC intervention 2: Pharmaceutical form: Solution for injection

Route of administration: SC

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity
According to template: Version Sanofi dated 12-SEP-2017 based on TransCelerate CPT version 4
Page 1
AMENDED CLINICAL TRIAL PROTOCOL 02
Protocol title:
A Randomized, Double-blind, Placebo-controlled, 
Parallel-group, Multicenter Study to Evaluate the Effect 
of Efpeglenatide on Cardiovascular Outcomes in Type 2 
Diabetes Patients at High Cardiovascular Risk
Protocol number:
EFC14828
Amendment number:
02
Compound number 
(Trademark/INN):
SAR439977/efpeglenatide
Short title:
Effect of Efpeglenatide on Cardiovascular Outcomes 
(AMPLITUDE-O)
Sponsor name:
Legal registered 
address:
Regulatory agency identifying number(s):
EudraCT number:
2017-002954-35
IND number:
112780
UTN number:
U1111-1182-1806
Approval Date:
30 July 2018
Total number of pages:
90
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Sponsor signatory:
Please refer to the last page of this document for electronic signatures including date and time.
Monitoring Team’s Representative
Name and Contact Information:
[will be provided separately OR can be found in XX]
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Country impacted 
by amendment
Date, version
Amended protocol 02
All
30 July 2018, version 1 (electronic 2.0)
Amended protocol 01
All
28 May 2018, version 1 (electronic 1.0)
Original Protocol
15 January 2018, version 1 (electronic 2.0)
Amended protocol 02 (30 July 2018)
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
The protocol is being amended to add an electrocardiogram (ECG) assessment at Week 12, when 
steady state has been achieved, to allow Investigators to assess the effects of efpeglenatide on the 
heart earlier in the study.
Protocol amendment summary of changes table
Section # 
and Name
Description of Change
Brief Rationale
Section 1.3 
Schedule of 
Activities (SOA)
An additional ECG assessment will be performed 
at the on-site visit at Week 12
Efpeglenatide is titrated in 2 mg steps every 4 weeks, so 
that the 4 mg dose will be achieved after 4 weeks and the 
6 mg dose after 8 weeks of treatment. Therefore, the 
steady state level of the 6 mg dose will be reached around 
Week 12
Section 1.1 
Synopsis,  
Section 3
Objectives and 
Endpoints, and 
Section 9.4.3 
Other analyses
Change of anti-drug antibody (ADA) 
objective/endpoint from secondary 
objective/endpoint to tertiary/exploratory
objective/endpoint
Removal of Table 9 describing the statistical 
analysis of ADA
To harmonize the ADA endpoint with the other
efpeglenatide Phase 3 clinical protocols
Section 9.4.3 describes statistical analysis of secondary
endpoints and the ADA endpoint has been moved to 
tertiary/exploratory endpoint
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Section 5.1 
Inclusion 
Criteria
Clarification of the documentation criteria for 
symptomatic myocardial infarction by adding a 
prior discharge hospital diagnosis and removal of 
cardiac enzymes
To clarify the documentation needed for history of 
symptomatic myocardial infarction
Throughout
Minor editorial and document formatting revisions
Minor, therefore have not been summarized
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE..................................................................3
DOCUMENT HISTORY...................................................................................................................................3
OVERALL RATIONALE FOR THE AMENDMENT........................................................................................3
TABLE OF CONTENTS..................................................................................................................................5
LIST OF TABLES ...........................................................................................................................................8
LIST OF FIGURES..........................................................................................................................................9
1
PROTOCOL SUMMARY ...............................................................................................................10
1.1
SYNOPSIS.....................................................................................................................................10
1.2
SCHEMA........................................................................................................................................17
1.3
SCHEDULE OF ACTIVITIES (SOA)..............................................................................................18
2
INTRODUCTION............................................................................................................................22
2.1
STUDY RATIONALE......................................................................................................................22
2.2
BACKGROUND .............................................................................................................................22
2.3
BENEFIT/RISK ASSESSMENT.....................................................................................................23
3
OBJECTIVES AND ENDPOINTS .................................................................................................25
3.1
APPROPRIATENESS OF MEASUREMENTS ..............................................................................26
4
STUDY DESIGN ............................................................................................................................27
4.1
OVERALL DESIGN........................................................................................................................27
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................28
4.3
JUSTIFICATION FOR DOSE ........................................................................................................30
4.4
END OF STUDY DEFINITION.......................................................................................................30
5
STUDY POPULATION ..................................................................................................................31
5.1
INCLUSION CRITERIA..................................................................................................................31
5.2
EXCLUSION CRITERIA ...............................................................................................................33
5.3
LIFESTYLE CONSIDERATIONS...................................................................................................35
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5.4
SCREEN FAILURES......................................................................................................................35
6
STUDY INTERVENTION ...............................................................................................................36
6.1
STUDY INTERVENTION(S) ADMINISTERED..............................................................................36
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY.......................................................37
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................38
6.4
STUDY INTERVENTION COMPLIANCE ......................................................................................39
6.5
CONCOMITANT THERAPY ..........................................................................................................39
6.6
DOSE MODIFICATION..................................................................................................................40
6.7
INTERVENTION AFTER THE END OF THE STUDY...................................................................40
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..........................................................................................41
7.1
DISCONTINUATION OF STUDY INTERVENTION .....................................................................41
7.1.1
Permanent discontinuation of study intervention...........................................................................41
7.1.2
Temporary discontinuation of study intervention ...........................................................................43
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................43
7.3
LOST TO FOLLOW UP .................................................................................................................44
8
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................45
8.1
EFFICACY ASSESSMENTS ........................................................................................................45
8.1.1
Primary endpoint: 3-point MACE ...................................................................................................45
8.1.2
Secondary efficacy endpoints........................................................................................................45
8.1.3
Exploratory efficacy endpoint.........................................................................................................45
8.2
SAFETY ASSESSMENTS ............................................................................................................45
8.2.1
Physical examinations ...................................................................................................................46
8.2.2
Vital signs.......................................................................................................................................46
8.2.3
Electrocardiograms ........................................................................................................................46
8.2.4
Clinical safety laboratory assessments..........................................................................................46
8.2.5
Severe hypoglycemia.....................................................................................................................47
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................48
8.3.1
Time period and frequency for collecting AE and SAE information...............................................49
8.3.2
Method of detecting AEs and SAEs...............................................................................................49
8.3.3
Follow-up of AEs and SAEs...........................................................................................................49
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8.3.4
Regulatory reporting requirements for SAEs .................................................................................50
8.3.5
Pregnancy......................................................................................................................................50
8.3.6
Cardiovascular and death events ..................................................................................................50
8.3.7
Disease-related events and other events not qualifying as AEs or SAEs .....................................51
8.3.8
Guidelines for reporting product complaints ..................................................................................51
8.4
TREATMENT OF OVERDOSE......................................................................................................52
8.5
PHARMACOKINETICS..................................................................................................................52
8.6
PHARMACODYNAMICS ...............................................................................................................52
8.7
GENETICS.....................................................................................................................................52
8.8
BIOMARKERS ...............................................................................................................................52
8.8.1
Immunogenicity assessments........................................................................................................52
8.9
HEALTH ECONOMICS..................................................................................................................53
9
STATISTICAL CONSIDERATIONS .............................................................................................54
9.1
STATISTICAL HYPOTHESES.......................................................................................................54
9.2
SAMPLE SIZE DETERMINATION ................................................................................................54
9.3
POPULATIONS FOR ANALYSES.................................................................................................55
9.4
STATISTICAL ANALYSES ............................................................................................................55
9.4.1
Efficacy analyses ...........................................................................................................................55
9.4.2
Safety analyses..............................................................................................................................58
9.4.3
Other analyses...............................................................................................................................59
9.5
INTERIM ANALYSES ...................................................................................................................59
9.5.1
Data Monitoring Committee (DMC)................................................................................................59
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................60
10.1
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......60
10.1.1
Regulatory and Ethical Considerations..........................................................................................60
10.1.2
Informed Consent Process ............................................................................................................60
10.1.3
Data Protection ..............................................................................................................................61
10.1.4
Committees Structure ....................................................................................................................61
10.1.5
Dissemination of Clinical Study Data.............................................................................................62
10.1.6
Data Quality Assurance .................................................................................................................63
10.1.7
Source documents .........................................................................................................................63
10.1.8
Study and Site Closure ..................................................................................................................64
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10.1.9
Publication Policy...........................................................................................................................64
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................64
10.3
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................66
10.4
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................70
10.5
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................73
10.6
APPENDIX 6: MONITORING AND MANAGEMENT OF PARTICIPANTS WITH 
INCREASED LIPASE AND/OR AMYLASE, OR CALCITONIN.....................................................79
10.6.1
Monitoring of participants with increased lipase and/or amylase >2 ULN .....................................79
10.6.2
Elevation of amylase and/or lipase >2 x ULN without clinical signs and/or symptoms .................79
10.6.3
Elevation of amylase and/or lipase >2 x ULN with clinical signs and/or symptoms. .....................79
10.6.4
Management of participants with increased calcitonin values.......................................................80
10.7
APPENDIX 7: GUIDANCE FOR THE FOLLOW-UP OF ACUTE WORSENING OF RENAL 
FUNCTION.....................................................................................................................................81
10.8
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................81
10.9
APPENDIX 9: ABBREVIATIONS...................................................................................................82
10.10
APPENDIX 10: PROTOCOL AMENDMENT HISTORY ................................................................84
OVERALL RATIONALE FOR THE AMENDMENT......................................................................................84
11
REFERENCES...............................................................................................................................89
LIST OF TABLES
Table 1 – IMP dose schedule........................................................................................................................14
Table 2 - Objectives and endpoints...............................................................................................................25
Table 3 - Established CVD criteria (need at least 1 from Section A, B or C)................................................31
Table 4 - CV Risk Factors (at least 1 criterion must be met) ........................................................................32
Table 5 - Overview of study interventions administered ...............................................................................36
Table 6 - Populations for analyses ................................................................................................................55
Table 7 - Efficacy analyses ...........................................................................................................................55
Table 8 - Safety analyses..............................................................................................................................58
Table 9 - Protocol-required safety laboratory assessments..........................................................................65
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Table 10 - Highly effective contraceptive methods .......................................................................................71
LIST OF FIGURES
Figure 1 – Graphical study design.................................................................................................................17
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1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Protocol title: A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter 
Study to Evaluate the Effect of Efpeglenatide on Cardiovascular Outcomes in 
Type 2 Diabetes Patients at High Cardiovascular Risk
Short title:
Effect of Efpeglenatide on Cardiovascular Outcomes (AMPLITUDE-O)
Rationale:
The Food and Drug Administration (FDA) requires new therapies for Type 2 Diabetes Mellitus 
(T2DM) to demonstrate that they do not result in an unacceptable increase in cardiovascular (CV) 
risk.  The European Medicines Agency (EMA) reflection paper on assessment of CV safety of 
medical products recommends assessment of CV risk by either a meta-analysis of Phase 3 studies 
or a dedicated cardiovascular outcome trial (CVOT). The present study is a CVOT that has been 
designed to demonstrate the CV safety of efpeglenatide by assessing the noninferiority (NI) of 
efpeglenatide over placebo on 3-point major adverse cardiac events (MACE). If NI is established, 
superiority will also be tested.
Objectives and endpoints
Objectives
Endpoints
Primary

To demonstrate that efpeglenatide 4 and 
6 mg is noninferior to placebo on 3-point 
MACE in T2DM patients with high CV
Risk

Time to the first occurrence of any of the 
following clinical events, positively 
adjudicated by the Clinical Endpoint 
Committee (CEC):
-
CV death
-
Non-fatal myocardial infarction (MI)
-
Non-fatal stroke 
Secondary

To demonstrate that efpeglenatide 4 and 
6 mg is superior to placebo on 3-point 
MACE in T2DM patients with high CV risk 

Time to the first occurrence of any of the 
following clinical events, positively 
adjudicated by the CEC:
-
CV death
-
Non-fatal MI
-
Non-fatal stroke 
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Objectives
Endpoints

To demonstrate that efpeglenatide 4 and 
6 mg is superior to placebo on the 
expanded CV outcome in T2DM patients 
with high CV risk 

Time to the first occurrence of any of the 
following clinical events, positively 
adjudicated by the CEC:
-
CV death
-
Non-fatal MI
-
Non-fatal stroke
-
Coronary revascularization
-
Hospitalization for unstable angina 

To demonstrate that efpeglenatide 4 and 
6 mg is superior to placebo on the 
composite outcome of new or worsening 
nephropathy in T2DM patients with high 
CV risk 

Time to the first occurrence of any of the 
following clinical events:
-
New onset or progression to macro 
albuminuria (>300 mg/g) accompanied 
by an albumin-to-creatinine ratio 
(UACR) value increase of ≥30% from 
Baseline
-
Sustained ≥40% decrease in estimated 
glomerular filtration rate (eGFR) from 
Baseline (for ≥30 days)
-
Chronic dialysis (for ≥90 days)
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2
(for ≥30 days)

To assess the safety of efpeglenatide 4 
and 6 mg once per week (QW), both 
added to standard of care in T2DM 
patients with high CV risk

Adverse events (AEs), serious adverse 
events (SAEs), AEs leading to treatment 
discontinuation, AEs of special interest 
(AESI), AEs requiring specific monitoring

Safety laboratory values 

Vital signs

12-lead electrocardiogram (ECG)
Overall design:
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study in approximately 4000 T2DM patients at High CV Risk. 
To be eligible for the study, patients must have T2DM with high CV risk and a glycated 
hemoglobin A1c (HbA1c) >7% at screening, and the antihyperglycemic treatment must have been 
stable for 12 weeks prior to randomization, in the opinion of the Investigator. 
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Prior to randomization, the Investigator will be asked to pre-specify which therapeutic approach 
will be implemented should intensification of the background antihyperglycemic treatment be 
considered necessary during the study.
Patients who meet all eligibility criteria will come back for the randomization visit (Visit 3) and, 
if they are still eligible for the study, they will be randomized 1:1:1 to efpeglenatide 4 mg, 
efpeglenatide 6 mg or placebo. Randomization will be stratified by the current or potential future 
use of a sodium-glucose linked transporter-2 (SGLT2) inhibitor (Current use, Potential future use, 
Neither current nor potential future use). 
Any antihyperglycemic treatment is allowed as background therapy (with the exception of 
glucagon-like peptide-1 [GLP-1] receptor agonists [RAs] and dipeptidyl peptidase-4 [DPP4]
antagonists). For participants with HbA1c <7.5% at time of Screening, and who are treated with 
either insulin, glinide, or sulfonylurea, the doses of the glucose-lowering medications may be 
decreased at Randomization in order to prevent possible hypoglycemia. Antihyperglycemic 
therapy must not be modified for the first 12 weeks after randomization (other than for medical 
necessity). After the first 12 weeks post randomization and during the remaining double-blind 
treatment period, the management of glycemia will be left to the Investigator’s and/or treating 
provider’s judgment, informed by clinical guidelines and local/regional standards of care. 
Investigators will monitor the glycemic status and potassium levels of participants throughout the 
study. If treatment intensification is still considered necessary after dose increase of the 
background antihyperglycemic treatment, the Investigator can prescribe any other 
antihyperglycemic medication (according to its labeling), with the exception of a GLP-1 RA or a 
DPP4 inhibitor, that must not be used during the study.
Participants with a suspected renal event (reduction of eGFR) should have a repeat assessment of 
renal function 30 to 45 days following the onset of the event to confirm it is sustained.
If a participant discontinues treatment with investigational medicinal product (IMP) prematurely, 
the participant will undergo a premature End-of-Treatment (pEOT) Visit, but every effort will be 
made to have the participants return to the site at the time corresponding to their scheduled visits, 
until the end of study. There must be at least 6 weeks of post-treatment safety follow-up between 
the last IMP administration and the Study Closeout Visit for participants who discontinue IMP 
prematurely.
Participants will continue taking IMP after a CV or renal outcome has occurred. If the participant
does not agree to continue taking IMP or to attend site visits, they will be contacted by telephone 
to inquire about safety status (including outcomes).
The study is event driven and will continue until 330 participants have at least one primary event 
(3-point MACE) positively adjudicated by the CEC. At that point all randomized patients have to 
be scheduled to return to the site for a Study Closeout Visit (timing and window will be 
communicated to the sites).
All randomized participants, including those who prematurely discontinued from IMP, will be 
followed from Randomization until the Study Closeout Visit or death, whichever comes first. A 
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post-treatment safety follow-up visit 6 weeks after the last dose of IMP will be implemented for 
patients still on study treatment at the Study Closeout Visit.
An independent Data Monitoring Committee (DMC) will review clinical study safety data and an 
independent CEC will review, assess and/or adjudicate all events of deaths, selected CV events 
(non-fatal MI, stroke, unstable angina leading to hospitalization, and heart failure leading to 
hospitalization), pancreatic events, and other selected AEs. An independent ophthalmologist 
expert will review in a treatment-blinded manner all reported AEs suspected to be diabetic 
retinopathy to assess the presence of retinopathy and the relationship of reported AE to IMP. See 
Appendix 1 (Section 10.1) for further details of study committees.
Number of participants:
Approximately 4000 patients will be randomly assigned to study intervention to end up with an 
estimated total of 330 participants with at least one positively adjudicated 3-point MACE event.
All randomized participants will be evaluable. See Section 9.2 for details.
Intervention groups and duration:
The study will consist of 3 periods: 

A 2- to 3-week screening period 

A double-blind, placebo-controlled, multiple dose treatment period, including up to 
8 weeks for dose titration 
-
If, at any time during the study, a participant does not tolerate the study treatment, the 
IMP may be temporarily discontinued or if medically necessary, permanently 
discontinued. 
-
If a maximum of 2 (two) consecutive doses are missed, the IMP can be restarted with 
the latest dose given; if 3 or more consecutive doses are missed, the IMP will be 
restarted using a new titration kit. 
-
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol.

A follow-up period of 6 weeks after the last dose of IMP
The estimated study treatment duration will be approximately 24 to 36 months, assuming 
approximately 12 months of recruitment, and approximately 24 months of treatment and follow-
up after the last randomized participant.
Study interventions
Investigational medicinal products
Efpeglenatide

Formulation: 0.5 mL of a sterile, non-pyrogenic, clear, colorless solution in a 1 mL 
disposable prefilled syringe (PFS). The two doses tested will be injected as 4 mg/0.5 mL 
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or 6 mg/0.5 mL. A third dose, 2 mg/0.5 mL will be used as the initial dose during the first 
4 weeks of the titration phase

Route of administration: Subcutaneous (SC) injection administered to the abdomen. 
Within this region, the site of injection should be changed (rotated) at each time to prevent 
skin reactions

Dose regimen: once weekly on the same week day (eg, each Monday) at any time of the 
day
-
Dose will be titrated during Weeks 0 to 8 as shown in Table 1.
Placebo

Formulation: matching placebo (sterile, non-pyrogenic, clear, colorless solution in a 1 mL 
disposable PFS)

Route of administration: SC injection administered to the abdomen. Within this region, the 
site of injection should be changed (rotated) at each time to prevent skin reactions

Dose regimen: once weekly on the same week day (eg, each Monday) at any time of the 
day
Table 1 – IMP dose schedule
Dose 1
Doses 2-4
Doses 5-8
Doses 9 onward
Day 1
Weeks 1-3
Weeks 4-7
As of Week 8
Efpeglenatide 4 mg
2 mg
2 mg
4 mg
4 mg
Efpeglenatide 6 mg
2 mg
2 mg
4 mg
6 mg
Placebo
Placebo
Placebo
Placebo
Placebo
No posttrial access to study medication is foreseen.
Statistical considerations:

Analysis of primary objective:
The primary analysis population will be the intent-to-treat (ITT) population that includes all 
randomized participants irrespective of compliance with the study protocol and procedures. 
Participants will be analyzed in the treatment group to which they are randomized.
The time to the first occurrence of the primary composite CV endpoint event (CV death, non-fatal 
MI, or non-fatal stroke) will be analyzed using Cox proportional hazards model with treatment 
(efpeglenatide 4 mg, efpeglenatide 6 mg, placebo), region, and randomization strata of current or 
potential future use of a SGLT2 inhibitor (Current use, Potential future use, Neither current nor 
potential future use) as the covariates. Participants who receive either 4 mg or 6 mg of 
efpeglenatide will be combined as one efpeglenatide treatment group when making comparisons 
using the appropriate contrast for the purposes of the primary analysis. The hazard ratio between 
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pooled efpeglenatide and placebo will be estimated along with the associated two-sided 95% 
confidence interval (CI).
The NI with the 1.8 and 1.3 margin will be demonstrated on the primary endpoint if the upper 
bound (UB) of the two-sided 95% CI is <1.8 and <1.3, respectively.
Kaplan-Meier curves of the cumulative incidence rate will also be provided by treatment groups.
All participants will be followed up to the Study Closeout Visit or death, whichever comes first. 
The primary analysis will be based on the ITT approach that includes events occurring from 
randomization to the end of study, even after the participant has discontinued the study treatment. 
In the ITT approach, all randomized participants will be included and analyzed as randomized. 
The analysis will be based on the positively-adjudicated CV endpoint events. Participants who 
have not experienced any of these primary CV outcomes as positively adjudicated by the CEC 
during the study will be censored at the last date with available information on the CV outcomes 
on or before the study end date for the participant.

Analysis of secondary objectives:
If the NI with the 1.8 and 1.3 margin is demonstrated on the primary endpoint, the superiority of 
pooled efpeglenatide group (4 and 6 mg) vs placebo for the 3-point MACE will be tested in a 
hierarchical fashion.
The two other secondary efficacy endpoints will be analyzed using the same Cox proportional 
hazards model used for the analysis of primary endpoint with treatment (efpeglenatide 4 mg, 
efpeglenatide 6 mg, placebo), region, and randomization strata as the covariates.
The safety analysis will be conducted on the safety population that includes all randomized 
participants who have received at least 1 dose of double-blind treatment, regardless of the amount 
of treatment administered. Participants will be analyzed for safety analyses according to the 
treatment actually received.
All safety summaries will be descriptive; no statistical significance tests will be performed on 
safety data. These analyses will be based on the Safety Population. Treatment-emergent adverse 
events (TEAEs) are defined as AEs that developed or worsened or became serious during the 
period from the administration of first double-blind IMP dose treatments up to 30 days after the 
last administration. 
Each of the two efpeglenatide treatment groups will be compared with the placebo group.
A pre-specified safety analysis will be performed in the subsets of participants on the background 
therapy of metformin + SGLT2, and on metformin + sulfonylurea. Safety summaries will be 
provided by treatment group for each of the subsets, including the summaries for AEs, SAEs, 
deaths, hypoglycemia, AESIs, and AEs requiring specific monitoring.
Data Monitoring Committee: Yes
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See Appendix 1 (Section 10.1) for further details on Steering Committee, DMC, CEC, and 
Independent Expert.
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1.2
SCHEMA
Figure 1 – Graphical study design
Double-blind, placebo-controlled treatment period
Week: 
Visit:   
Baseline
-3
1
12
4
-1
2
Phone call visit
On site visit
Randomization
R
48
6
0
3
Study 
closeout
visita
3 weeks
7
60

8
Follow-up
period
Follow-up
visit
6 weeks
Efpeglenatide 4 mg; N ~ 1333
Efpeglenatide 6 mg; N ~ 1333
Placebo; N ~ 1333
72
9
2 mg
4 mg
2 mg 4 mg
6 mg
Placebo
Screening 
period
R
24
36

5
84

10
Onsite visits every 24 weeks until study
closeout; one phone visit is held between
2 consecutive onsite visits
4
8
1:1:1 randomization, stratified by the current or potential future use of SGLT2 inhibitor (Current use, Potential future use, Neither current nor potential future use).
a All randomized patients will be asked to return to the study site for a Study Closeout Visit when approximately 330 participants have at least one primary event (3-point MACE) positively adjudicated by the CEC
R: randomization; CEC: Clinical Endpoint Committee; SGLT2: sodium-glucose linked transporter-2 
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1.3
SCHEDULE OF ACTIVITIES (SOA)
Screening
Intervention Periodb
Participants 
who 
prematurely 
discontinued 
IMP
Participants who 
did not 
prematurely 
discontinue IMP
Notes
Month
0
3
6
9
12/ 24/ 
…
15/21/ 
27/ …
18/30/
…
Week
-3
-1
0
12
24
36
48/96/
…
60/84/ 
108/…
72/120/
…
Visit
1
2
3
R
4
5
6 

7/11/…
8/10/12/… 

9/13/…
pEOT
c
Study 
closeoutd
Study 
closeoutd
Follow-up
Acceptable 
range (days)
+7a
± 3a
± 7
± 7
± 7
± 7
± 7
± 7
Closeout 
+ 6 weeks
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Demography
X
Physical examination
X
X
X
X
X
Medical/surgical 
history
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Height
X
X
X
Body weight
X
X
X
X
X
X
X
X
X
Ophthalmologic exam 
with fundoscopy
Xe
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Screening
Intervention Periodb
Participants 
who 
prematurely 
discontinued 
IMP
Participants who 
did not 
prematurely 
discontinue IMP
Notes
Month
0
3
6
9
12/ 24/ 
…
15/21/ 
27/ …
18/30/
…
Week
-3
-1
0
12
24
36
48/96/
…
60/84/ 
108/…
72/120/
…
Visit
1
2
3
R
4
5
6 

7/11/…
8/10/12/… 

9/13/…
pEOT
c
Study 
closeoutd
Study 
closeoutd
Follow-up
Acceptable 
range (days)
+7a
± 3a
± 7
± 7
± 7
± 7
± 7
± 7
Closeout 
+ 6 weeks
12-lead ECG
X
X
X
X
Recording at Week 0 (Visit 3) should 
be obtained prior to first dose of 
double-blind IMP 
Randomization
X
Interactive response 
technology (IRT) 
contact
X
X
X
X
X
X
X
X
X
X
X
Injection 
training/retraining and 
self-injection at site
X
IMP dispensed
X
X
X
X
X
IMP accounting
X
X
X
X
X
X
IMP compliance
X
X
X
X
X
X
X
X
Concomitant 
medication review
X
X
X
X
X
X
X
X
X
X
X
X
AE and SAE review
=======================================================================================
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Screening
Intervention Periodb
Participants 
who 
prematurely 
discontinued 
IMP
Participants who 
did not 
prematurely 
discontinue IMP
Notes
Month
0
3
6
9
12/ 24/ 
…
15/21/ 
27/ …
18/30/
…
Week
-3
-1
0
12
24
36
48/96/
…
60/84/ 
108/…
72/120/
…
Visit
1
2
3
R
4
5
6 

7/11/…
8/10/12/… 

9/13/…
pEOT
c
Study 
closeoutd
Study 
closeoutd
Follow-up
Acceptable 
range (days)
+7a
± 3a
± 7
± 7
± 7
± 7
± 7
± 7
Closeout 
+ 6 weeks
Laboratory assessments
Laboratory assessments performed 
at Week 0 (Visit 3) should occur prior 
to first dose of double-blind IMP
HbA1c
X
X
X
X
X
X
X
HBsAg and HCAb
X
Hematologyf
X
X
X
X
X
X
X
X
X
X
Clinical chemistryg
X
X
X
X
X
X
X
X
X
X
Lipid profileh
X
X
X
X
X
Amylase, lipase, and 
calcitonin
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Urine analysis: pH, glucose, ketones, 
leucocytes, blood/hemoglobin, 
protein. 
Urinalysis (spot)
X
X
X
X
X
X
X
X
Urinary albumin-to-creatinine ratio
(UACR) performed by spot urine
Pregnancy test 
(WOCBP only)i
X
X
X
X
X
X
X
X
X
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Screening
Intervention Periodb
Participants 
who 
prematurely 
discontinued 
IMP
Participants who 
did not 
prematurely 
discontinue IMP
Notes
Month
0
3
6
9
12/ 24/ 
…
15/21/ 
27/ …
18/30/
…
Week
-3
-1
0
12
24
36
48/96/
…
60/84/ 
108/…
72/120/
…
Visit
1
2
3
R
4
5
6 

7/11/…
8/10/12/… 

9/13/…
pEOT
c
Study 
closeoutd
Study 
closeoutd
Follow-up
Acceptable 
range (days)
+7a
± 3a
± 7
± 7
± 7
± 7
± 7
± 7
Closeout 
+ 6 weeks
Anti-efpeglenatide 
antibody sampling
X
X
X
X
X
Xj
Samples will be drawn before the IMP 
dosing at the site
a
There must be not more than 3 weeks + 3 days between screening visit and randomization. In some cases, Visit 2 might be combined with Visit 3 (Randomization), as per Investigator’s judgement, according to the 
patient’s medical profile.
b
Additionally, in between each on site visit, starting after Visit 5, participants will be contacted by phone to collect endpoint events, IMP administration information, and safety data.
c
If a participant prematurely permanently discontinues treatment with IMP, the participant will undergo a pEOT Visit as soon as possible. Participants will then continue in the study with all study procedures/visits 
except those associated with IMP administration. Participants will continue to be followed after a CV or renal endpoint occurs irrespective of their treatment status. If the participant does not agree to site visits, 
he/she will be contacted by telephone to inquire about safety status (including hospitalizations and endpoints).
d
All randomized participants will be asked to return to the study site for a Study Closeout Visit when primary 3-point MACE are positively adjudicated in approximately 330 participants. The timing and window of this 
visit will be communicated to sites. For participants who previously prematurely permanently discontinued IMP, there must be at least 6 weeks between the last IMP administration and the Study Closeout Visit, the 
Study Closeout Visit will be the final study visit, and no further visits are planned.
e
Examination to be done unless exam has been performed within the last 6 months prior to randomization or within 3 months in patients with severe non proliferative diabetic retinopathy (NPDR)/ proliferative 
diabetic retinopathy (PDR)/Diabetic Macular Edema (DME) and documented. The ophthalmologic exam, whether completed within the last 6 months prior to randomization or at screening, will serve as the 
baseline assessment.
f
Hemoglobin, hematocrit, red blood cell (RBC) count with indices, white blood cell (WBC) count with differential, and platelets.
g
Total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), non-fasting plasma glucose, creatinine, estimated creatinine clearance, uric acid, sodium, potassium.
h
Non-fasting triglyceride, total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL); will be done once a year for the duration of the study after Week 24.
i
FSH and estradiol may be checked in case the status of post-menopausal cannot be decided. Serum beta-human chorionic gonadotropin (β-HCG) test at screening; urine pregnancy test for subsequent 
monitoring; if the urine test is positive, serum β-HCG should be tested for confirmation of the pregnancy. A monthly home urine pregnancy test should be performed by the patient between visits.
j
Participants with positive anti-drug antibody (ADA) at the end of study, and who experienced severe injection site or hypersensitivity reaction at whatever time during the study, will be asked to provide sample for 
anti-efpeglenatide antibodies assessments 4 and 6 months after the end of the treatment.
AE: adverse event; DME: diabetic macular edema; ECG: electrocardiogram; IMP: investigational medicinal product; HbA1c: glycated hemoglobin; HBsAg: hepatitis B surface antigen; HCAb: hepatitis C antibody; IRT: 
interactive response technology; NPDR: non proliferative diabetic retinopathy; PDR: proliferative diabetic retinopathy; pEOT: premature end of treatment; R: randomization; RBC: red blood cells; SAE: serious adverse 
event; WBC: white blood cells; WOCBP: woman of childbearing potential
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2
INTRODUCTION
Efpeglenatide (LAPS-exendin-4, SAR439977, previous code HM11260C), a glucagon-like 
peptide-1 receptor agonist, is a novel long-acting form of CA exendin-4 (an exendin-4 analogue) 
that is being developed for the treatment of adults with T2DM.
2.1
STUDY RATIONALE
In 2008, the FDA issued a guidance requiring new therapies for T2DM to demonstrate that they 
do not result in an unacceptable increase in CV risk (1).  The 2016 EMA reflection paper on 
assessment of CV safety of medical products recommends assessment of CV risk by either a 
meta-analysis of Phase 3 studies or a dedicated CVOT (2).  In this CVOT, CV safety of 
efpeglenatide will be assessed by demonstrating NI of efpeglenatide over placebo on 3-point 
MACE (CV death, non-fatal MI, or non-fatal stroke) at the 1.8 and 1.3 NI margins (UB of the 
2-sided 95% CI) as specified by the 2008 FDA Guidance discussed above.  If NI is established, 
superiority will also be tested.
2.2
BACKGROUND
In recent years, the GLP-1 RA class of pharmacotherapy for T2DM has evolved as an effective 
treatment option from multiple daily injections to daily and then to weekly injections. Glucagon-
like peptide-1 is an endogenous enteroendocrine hormone secreted by L-cells of the distal 
intestine in response to oral nutrient ingestion, and it has multiple physiologic effects that 
contribute to ameliorating hyperglycemia. These effects include enhancing insulin secretion from 
pancreatic β-cells in a glucose dependent manner, suppressing glucagon secretion, and slowing 
gastric emptying. Due to its glucose-dependent mechanism of action, GLP-1 RAs are generally 
associated with a low risk of hypoglycemia.
Glucagon-like peptide-1 RAs exhibit multiple effects across several organ systems, including the 
gastrointestinal (GI), CV, renal and central nervous systems that could decrease the CV risk of 
patients with diabetes. Cardioprotective mechanisms of GLP-1 RAs include weight loss, 
improvement of glucose metabolism, blood pressure (BP) reduction, antiatherogenic properties 
and lipid lowering effects. Glucagon-like peptide-1 RAs are associated with clinically relevant 
weight loss, perhaps via early satiety and delayed gastric emptying, resulting in decreased food 
intake and appetite, without an increase in energy expenditure (3, 4). The adipocyte releases 
regulators of BP and vascular tone, which may influence vasculature, and also myocardial 
ischemia, infarction and contractility. With an injured heart, metabolism shifts toward greater 
oxidation of glucose, rather than free fatty acids (normally 60-90%), due to less oxygen 
consumption. Glucagon-like peptide-1 RAs may increase glucose uptake and facilitate this 
metabolic shift (5). 
Glucagon-like peptide-1 RAs decrease both systolic and diastolic blood pressure (SBP and DBP)
perhaps via a natriuretic/diuretic effect on the kidney, vasodilation and/or decreased sympathetic 
nervous system activity. Glucagon-like peptide-1 receptors are expressed in endothelial cells 
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vascular smooth muscle cells, monocytes, macrophages and lymphocytes, and therefore, may 
directly affect atherosclerosis, inflammation and may reduce vascular endothelial dysfunction 
(which precedes atherosclerosis) (3, 4). Finally, GLP-1 RAs can lower total cholesterol, LDL, 
fatty acid and triglyceride levels (5).
2.3
BENEFIT/RISK ASSESSMENT
Efpeglenatide is a long-acting GLP-1 RA; it is being developed as an adjunct to diet and exercise 
to improve glycemic control in adults with T2DM.
In 2 Phase 1 and 5 Phase 2 studies, efpeglenatide at doses ranging from 1 to 6 mg weekly and 8 to 
16 mg monthly has been shown to lower blood glucose in participants with T2DM in comparison 
with placebo. A Phase 2 study in obese subjects without diabetes (HM-EXC-205) provided 
evidence for a benefit of efpeglenatide in combination with a hypocaloric diet in terms of body 
weight loss.
HM-EXC-203 and HM-EXC-204, both Phase 2 studies, showed administration of efpeglenatide 
to patients (n=254 and n=209, respectively) with T2DM improved several metabolic parameters 
including HbA1c levels, proportion of patients who had a goal HbA1c level of <7%, LS mean 
changes from baseline in the levels of certain 7-point blood glucose profile parameters, glycated 
albumin levels, and LDL C levels. In addition, decreases from baseline in body weight were 
statistically significantly greater (at least p<0.049 for both) compared to placebo. 
Study HM-EXC-205 was conducted in 295 overweight/obese patients without T2DM.  The 
primary objective of this study was to evaluate the efficacy of efpeglenatide in reducing body 
weight. In this study, 6 mg efpeglenatide administered once weekly for 20 weeks resulted in 
slightly greater weight reduction than what was observed for the 4 mg weekly dose (LS mean 
change from baseline of -7.32 kg [SE 0.63] versus -6.63 kg (SE 0.62), for the 6 and 4 mg weekly 
dose groups, respectively). 
The non-clinical toxicological data and the safety data from clinical studies with efpeglenatide to 
date suggest a safety profile consistent with the known AE profile of currently marketed GLP-1 
RAs, with the exception of potential liver toxicity. Below is a summary of safety findings in all 
Phase I and 2 studies with a data lock date of 22 June 2017.

No major safety concerns were found in the Phase 1 and 2 program of efpeglenatide.

Gastrointestinal AEs, in particular, nausea, were the most common. The trend over time 
for nausea and vomiting events appeared dose related with an increase after the first 
injection, and generally decreasing thereafter. In studies where a titration phase (ie, where 
a schedule of gradual dose escalation up to the randomized dose) occurred, the effect was 
less pronounced during the titration phase. The percent of TEAEs, discontinuations and 
nausea and vomiting appeared to be dose dependent.

There were no reports of pancreatitis.
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
TEAEs leading to discontinuation in the GI disorders system organ class (SOC) for 
efpeglenatide in Studies HM-EXC-203, HM-EXC-204 and HM-EXC-205 (the large 
Phase 2 studies) were 2.2%, 8.3% and 9.8%, respectively. 

There was one case of medullary thyroid cancer and one case of pancreatic cancer reported 
in the Phase 1 and 2 programs. They were considered by the investigators to be unrelated 
or unlikely related to efpeglenatide respectively.

No serious or severe immunogenicity events (eg, allergic reactions or immune complex 
disease and injection site reactions) were reported. 

No severe hypoglycemia was reported.

No fetal toxicity was reported.

Elevated ALT levels ≥3 x upper limit of normal (ULN) post-baseline were seen in 15 of 
754 subjects in the large Phase 2 studies (HM-EXC-203 and HM-EXC-204 in patients 
with T2DM and HM-EXC-205 in obese subjects); 2 of 147 subjects on placebo, 12 of
571 subjects on efpeglenatide, and 1 of 36 subjects on liraglutide. There were several 
confounding factors such as acetaminophen (paracetamol) used and elevated levels at 
either baseline or screening. None of these subject experienced increased bilirubin 
>2 x ULN. Four of the 15 subjects discontinued study medication due to abnormal liver 
function tests. There were no cases of ALT increase ≥3 x ULN in the Phase 1 studies 
(HM-EXC-101 and HM-EXC-102) and the Phase 2 studies (HM-EXC-201 and 
HM-EXC-202).

Diabetic retinopathy complications have been reported for one of GLP-1 RAs (as of 
05 December 2017). No case has been reported for efpeglenatide. 

The 24-hour ECG performed in Study HM-EXC-102 showed that the increase of heart rate 
(HR) seen with 6 mg efpeglenatide was in the range of liraglutide 1.8 mg.

There were no deaths in the studies.

The SAEs considered related to efpeglenatide included severe dehydration and renal 
failure, in a single subject (6 days after starting efpeglenatide 6 mg QW), possibly caused 
by GI complications (vomiting); and constipation in another patient.
Overall, the potential benefits of efpeglenatide therapy for patients with T2DM, including 
improvement in glycemic control and reduction in body weight, outweigh the potential risks. The 
favorable benefit-risk assessment to date supports the further development. 
The risks to the study participants will be minimized by careful participant selection according to 
appropriate inclusion and exclusion criteria based on existing nonclinical and clinical data. 
During the study participants will be closely monitored at the regular visits, including physical 
examinations and laboratory tests to early detect eventual adverse reactions.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of efpeglenatide may be found in the Investigator’s Brochure (IB) (6).
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3
OBJECTIVES AND ENDPOINTS
Table 2 - Objectives and endpoints
Objectives
Endpoints
Primary

To demonstrate that efpeglenatide 4 and 6 mg is 
noninferior to placebo on 3-point MACE in T2DM 
patients with high CV Risk

Time to the first occurrence of any of the following 
clinical events, positively adjudicated by the Clinical 
Endpoint Committee (CEC):
-
CV death
-
Non-fatal myocardial infarction (MI)
-
Non-fatal stroke 
Secondary

To demonstrate that efpeglenatide 4 and 6 mg is 
superior to placebo on 3-point MACE in T2DM 
patients with high CV risk 

Time to the first occurrence of any of the following 
clinical events, positively adjudicated by the CEC:
-
CV death
-
Non-fatal MI
-
Non-fatal stroke 

To demonstrate that efpeglenatide 4 and 6 mg is 
superior to placebo on the expanded CV outcome in 
T2DM patients with high CV risk 

Time to the first occurrence of any of the following 
clinical events, positively adjudicated by the CEC:
-
CV death
-
Non-fatal MI
-
Non-fatal stroke
-
Coronary revascularization
-
Hospitalization for unstable angina 

To demonstrate that efpeglenatide 4 and 6 mg is 
superior to placebo on the composite outcome of new 
or worsening nephropathy in T2DM patients with high 
CV risk 

Time to the first occurrence of any of the following 
clinical events:
-
New onset or progression to macro albuminuria 
(>300 mg/g) accompanied by an albumin-to-
creatinine ratio (UACR) value increase of ≥30% 
from Baseline
-
Sustained ≥40% decrease in estimated 
glomerular filtration rate (eGFR) from Baseline 
(for ≥30 days)
-
Chronic dialysis (for ≥90 days)
-
Renal transplant
-
Sustained eGFR <15 mL/min/1.73 m2 (for 
≥30 days)

To assess the safety of efpeglenatide 4 and 6 mg 
once per week (QW), both added to standard of care 
in T2DM patients with high CV risk

Adverse events (AEs), serious adverse events 
(SAEs), AEs leading to treatment discontinuation, 
AEs of special interest (AESI), AEs requiring specific 
monitoring

Safety laboratory values 

Vital signs
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Objectives
Endpoints

12-lead electrocardiogram (ECG)
Tertiary/exploratory

To compare efpeglenatide versus placebo on the 
occurrence of the following events in T2DM patients 
with high CV Risk :  
-
CV death
-
Stroke (fatal and non-fatal) 
-
MI (fatal and non-fatal)
-
All cause death
-
Hospitalization for unstable angina
-
Hospitalization for Heart Failure (HHF)
-
Coronary revascularization procedures 
(percutaneous coronary intervention [PCI] or 
coronary artery bypass graft [CABG]

Time to CV death

Time to first occurrence of Stroke (fatal and non-fatal) 

Time to first occurrence of MI (fatal and non-fatal

Time to all cause death

Time to first occurrence of hospitalization for unstable 
angina

Time to first occurrence of HHF

Time to first occurrence of coronary revascularization 
procedures (PCI or CABG)

To compare efpeglenatide versus placebo on the 
following endpoints: 
-
Change in HbA1c
-
Change in body weight
-
Change in BP
-
Change in Urinary Albumin-Creatinine Ratio
(UACR)

Change in HbA1c

Change in body weight 

Change in BP

Change in UACR

To compare efpeglenatide versus placebo on 
immunogenicity

Anti-drug (efpeglenatide) antibody (ADA):
-
Number of participants by ADA status 
(positive/negative) at baseline
-
Number of participants with treatment boosted 
ADAs
-
Number of participants with treatment induced 
ADAs
-
Number of participants by ADAs cross-reactivity 
to endogenous GLP-1
-
Number of participants by ADAs cross-reactivity 
to endogenous Glucagon
-
Number of participants with ADAs directed 
against the PEG linker of Efpeglenatide
3.1
APPROPRIATENESS OF MEASUREMENTS
As explained in Section 2, the first primary endpoint of 3-point MACE is in concordance with 
appropriate guidance from the Health Authorities (1, 2). If NI of efpeglenatide on 3-point MACE
is met, superiority will also be assessed.
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4
STUDY DESIGN
4.1
OVERALL DESIGN
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group 
study in approximately 4000 T2DM patients at High CV Risk. The study will consist of 3 periods:

A 2- to 3-week screening period 

A double-blind, placebo-controlled, multiple dose treatment period, including up to 
8 weeks for dose titration 
-
If, at any time during the study, a participant does not tolerate the study treatment, the 
IMP may be temporarily discontinued or if medically necessary, permanently 
discontinued. 
-
If a maximum of 2 (two) consecutive doses are missed, the IMP can be restarted with 
the latest dose given; if 3 or more consecutive doses are missed, the IMP will be 
restarted using a new titration kit. 
-
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol.

A follow-up period of 6 weeks after the last dose of IMP
The study is event driven and will continue until 330 participants have at least one primary event 
(3-point MACE) positively adjudicated by the CEC.  
To be eligible for the study, patients must have T2DM with high CV risk and an HbA1c >7% at 
screening, and the antihyperglycemic treatment must have been stable for 12 weeks prior to 
randomization, in the opinion of the investigator.
Prior to randomization, the Investigator will be asked to pre-specify which therapeutic approach 
will be implemented should intensification of the background antihyperglycemic treatment be 
considered necessary during the study.
Patients who meet all eligibility criteria will come back for the randomization visit (Visit 3) and, 
if they are still eligible for the study, they will be randomized 1:1:1 to efpeglenatide 4 mg, 
efpeglenatide 6 mg or placebo. Randomization will be stratified by the current or potential future 
use of an SGLT2 inhibitor:

Current use

Potential future use

Neither current nor potential future use
Any antihyperglycemic treatment is allowed as background therapy with the exception of GLP-1 
agonists and DPP4 inhibitors. For participants with HbA1c <7.5% at time of Screening, and who 
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are treated with either insulin, glinide, or sulfonylurea, the doses of the glucose-lowering 
medications may be decreased at Randomization in order to prevent possible hypoglycemia.
Antihyperglycemic therapy must not be modified for the first 12 weeks after randomization (other 
than for medical necessity). After the first 12 weeks post randomization and during the remaining 
double-blind treatment period, the management of glycemia will be left to the Investigator’s 
and/or treating provider’s judgment, informed by clinical guidelines and local/regional standards 
of care. Investigators will monitor the glycemic status and potassium levels of participants
throughout the study. If treatment intensification is still considered necessary after dose increase 
of the background antihyperglycemic treatment, the Investigator can prescribe any other 
antihyperglycemic medication (according to its labeling), with the exception of a GLP-1 RA or a 
DPP4 inhibitor, that must not be used during the study.
Participants with a suspected renal event (reduction of eGFR) should have a repeat assessment of 
renal function 30 to 45 days following the onset of the event to confirm it is sustained.
If a participant discontinues treatment with IMP prematurely, the participant will undergo a pEOT 
Visit, but every effort will be made to have the participants return to the site at the time 
corresponding to their scheduled visits, until the end of study. There must be at least 6 weeks of 
post-treatment safety follow-up between the last IMP administration and the Study Closeout Visit 
for participants who discontinue IMP prematurely.
Participants will continue taking IMP after a CV or renal outcome occurs. If the participant does 
not agree to continue taking IMP or to attend site visits, they will be contacted by telephone to 
inquire about safety status (including outcomes).
When 330 participants will have at least one primary event (3-point MACE) positively 
adjudicated by the CEC, all randomized participants will be scheduled to return to the site for a 
Study Closeout Visit (timing and window will be communicated to the sites). 
All randomized participants, including those who prematurely discontinued from IMP, will be 
followed from Randomization until the Study Closeout Visit or death, whichever comes first. A 
post-treatment safety follow-up visit 6 weeks after the last dose of IMP will be implemented for 
participants still on study treatment at the Study Closeout Visit.
An independent DMC will review clinical study safety data and an independent CEC will review, 
assess and/or adjudicate all events of deaths, selected CV events (non-fatal MI, stroke, unstable 
angina leading to hospitalization, and heart failure leading to hospitalization), pancreatic events,
and selected AEs. An independent ophthalmologist expert will review in a treatment-blinded 
manner all reported AEs suspected to be diabetic retinopathy to assess the presence of retinopathy 
and the relationship of reported AE to IMP. See Appendix 1 (Section 10.1) for further details of 
study committees.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
Results from 4 CVOTs with GLP-1 agonists (LEADER, ELIXA, SUSTAIN-6 and EXSCEL) 
showed varying effects on cardiovascular outcomes (7, 8, 9, 10). In the LEADER trial liraglutide 
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significantly reduced the risk of the composite primary endpoint of CV death, non-fatal MI or 
non-fatal stroke by 13% vs placebo (95%CI: 0.78 to 0.97, p=0.01), when added to standard of 
care in patients with T2DM at high CV risk (7). ELIXA showed NI of lixisenatide to placebo 
(hazard ratio=1.02; 95%CI, 0.89 to 1.17) (p for NI <0.001) for the primary outcome of 
cardiovascular death, MI, stroke, or hospitalization for unstable angina after a recent acute 
coronary event (8). SUSTAIN-6 showed that semaglutide was noninferior to placebo on the 
composite primary endpoint of CV death, non-fatal MI (heart attack) or non-fatal stroke (hazard 
ratio=0.74; 95% CI:  0.58 to 0.95; p <0.001) in patients with T2DM at high CV risk. The study 
also showed superiority with p=0.02; however, this analysis was not prespecified in the 
hierarchical testing plan (9).  EXSCEL showed that exenatide was noninferior to placebo on the 
composite primary endpoint of CV death, non-fatal MI or non-fatal stroke in patients with T2DM 
with or without cardiovascular disease (CVD) (hazard ratio, 0.91; 95% CI, 0.83 to 1.00; p <0.001 
for NI) and was not superior (p=0.06 for superiority) (10). The CV effects of the various GLP-1 
RAs in the 4 CVOTs discussed above cannot be directly compared due to differences in study 
design, duration of follow-up, and enrolled patient populations. The ELIXA trial, for example, 
was the only CVOT that investigated the CV effect of a GLP-1 RA in patients with a recent acute 
coronary syndrome. This population with very high CV risk was selected because it should be
ideally suitable for demonstration of CV safety. However, the short duration of follow-up likely 
decreased the ability to detect potential cardioprotective effects of Lixisenatide (8).
In 2015, the EMPA-REG OUTCOME trial showed that the SGLT2 inhibitor empagliflozin, 
reduced the risk of 3-point MACE (CV death, non-fatal MI, or non-fatal stroke) compared to 
placebo (hazard ratio=0.86, p <0.001 NI and p=0.04 for superiority) in patients with T2DM and 
established CV disease (CVD). The CV benefit was primarily driven by a reduction of CV death 
(hazard ratio=0.62, p <0.001) (11). In 2017, the CANVAS program showed that another SGLT2 
inhibitor, canagliflozin, also reduced the risk of 3-point MACE (CV death, non-fatal MI or non-
fatal stroke) by approximately 14% (hazard ratio=0.86; p <0.001 for NI and p=0.02 for 
superiority) in patients with T2DM and established CVD or at high risk for CV events (12). 
Of note, FDA recently approved a new indication for empagliflozin for reducing the risk of CV 
death in adult patients with T2DM and established CVD, and liraglutide for reducing the risk of 
non-fatal stroke, non-fatal MI and CV death in patients with T2DM and established CVD (13, 14).
The EU Summaries of Product Characteristics (SmPCs)  have also been updated to include the 
findings from the empagliflozin and liraglutide CVOT studies (15, 16).
This study is designed to assess the CV effects of efpeglenatide in patients with T2DM and high 
CV risk (see Section 5.1). Therefore it is important to mitigate any potential imbalance between 
the treatment arms in the use of concomitant medications that have been shown to affect the CV 
risk of the patient population. Therapies belonging to two classes of antihyperglycemic 
medications have been shown to be cardioprotective: the GLP1-RAs and the SGLT2 inhibitors. 
Since efpeglenatide is a GLP1-RA, treatment with other GLP1-RA will not be allowed during this
study. Patients will be allowed to participate in this study even if they currently use an SGLT2 
inhibitor, if deemed appropriate based on their comorbid profile. In order to mitigate an imbalance 
in the use of SGLT2 inhibitors, the Investigators will be asked to pre-specify before 
randomization whether they will consider starting an SGLT2 inhibitor should intensification of 
the background antihyperglycemic treatment be considered necessary for a specific patient during 
the study. Both the use at baseline and potential future use of SGLT2 inhibitor will be considered 
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in the randomization stratification, using the following 3 levels: Current use, Potential future use, 
Neither current nor potential future use. 
The primary analysis will be performed in the ITT population, and all data from randomization to 
the Study Closeout Visit will be included. Patients who start or stop a SGLT2 inhibitor during the 
trial will continue study treatment, will remain in the study and their data will be included in the 
primary analysis. The supportive analysis will include the ITT population with censoring of 
patients at the time of starting or stopping a SGLT2 inhibitor. 
4.3
JUSTIFICATION FOR DOSE
The selection of efpeglenatide 4 and 6 mg once-weekly doses is based on the results of early 
phase studies. Efpeglenatide Phase 2 studies have been conducted in both patients with T2DM as 
well as obese non-diabetic individuals, using a variety of dose regimens including weekly doses 
up to 4 mg (in patients with T2DM) and 6 mg (in non-diabetic overweight/obese patients) as well 
as monthly doses up to 16 mg (T2DM). These studies have demonstrated efpeglenatide’s effect in 
glycemic improvement and weight reduction, with an overall favorable safety and tolerability 
profile.
The once-weekly doses of 4 and 6 mg were chosen for further evaluation based on their HbA1c 
lowering effects and the overall safety observed at these doses. The initial dose will be 2 mg, and 
dose increases to achieve maximum of 6 mg (in the corresponding arm) will be in 2-mg step 
interval every 4 weeks in order to minimize the GI adverse effects. 
Please refer to the IB (6) for more details.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he/she has completed the Study 
Closeout Visit (in person or by phone) or has died prior to the Study Closeout Visit.
The study is event driven and will continue until it is projected that 330 participants will have at 
least one primary event (3-point MACE) positively adjudicated by the CEC.
All randomized patients will be asked to return to the study site for a Study Closeout Visit when 
approximately 330 participants have at least one primary event (3-point MACE) positively 
adjudicated by the CEC. The timing and window of this visit will be communicated to sites once 
the date on which the required number of events is projected to be positively adjudicated has been 
determined.
For patients who previously prematurely permanently discontinued IMP, the Study Closeout 
Visit, planned at least 6 weeks after the pEOT visit for post-treatment follow-up, will be the final 
study visit. Participants still taking the IMP at the time of the Study Closeout Visit will have their 
final study visit (Follow-up Visit) 6 weeks after their Study Closeout Visit.
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5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
I 01.
Participant must be ≥18 years of age at the time of signing the informed consent.
Type of participant and disease characteristics
I 02.
Participants with T2DM and HbA1c >7% 
I 03.
Participants who meet at least one of the 9 CVD criteria in Table 3
OR
male participants who are ≥50 years of age or female participants who are ≥55 years of 
age and have an eGFR ≥25 and <60 mL/min and have at least one of the 6 CV risk factors 
listed in Table 4
Table 3 - Established CVD criteria (need at least 1 from Section A, B or C)
Section A: Presence of Coronary Artery Disease (CAD)
1.
Documented (with ECG changes or prior discharge hospital diagnosis)  history of symptomatic myocardial infarction 
(>2 months prior to screening)
2.
Evidence of multi-vessel coronary artery disease, ie, ≥2 major coronary arteries or the left main coronary artery, 
documented by any of the following: 
-
Presence of a significant stenosis (imaging evidence of ≥50% narrowing of the luminal diameter measured during 
a coronary angiography or a multi-sliced computed tomography)
-
Previous revascularization of ≥2 major coronary arteries  (percutaneous transluminal coronary angioplasty (with or 
without stent), or CABG) (>2 months prior to screening) 
-
The combination of revascularization in one major coronary artery (>2 months prior to screening) and the 
presence of a significant stenosis in another major coronary artery {≥50% luminal narrowing during an 
angiography (coronary or  multi-sliced computed tomography)}
3.
Evidence of  single vessel coronary artery disease of at least  ≥50% luminal narrowing during a angiography (coronary 
or  multi-sliced computed tomography) not subsequently successfully revascularized, with at least 1 of the following:
-
A positive non-invasive stress test for ischemia 
-
Hospitalization for unstable angina within the prior 12 months 
Section B: Presence of Cerebrovascular Disease
4.
History of Ischemic or Haemorrhagic stroke (>2 months prior to screening) 
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Section C: Presence of Peripheral Arterial Disease (PAD) (symptomatic or not)
5.
Previous limb angioplasty
6.
Stenting or bypass surgery of peripheral artery
7.
Previous limb or foot amputation due to circulatory insufficiency
8.
Ankle-brachial index <0.9
9.
Angiographic evidence of PAD
CABG: coronary artery bypass graft; ECG: electrocardiogram
Table 4 - CV Risk Factors (at least 1 criterion must be met)
1.
Body mass index ≥35 kg/m2 at Screening
2.
Dyslipidemia despite maximally-tolerated statin therapy: 
-
Based on the last measured and documented laboratory measurement in the previous 6 months
-
LDL cholesterol >130 mg/dL (>3.36 mmol/L) 
-
OR
-
HDL cholesterol <40 mg/dL (<1.03 mmol/L) for men or <50 mg/dL (<1.29 mmol/L) for women
3.
Currently smoking tobacco (Consumes an average of at least 1 cigarette, pipe, or cigar per day, at Screening) 
4.
UACR ≥30 mg/g (3 mg/mmol) during Screening period, based on central laboratory (spot urine)
5.
SBP >140 mmHg and DBP >90 mmHg despite antihypertensive therapy at the Screening Visit 
6.
Family history (in a male relative <55 years or in a female relative <65 years) of premature coronary heart disease 
(defined as MI or coronary revascularization procedure) in a first degree relative. 
DBP: diastolic blood pressure; HDL: high density lipoprotein; LDL: low density lipoprotein; SBP: systolic blood pressure; UACR: urinary 
albumin-creatinine ratio
Sex
I 04.
Male or Female
A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 10.4]), not breastfeeding, and at least one of the following conditions applies:
-
Not a WOCBP as defined in Appendix 4 (Section 10.4)
OR
-
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the study and for at least 5 weeks after the last dose of study 
treatment and who agrees to refrain from donating ova for the duration of the study 
and at least 5 weeks after last dose of study treatment.
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Informed Consent
I 05.
Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2)
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
5.2
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01. Clinically relevant history of GI disease associated with prolonged nausea and vomiting, 
including (but not limited to) gastroparesis, unstable and uncontrolled gastroesophageal 
reflux disease within 6 months prior to screening
E 02. History of pancreatitis (unless pancreatitis was related to gallstone and cholecystectomy 
has been performed) and pancreatitis during previous treatment with incretin therapies, 
chronic pancreatitis, and pancreatectomy
E 03. Personal or family history of medullary thyroid cancer (MTC) or genetic conditions that 
predisposes to MTC (eg, multiple endocrine neoplasia syndromes)
E 04. Estimated glomerular filtration rate <25 mL/min/1.73 m² by the 4 variable Modification of 
Diet in Renal Disease (MDRD) equation (at Screening, based on central laboratory)
E 05. Systolic BP >180 mmHg and/or DBP >100 mmHg at randomization
E 06. Hospitalization for  hypertensive emergency within 3 months prior to randomization
E 07. Planned coronary revascularization procedures, electrophysiologic device implantation, 
cardiac mechanical support implantation or other cardiac surgery
E 08. History of solid organ transplant
E 09. Hypersensitivity to any of the study treatments, any components thereof, or any GLP-1 
RAs (eg, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide)
E 10. No documented ophthalmologic exam with fundoscopy within 6 months prior to 
randomization (or within 3 months in patients with severe non proliferative diabetic 
retinopathy [NPDR]/ proliferative diabetic retinopathy [PDR]/Diabetic Macular Edema 
[DME])
E 11. Retinopathy or maculopathy with one of the following treatments, either recent (3 months
prior to randomization) or planned during the study: intravitreal injections or laser or 
vitrectomy surgery
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E 12. Patients with short life expectancy or with any clinically significant abnormality identified 
in their medical history (including severe anemia, congestive heart failure-New York Heart 
Association [NYHA] III/IV, respiratory, hepatic, neurological, psychiatric, active 
malignant tumor or other major systemic disease), during screening evaluation (eg, 
physical examination, laboratory tests, ECG, vital signs), or due to any AE during the 
screening period, which, in the judgement of the investigator, would preclude safe 
participation in the study or constrain efficacy assessment
E 13. History of drug or alcohol abuse within 6 months prior to the time of screening
Prior/concomitant therapy
E 14. Treated with any GLP-1 RA product alone (eg, exenatide, liraglutide, lixisenatide, 
albiglutide, dulaglutide, semaglutide) or in combination, within 3 months prior to 
screening
E 15. Use of any DPP4 inhibitor within 3 months prior to screening
E 16. Diabetic treatment has not been stable in the 3 months prior to screening, in the opinion of 
the investigator
Prior/concurrent clinical study experience
E 17. Exposure to any investigational drugs in the last 4 weeks or 5 half-lives, whichever is 
longer, prior to screening
E 18. Current enrollment in any other clinical study involving an investigational study treatment
E 19. Participation in any previous efpeglenatide/HM11260C clinical trial within 3 months prior 
to screening
Diagnostic assessments
E 20. Laboratory findings at the Screening Visit:
-
ALT or AST >3 times the ULN 
-
Total bilirubin >1.5 times the ULN (except in case of documented Gilbert’s syndrome)
-
Amylase and/or lipase >3 times the ULN laboratory range
-
Calcitonin ≥5.9 pmol/L (20 pg/mL)
Other exclusions
E 21. Presence of any other conditions (eg, geographic, social) actual or anticipated, that the 
Investigator feels would restrict or limit the patient’s participation for the duration of the 
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E 22. Participant is an employee of the Sponsor, or is the Investigator or any Subinvestigator, 
research assistant, pharmacist, study coordinator, other staff or relative thereof directly 
involved in the conduct of the protocol
E 23. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol
E 24. Participants who withdraw consent during the Screening Period (starting from signed ICF)
E 25. Any country-related specific regulation that would prevent the participant from entering 
the study  (eg, individuals committed to an institution by virtue of an order issued either by 
the judicial or the administrative authorities) – see Appendix 8 (Section 10.8) (country 
specific requirements)
5.3
LIFESTYLE CONSIDERATIONS
No restrictions are required.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE.
In cases where a patient fails Screening due to reasons expected to change upon rescreening based 
on the Investigator’s clinical judgment, the patient can be rescreened once. In these cases, the 
patient should be registered as a screen failure in IRT. The patient will then need to sign a new 
ICF, be registered as a rescreen in IRT and assigned a new patient number, and again complete 
Screening Visit procedures/assessments.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
The IMP includes efpeglenatide in 3 doses (2, 4 and 6 mg) and placebo for SC injection during 
the course of the study.
6.1
STUDY INTERVENTION(S) ADMINISTERED
Table 5 - Overview of study interventions administered
Study intervention name
Efpeglenatide
Placebo
Dosage formulation
Sterile, non pyrogenic, clear, colorless 
solution in a 1 mL disposable PFS in 
the formulation buffer (containing citric 
acid monohydrate, L-methionine, 
polysorbate 20, D-mannitol, sodium 
hydroxide and water for injection).
Sterile, non pyrogenic, clear, colorless 
solution in a 1 mL disposable PFS in 
the formulation buffer (containing citric 
acid monohydrate, L-methionine, 
polysorbate 20, D-mannitol, sodium 
hydroxide and water for injection).
Unit dose strength(s)/Dosage level(s)
2, 4 and 6 mg/ 0.5 mL (at 4, 8 and 
12 mg/mL concentrations, 
respectively)
Not applicable
Route of administration
SC Injection
SC Injection
Dosing instructions
The injection interval of the IMP is once weekly on the same week day (eg, each 
Monday) at any time of the day.  Injections should be administered SC to the 
abdomen.  Within this region, the site of the injection should be changed 
(rotated) at each time to prevent skin reactions.
Packaging and labeling
Study intervention will be provided in different types of kit boxes. Each kit will be 
labeled as required per country requirement.
INVESTIGATIONAL MEDICINAL PRODUCTS
The appropriate number of kits will be dispensed for the period until the next dispensing visit 
(please refer to SoA in Section 1.3). Storage conditions and use-by-end date (when required by 
country regulations) are part of the label text.
Participants will be trained on the use of the PFS by the study staff at Visit 2 (Week -1) and 
provided with an “instructions for use” leaflet which will describe the handling procedures for the 
PFS and administration technique. The injection training pads can be used, if needed. Initial 
injection technique training at Visit 2 will include mandatory self-injection with a training PFS 
and assessment of participant’s skills and understanding by observing teach-back. If needed, an 
additional training PFS can be used for self-injection technique training any time prior to the day 
of randomization. In some cases, Visit 2 might be combined with Visit 3 (Randomization), as per 
Investigator’s judgement, according to the patient’s medical profile.
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Review of injection technique can be done at any other visit as needed. Review of injection sites 
will be performed at all onsite visits. Injections should be administered SC to the abdomen. 
Within this region, the site of injection should be changed (rotated) at each time to prevent skin 
reactions.
Prefilled syringe related issues (malfunctions) should be reported to the Sponsor by the means of a 
procedure on Product Technical Complaint forms, which are described in a separate manual.
Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing.
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor.
The expiry date is mentioned on the IMP labels (when required by country regulation), and 
storage conditions are written on the IMP labels and in the instruction leaflet.
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply 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 site staff.
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions
are provided in a separate study document.
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. All IMPs 
will be dispensed in accordance with the Investigator's prescription and it is the Investigator's 
responsibility to ensure that an accurate record of IMP issued and returned is maintained.
Any quality issue noticed with the receipt or use of an IMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
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the Sponsor. Some deficiencies may be recorded through a complaint procedure (see 
Section 8.3.8).
A potential defect in the quality of IMP/device may be subject to initiation of a recall procedure 
by the Sponsor. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP/device and eliminate potential hazards.
Under no circumstances will the Investigator supply IMP to a third party (except for direct to 
patient shipment, for which a courier company has been approved by the Sponsor), allow the IMP 
to be used other than as directed by this clinical trial protocol, or dispose of IMP in any other 
manner.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
The randomization will be stratified by the current or potential future use of SGLT2 inhibitor 
(Current use, Potential future use, Neither current nor potential future use).
All participants will be centrally assigned to randomized study intervention using IRT. Before the 
study is initiated, instructions on how to access IRT will be provided to each site.
A randomized participant is a participant who has been allocated to a randomized intervention 
regardless whether the intervention kit was used or not. A participant cannot be randomized more 
than once in the study.
Study intervention will be dispensed at the study visits summarized in SoA. 
Returned study intervention should not be re-dispensed to the participants.
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a participant’s treatment 
assignment is warranted. Participant safety must always be the first consideration in making such 
a determination. If a participant’s treatment assignment is unblinded, the Sponsor must be notified 
within 24 hours after breaking the blind. The date and reason that the blind was broken must be 
recorded in the source documentation and case report form, as applicable. When documenting the 
reason for unblinding, the Investigator must not provide any detail regarding the nature of the 
IMP. The Investigator should not divulge IMP detail to the Sponsor’s representative or to any 
staff members until database (DB) closure. Furthermore, when completing forms (eg, AE, SAE, 
adjudication information), the study treatment should not be disclosed on the forms. If the blind is 
broken by the Investigator, the patient must be permanently withdrawn from IMP administration 
but shall continue to be followed in the study.
Methods of blinding
During the double-blind treatment period, which includes titration, Investigators and participants 
will be blinded to the allocation of active or placebo treatment arms. Efpeglenatide and placebo 
will be provided in indistinguishable PFSs, in identical kits. Titration kits differ from treatment 
kits by the number of PFSs inside the kits. Each titration and treatment kit (and the corresponding 
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syringes) will be labeled with a unique number. The list of kit numbers will be generated by 
Sanofi.
In accordance with the double-blind design, Investigators will remain blinded to study treatment 
and will not have access to the randomization (treatment) codes except under exceptional medical 
circumstances. 
Randomization code breaking will also be performed during the analysis of the ADA samples. 
Only the Project manager and lead scientist at the Bioanalytical laboratory will have access to the 
randomization code to allow for the sorting of the efpeglenatide blood samples. The Bioanalytical 
laboratory and responsible personnel will follow the standard procedures to ensure the protection 
of the blind within the Sponsor’s clinical team. The randomization code or the individual 
analytical results will not be disclosed to any clinical team personnel prior to the DB lock.
Members of the CEC will review and adjudicate events in a blinded manner (please also refer to 
Appendix 1 [Section 10.1]).
The DMC receives unblinded safety data from an independent statistician for review, which will 
be handled strictly confidentially. None of these reports may be delivered to unauthorized persons 
(Appendix 1 [Section 10.1]).
Refer to Section 8.3.4 for suspected unexpected serious adverse drug reaction unblinding by the 
Sponsor.
6.4
STUDY INTERVENTION COMPLIANCE
Measures taken to ensure and document treatment compliance and IMP accountability include:

Proper recording of treatment kit number as required on appropriate electronic case report 
form (e-CRF) page for accounting purposes

All medication treatment kits (whether empty or unused) are returned by the participant at 
each visit when a treatment dispensing is planned

The Investigator or his/her delegate tracks treatment accountability/compliance comparing 
the treatment kit number with the treatment kit number of returned treatment kits (whether 
empty or unused) and fills in the participant treatment log

The monitor in charge of the study then checks the data entered on the IMPs 
administration page of the e-CRF by comparing them with the IMPs that has been 
retrieved and the participant treatment log form
6.5
CONCOMITANT THERAPY
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with dates of administration including start and end 
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During the study, the following treatments are prohibited:

Any GLP-1 RA product alone (eg, exenatide, liraglutide, lixisenatide, albiglutide, 
dulaglutide, semaglutide) or in combination

Any DPP-4 inhibitor

Any investigational drug other than IMP for this study
Other medications which are unlikely to interfere with the IMP and the study procedures are 
allowed as needed and have to be recorded in the source data and in the e-CRF. However, doses 
of chronically administered medicines should be kept fixed during the trial if at all possible. 
Glucagon-like peptide-1 receptor agonists are known to decelerate gastric emptying. The delay of 
gastric emptying may impact absorption of concomitantly administered oral medicinal products. 
As drug-drug interaction data are not yet available for efpeglenatide, caution should be exercised. 
Drug levels of oral medications with narrow therapeutic index should be adequately monitored.
During the double-blind study treatment period, the management of glycemia will be left to the 
Investigator’s judgment, informed by clinical guidelines. Investigators will monitor the glycemic 
status and potassium levels of patients throughout the study. For patients with HbA1c <7.5% at 
time of Screening, and who are treated with either insulin, glinide, or sulfonylurea, the doses of 
the glucose-lowering medications may be decreased at Randomization in order to prevent possible 
hypoglycemia. If treatment intensification is still considered necessary after dose increase of the 
background antihyperglycemic treatment, the Investigator can prescribe any other 
antihyperglycemic medication (according to its labeling), with the exception of a GLP-1 RA or a 
DPP4 inhibitor as mentioned above.
6.6
DOSE MODIFICATION
Up-titration of IMP from Randomization to Week 8 is described in Table 1. From Week 8
throughout the rest of the entire double-blind treatment period, participants will remain on the 
randomized IMP dose or placebo until the end of study, except in case of temporary treatment 
discontinuation if, at any time during the study, a participant does not tolerate the study treatment. 
If a maximum of 2 consecutive doses are missed, the IMP can be restarted with the latest dose 
given. In cases of 3 or more missed consecutive doses, the participant will restart treatment using 
a new titration kit (see Section 7.1.2.1). 
6.7
INTERVENTION AFTER THE END OF THE STUDY
The IMPs will not be provided after the end of the treatment period.
When a participant’s participation in the trial ends, the subject will consult with his/her 
Investigator to decide on the best available treatment.
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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
Withdrawal of consent for treatment (ie, treatment discontinuation at patient request) should be 
distinguished from (additional) withdrawal of consent for follow-up visits and from withdrawal of 
consent for non-patient contact follow-up (eg, medical record checks) follow-up. The site should 
document any case of withdrawal of consent.
7.1
DISCONTINUATION OF STUDY INTERVENTION
The IMP should be continued whenever possible. Patients who report a CV or renal endpoint as 
described in Section 3 should remain on IMP until the end of the study, unless there is a safety 
concern. 
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
permanent IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. In any case, the participant should remain in the study as long as 
possible and followed until study end to collect vital safety status and endpoint data.
7.1.1
Permanent discontinuation of study intervention
Permanent intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP whatever the reason.
The participants may withdraw from treatment with IMP if they decide to do so, at any time and 
irrespective of the reason. Patients should discuss stopping study medication with the site before
doing so in order that questions can be addressed, concomitant therapy can be adjusted if needed,
and a follow-up assessment arranged. All efforts should be made to document the reasons for
treatment discontinuation and this should be documented in the e-CRF.
A participant should withdraw from treatment with IMP in case of the following:

Intercurrent condition that requires discontinuation of IMP including: 
-
laboratory abnormalities (see decision tree and general guidance for the follow up of 
laboratory abnormalities in Appendix 5 [Section 10.5])
-
diagnosis of acute pancreatitis confirmed by gastroenterologic evaluation and imaging, 
unless a clear cause unrelated to IMP is confirmed and the participant has recovered 
from pancreatitis (see Appendix 6 [Section 10.6])
-
calcitonin value ≥50 pg/mL (see Appendix 6 [Section 10.6])

If, in the Investigator's opinion, continuation with the administration of IMP would be 
detrimental to the participant's well-being
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
Pregnancy (in female patients)

Confirmed intolerance to the allocated dose of IMP

Any code breaking requested by the Investigator

At the specific request of the Sponsor
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluations that need to be completed.
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation (as soon as possible, preferably within 24 hours) before making a decision of 
permanent discontinuation of the IMP for the concerned participant.
Handling of participants after permanent intervention discontinuation
Every effort should be made to maintain patients in the study. Participants will be followed-up 
according to the study procedures specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last.
If possible, and after the permanent discontinuation of intervention, the participant will undergo a 
pEOT Visit as soon as possible. Participants will then continue in the study with all study 
procedures/visits except those associated with IMP administration. Patients will continue to be 
followed after a CV or renal endpoint occurs irrespective of their treatment status. If the patient 
does not agree to site visits, he/she will be contacted by telephone to inquire about safety status 
(including hospitalizations and endpoints). See the SoA (Section 1.3) for data to be collected at 
the time of intervention discontinuation and follow-up and for any further evaluations that need to 
be completed. 
As all data until the scheduled date of study completion will be used in statistical analyses, it is 
important to collect data for all participants, under treatment or not, during the whole duration of 
the study. A high rate of missing data could jeopardize efficacy results of the study. The 
Investigators should discuss with the participant key visits to attend. The value of critical study 
data collected during the participant’s continued involvement will be emphasized as important to 
the public health value of the study. Site personnel will receive training regarding strategies for 
patient retention, and access to tools to assist with this during the study.
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented.
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed.
If after permanent treatment discontinuation, a participant who has discontinued from treatment 
has reconsidered the decision to permanently discontinue treatment and wishes to later resume 
IMP, and if the Investigator has determined there is no safety reason prohibiting the patient from 
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resuming IMP and the selection criteria for the study are still met, the participant may resume 
IMP with Sponsor approval.
7.1.2
Temporary discontinuation of study intervention
Temporary intervention discontinuation corresponds to at least 1 dose not administered to the 
patient.
If, at any time during the study, a participant does not tolerate the study treatment, the IMP may 
be discontinued. All IMP discontinuation should initially be considered as temporary unless 
permanent discontinuation is mandated by the protocol (see Section 7.1.1), and the Investigator 
should make best effort to resume IMP treatment as early as practically possible. There is no 
defined limit to the duration of temporary discontinuation.
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. For all temporary intervention discontinuations, duration should be recorded by
the Investigator in the appropriate pages of the eCRF.
7.1.2.1
Rechallenge
Participants who temporarily discontinue IMP should be reassessed at every visit to determine 
whether it is possible to safely resume IMP. Reinitiation of intervention with the IMP will be done 
under close and appropriate clinical/and or laboratory monitoring once the Investigator will have 
considered according to his/her best medical judgment that the responsibility of the IMP(s) in the 
occurrence of the concerned event was unlikely.
If a maximum of 2 consecutive doses are missed, the IMP can be restarted with the latest dose 
given. In cases of 3 or more missed consecutive doses, a new titration kit will be allocated to the 
participant (see Section 6.6).
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons.
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records.
See SoA (Section 1.3) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed.
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If participants no longer wish to take the IMP, they will be encouraged to remain in the study and 
attend the remaining visits (see Section 7.1).
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the patient’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.
If a participant withdraws consent for follow-up, the Investigator should still make best efforts to 
determine the patient’s health status, including at least his/her vital status (including time of 
death), where permitted by local regulations. The patient’s final vital status will be confirmed at 
the time of the study close-out visit.
Participants who have withdrawn from the study cannot be re-randomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused.
7.3
LOST TO FOLLOW UP
A participant will be considered as potential lost to follow-up if he or she repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue to 
take IMP or permanently discontinue IMP while still continuing attend study visits.

Before a participant is deemed potential lost to follow up, the Investigator or designee 
must make every effort to regain contact with the participant (where possible, at least 
3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods, contact patient’s family or private physician, review 
available registries, or health care DBs). These contact attempts should be documented in 
the participant’s medical record and continue until DB lock.
The patient informed consent should mention that the study organization including the Sponsor
will make every possible effort to determine this vital status during the scheduled duration of the 
study.
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8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3).
8.1
EFFICACY ASSESSMENTS
8.1.1
Primary endpoint: 3-point MACE
Cardiovascular death, non-fatal MI and non-fatal stroke events will be adjudicated by the CEC 
(see Appendix 1 [Section 10.1.4.3]).
8.1.2
Secondary efficacy endpoints
All cardiac events (see Section 3) will be adjudicated by the CEC (see Appendix 1 
[Section 10.1.4.3]). 
Renal events (see Section 3) will be reported by the Investigator in the eCRF. Participants with a 
suspected renal event (reduction of eGFR) should have a repeat assessment of renal function 30 to 
45 days following the onset of the event to confirm it is sustained.
8.1.3
Exploratory efficacy endpoint
HbA1c will be measured at different time points during study by a certified level I “National 
Glycohemoglobin Standardization Program” central laboratory. 
8.2
SAFETY ASSESSMENTS 
Planned time points for all safety assessments are provided in the SoA.
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8.2.1
Physical examinations

A complete physical examination will be performed as per clinical practice in order to 
assess the health status of the participant at Screening and evaluate the inclusion/exclusion 
criteria.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

Any new finding or worsening of previous finding should be reported as a new adverse 
event.

Height and body weight will be measured as described in the SoA (see Section 1.3).
8.2.2
Vital signs

Blood pressure and pulse measurements will be assessed in a seated position using the 
same device (automated BP monitor or a manual sphygmomanometer) for each 
participant. 
At the Screening Visit (Visit 1), BP will be measured on both arms to identify and select 
the appropriate arm for future measurements. Seated BP should be measured in both arms 
after at least a 5-minute rest period, and then again after 1 minute in both arms in seated 
position. The arm with the highest systolic BP will be determined at this visit, and BP 
should be measured in this arm throughout the study. This highest value will be recorded in 
the e-CRF.

At subsequent visits, BP and pulse measurements are to be done at participants’ identified 
appropriate arm and should be preceded by at least 5 minutes of rest for the participant in a 
quiet setting without distractions (eg, television, cell phones).

Heart rate will be measured at the time of the measurement of seated BP.
8.2.3
Electrocardiograms

The 12-lead ECG should be performed after at least 10 minutes in supine position and 
prior to other study procedures at that visit (eg, blood collection, IMP administration, etc). 
The Investigator should review the ECG and document the interpretation, sign and date it 
on the ECG print out and report it in the e-CRF. Each ECG trace is analyzed in 
comparison with the Screening ECG. All original ECG traces are kept as source data. The 
ECG assessment of “normal” or “abnormal” will be analyzed.
Note: Any new ECG abnormality should be rechecked for confirmation and reported as an 
AE if considered clinically significant by the Investigator.
8.2.4
Clinical safety laboratory assessments
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA (see Section 1.3) for the timing and frequency. 
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
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or medical monitor.
-
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor
notified.
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA.

If local laboratory results are used to make a study treatment decision, for response 
evaluation, or to diagnose/follow-up an AE, then the results must be recorded in the eCRF.

Recommended decision trees for the management of certain laboratory abnormalities are 
provided in Appendix 5 (Section 10.5).
8.2.5
Severe hypoglycemia
The definition of severe hypoglycemia is based on the American Diabetes Association workgroup
on hypoglycemia classification (17, 18): severe hypoglycemia is an event requiring assistance of 
another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure, unconsciousness or 
coma. Plasma glucose measurements may not be available during such an event, but neurological 
recovery attributable to the restoration of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration. The definition of 
severe symptomatic hypoglycemia includes all episodes in which neurological impairment was 
severe enough to prevent self-treatment and which were thus thought to place participants at risk 
for injury to themselves or others. Note that “requiring assistance of another person” means that 
the participant could not help himself or herself. Assisting a participant out of kindness, when 
assistance is not required, should not be considered a “requiring assistance” incident.
Severe hypoglycemia will be reported as an AE. Additional information will be recorded 
including symptoms and/or signs, associated glucose value (if available), whether assistance was 
required and the treatment.
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria (see Appendix 3 
[Section 10.3]). For example, events of seizure, unconsciousness or coma must be reported as 
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8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Adverse event of special interest
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. Adverse events of special interest may be added, modified or 
removed during a study by protocol amendment.

Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP (see Section 8.3.5); 

Symptomatic overdose (serious or nonserious) with IMP
-
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the planned dose (e.g. two or more injections) if given within 3 days (72 hours).
-
Of note, asymptomatic overdose has to be reported as a standard AE.

ALT ≥3 ULN (if baseline ALT <ULN) Or ALT ≥2 times the baseline value (if baseline 
ALT ≥ULN) (Please refer to related flowchart in Appendix 5 [Section 10.5])
Adverse events requiring specific monitoring
An AE requiring specific monitoring is a serious or non-serious AE of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring may be 
appropriate. Such events may require further investigation to characterize and understand them. 
These events should be reported on the AE page and additional information required on specific 
e-CRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria).
The AE requiring specific monitoring for this study are: 

Severe GI events

Severe hypoglycemia (see Section 8.2.5)

Pancreatic events (including abnormal values of pancreatic enzymes [see Appendix 6, 
Section 10.6])

Calcitonin increase >5.9 pmol/L (20 pg/mL) and thyroid C-cell neoplasm (see Appendix 6, 
[Section 10.6])

Acute renal failure (see Appendix 7 [Section 10.7])

Diabetic retinopathy complications (will be reviewed by an independent ophthalmologist 
expert, see Appendix 1 [Section 10.1.4.4]); a written report from professional eye care 
provider will be required

Severe injection site reactions

Severe allergic reactions
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
Severe immune complex disease
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
AE will be reported by the participant (or, when appropriate, by a caregiver or surrogate). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
Expedited reporting of AE for primary or secondary endpoint is waived (see Section 8.3.7).
8.3.1
Time period and frequency for collecting AE and SAE information 
All SAEs and AEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA (Section 1.3).
All SAEs and AESI will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).
8.3.2
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. At the pre-specified study end-date, all SAEs, non-serious AEs of 
special interest (as defined in Section 8.3), and AEs requiring specific monitoring (as defined in 
Section 8.3) will be followed until resolution, stabilization, the event is otherwise explained, or 
the participant is lost to follow-up (as defined in Section 7.3). Moreover, the ADA levels of 
subjects tested positive at the end of study associated with severe injection site reaction, or 
systemic allergic reaction will be monitored adequately over time up to 6 months from the last 
dose of IMP (see Section 8.8.1).
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Further information on follow-up procedures is given in Appendix 3 (Section 10.3).
8.3.4
Regulatory reporting requirements for SAEs

Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 

The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary.

An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
8.3.5
Pregnancy

Details of all pregnancies in female participants and female partners of male participants
will be collected after the start of study intervention and until the follow-up visit.

The Investigator may perform additional pregnancy tests at their discretion or as required 
by local regulations.

If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4).

Pregnancy will be qualified as an SAE only if it fulfills one of the seriousness criteria (see 
Appendix 3 [Section 10.3]).

In the event of pregnancy in a female participant, IMP should be discontinued. 

Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4])

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6
Cardiovascular and death events
Cardiovascular and death events that are endpoints for the primary and secondary efficacy 
analysis will not be reported according to the standard process for expedited reporting of SAEs 
even though the event may meet the definition of a SAE (see Section 8.3.7).
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8.3.7
Disease-related events and other events not qualifying as AEs or SAEs
This study is designed to ascertain whether the following events (primary and secondary 
endpoints) are affected by efpeglenatide:

CV death

Non-fatal MI

Non-fatal stroke

Unstable angina requiring hospitalization

New onset or progression to macro albuminuria (>300 mg/g) accompanied by a UACR 
value increase of ≥30% from Baseline

Sustained ≥40% decrease in eGFR from Baseline (for ≥30 days)

Chronic dialysis (for ≥90 days)

Renal transplant

Sustained eGFR <15 mL/min/1.73 m² (for ≥30 days)
Because these events will be reported and analyzed as efficacy endpoints, they will not be 
reported according to the standard process for expedited reporting of SAEs even though the event 
may meet the definition of a SAE. They are waived from expedited regulatory reporting to Health 
Authorities and they will not be reported to pharmacovigilance except if the Investigator, 
according to his/her best medical judgment, considers these events as related to the IMP taking 
into consideration the patient’s underlying disease. In that case, the Investigator will report it 
within 24 hours to the Sponsor. These events will be recorded on the corresponding CRF page in 
the participant’s CRF within the appropriate time frame. An independent CEC will review and 
adjudicate all events of death, MACE, other selected CV events and other selected AEs. In 
addition, an independent DMC will collect, track and monitor information regarding the 
endpoints. The members, roles and responsibilities of the CEC and DMC will be described in a 
separate charter.
8.3.8
Guidelines for reporting product complaints
Any defect in the IMP/device must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a Product Complaint Form within required timelines.
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator
will assess whether or not the quality issue has to be reported together with an AE or SAE.
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8.4
TREATMENT OF OVERDOSE
Overdose is defined in Section 8.3. 
In the event of an overdose, the Investigator should:
1. Contact the Medical Monitor immediately.
2. Blood glucose levels, HR (telemetry) and liver enzymes should be monitored and 
appropriate supportive treatment should be initiated according to the patient’s clinical 
signs and symptoms.
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities.
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5
PHARMACOKINETICS
Pharmacokinetic parameters are not evaluated in this study.
8.6
PHARMACODYNAMICS
Pharmacodynamic parameters are not evaluated in this study.
8.7
GENETICS
Genetics are not evaluated in this study.
8.8
BIOMARKERS
Biomarkers are not evaluated in this study.
8.8.1
Immunogenicity assessments
Antibodies to efpeglenatide will be evaluated in serum samples collected from all participants 
according to the SoA (see Section 1.3). These samples will be tested by the Sponsor or Sponsor's 
designee.
Serum samples will be screened for antibodies binding to efpeglenatide and the titer of confirmed 
positive samples will be reported. Cross-reactivity of confirmed positive samples to endogenous 
GLP-1 (positive/negative), endogenous glucagon (positive/negative), neutralizing capacity of 
ADAs, and presence of anti-polyethylene glycol (PEG) antibodies (positive/negative) will also be 
evaluated in serum.
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Participants with positive ADA at the end of study, and who experienced severe injection site or 
hypersensitivity reaction at whatever time during the study, will be asked to provide a sample for 
anti-efpeglenatide antibodies assessments 4 and 6 months after the end of the treatment.
The detection and characterization of antibodies to efpeglenatide will be performed using a 
validated assay method by or under the supervision of the Sponsor.
8.9
HEALTH ECONOMICS
Health Economics and Health Economics parameters are not evaluated in this study.
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9
STATISTICAL CONSIDERATIONS 
9.1
STATISTICAL HYPOTHESES
The statistical hypothesis for the primary endpoint of 3-point MACE is to test that efpeglenatide is 
noninferior (1.8 and 1.3 margin) to placebo at the two-sided 5% alpha level:

H0: Hazard ratio of efpeglenatide versus placebo ≥1.8 vs. Ha: Hazard ratio of 
efpeglenatide versus placebo <1.8
and 

H0: Hazard ratio of efpeglenatide versus placebo ≥1.3 vs. Ha: Hazard ratio of 
efpeglenatide versus placebo <1.3
9.2
SAMPLE SIZE DETERMINATION 
It is estimated that approximately 4000 participants are needed to obtain approximately 
330 participants with a positively adjudicated event for the primary composite cardiovascular 
endpoint (3-point MACE), based on the following trial design characteristics assumptions:

a recruitment period of approximately 12 months 

Study duration is estimated to be approximately 24 months of  follow-up after the last 
randomized patient, estimated follow-up ranging from 24 to 36 months

2% annual early study discontinuation

Yearly event rate in placebo group: 4.4% for participants not  using a SGLT2 inhibitor, 
and 3.7% for participants using a SGLT2 inhibitor 

Treatment effect of efpeglenatide compared to placebo: 15% risk reduction for participants 
not using a SGLT2 inhibitor, and  a neutral effect for participants using a SGLT2 inhibitor

20% of participants using a SGLT2 inhibitor at baseline, and additional 10% participants 
in placebo group and 5% participants in efpeglenatide group adding a SGLT2 inhibitor 
during the study period
This will provide:

90% power to demonstrate NI of efpeglenatide vs placebo with a 1.3 NI margin {UB of 
the 95% CI of the estimated hazard ratio <1.3} for the 3-point MACE (CV death, non-fatal 
MI or non-fatal stroke)

>99% power to demonstrate NI with a 1.8 margin
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9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined (Table 6):
Table 6 - Populations for analyses
Population
Description
Screened
All participants who sign the ICF
Randomized
All screened participants who have a treatment kit number allocated and recorded in 
IRT DB, regardless of whether the treatment kit was used or not.
ITT
All randomized participants irrespective of compliance with the study protocol and 
procedures. Participants will be analyzed in the treatment group to which they are 
randomized.
Safety
All randomized participants who have received at least 1 dose of double-blind 
treatment, regardless of the amount of treatment administered. Participants will be 
analyzed for safety analyses according to the treatment actually received.
ADA
All participants from the safety population with at least 1 post-baseline valid ADA 
sample after drug administration 
ADA: anti-drug antibody; ICF: informed consent form; IRT: interactive response technology; ITT: intent to treat
9.4
STATISTICAL ANALYSES
The statistical analysis plan will be developed and finalized before DB lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.
9.4.1
Efficacy analyses
All efficacy analyses will be performed on the ITT population, unless otherwise specified.
Table 7 - Efficacy analyses
Endpoint
Statistical Analysis Methods
Primary
Time to the first occurrence of any of the 
following clinical events, positively 
adjudicated by the CEC:

CV death

Non-fatal MI

Non-fatal stroke
The time to the first occurrence of the primary composite CV endpoint event (CV 
death, non-fatal MI, or non-fatal stroke) will be analyzed using Cox proportional 
hazards model with treatment (efpeglenatide 4 mg, efpeglenatide 6 mg, placebo), 
region and randomization strata of current or potential future use of a SGLT2 
inhibitor (Current use, Potential future use, Neither current nor potential future 
use) as the covariates. Participants who receive either 4 mg or 6 mg of 
efpeglenatide will be combined as one efpeglenatide treatment group when 
making comparisons using appropriate contrast for the purposes of the primary 
analysis. The hazard ratio between pooled efpeglenatide and placebo will be 
estimated along with the associated two-sided 95%CI.
The NI with the 1.8 and 1.3 margin will be demonstrated on the primary endpoint 
if the UB of the two-sided 95% CI is <1.8 and 1.3, respectively.
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Endpoint
Statistical Analysis Methods
Kaplan-Meier curves of the cumulative incidence rate will also be provided by 
treatment groups.
All participants will be followed up to the Study Closeout Visit or death, whichever 
comes first. The primary analysis will be based on the ITT approach that includes 
events occurring from randomization to the end of study, even after the participant
has discontinued the study treatment. In the ITT approach, all randomized 
participants will be included and analyzed as randomized. 
The analysis will be based on the positively-adjudicated CV endpoint events. 
Time to the first occurrence of the primary CV event is the time from 
randomization to the first occurrence of cardiovascular death, non-fatal MI, or 
non-fatal stroke over the duration of the study (ie, randomization to the study end 
date inclusive). Participants who have not experienced any of these primary 
cardiovascular outcomes as positively adjudicated by the CEC during the study 
will be censored at the last date with available information on the CV outcomes on 
or before the study end date for the participant.
If the NI with the 1.8 and 1.3 margin is demonstrated on the primary endpoint, the 
superiority of pooled efpeglenatide vs placebo for the primary endpoint will be 
tested in a hierarchical fashion. The superiority will be claimed if the UB of the 
2-sided 95% CI of hazard ratio is less than 1. The p-value using the log-rank test 
will also be calculated.
Sensitivity analysis:
Sensitivity analyses will also be performed for the primary CV endpoint as 
appropriate, including the analyses that censor the events at the time a participant
starts treatment with a SGLT2 inhibitor (for participants who were not receiving an 
SGLT2 inhibitor at baseline) or stops treatment with a SGLT2 inhibitor (for 
participants who were already receiving an SGLT2 inhibitor at baseline).
Assessment of treatment effect by subgroup:
For the primary composite cardiovascular endpoint, the treatment effects across 
the following subgroup factors will be examined based on ITT population:

Gender (Male, Female)

Age group (<65 and ≥65 years of age).

Race (White, Black or African American, Asian/Oriental, and Other) 
(any race groups with fewer than 5 participants may be combined with 
"Other" category as appropriate).

Ethnicity (Hispanic, Not Hispanic) 

Duration of diabetes categories.

Use of SGLT2 inhibitor at baseline (Yes, No)
The Cox proportional hazards model will be used to estimate the treatment effect 
across the above subgroups, with treatment (efpeglenatide 4 mg, efpeglenatide 
6 mg, placebo), region, randomization strata of current or potential future use of a 
SGLT2 inhibitor (Current use, Potential future use, Neither current nor potential 
future use), subgroup factor, and treatment by subgroup factor interaction as the 
covariates. Hazard ratios between pooled efpeglenatide and placebo for 
categories from a subgroup factor in question will be estimated from this Cox 
model. The corresponding 95% CIs will be provided. Additional subgroups and 
analysis details will be provided in the statistical analysis plan.
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Endpoint
Statistical Analysis Methods
Secondary
Time to the first occurrence of any of the 
following clinical events, positively 
adjudicated by the CEC:

CV death

Non-fatal MI

Non-fatal stroke

Coronary revascularization

Hospitalization for unstable angina
Time to the first occurrence of any of the 
following clinical events:

New onset or progression to macro 
albuminuria (>300 mg/g) 
accompanied by a UACR value 
increase of ≥30% from Baseline

Sustained ≥40% decrease in 
eGFR from Baseline (for ≥30 days)

Chronic dialysis (for ≥90 days)

Renal transplant,

Sustained eGFR 
<15 mL/min/1.73 m2 (for ≥30 days)
The two secondary endpoints will be analyzed using the same Cox proportional 
hazards model as used for the analysis of primary endpoint.  The Cox model will 
include treatment (efpeglenatide 4mg, efpeglenatide 6 mg, placebo), region, and 
randomization strata of current or potential future use of a SGLT2 inhibitor 
(Current use, Potential future use, Neither current nor potential future use) as the 
covariates. The hazard ratio between pooled efpeglenatide and placebo will be 
estimated along with the associated two-sided 95%CI.
Tertiary/Exploratory
Will be described in the statistical analysis plan finalized before DB lock
9.4.1.1
Multiplicity adjustments
A hierarchical testing procedure will be used for adjustment of multiplicity for the testing of NI 
and superiority on the primary endpoint and in the analysis of the secondary endpoints to strongly 
control the overall Type-1 error rate at 0.05, with the hierarchy defined as:

Non-inferiority (1.8 and 1.3 margin) of efpeglenatide versus placebo on 3-point MACE 
(CV death, non-fatal MI or non-fatal stroke), and then Superiority of efpeglenatide versus 
placebo on 3-point MACE (CV death, non-fatal MI or non-fatal stroke)

Superiority of efpeglenatide versus placebo on time to the first occurrence of the expanded
cardiovascular outcome of cardiovascular death, non-fatal MI, non-fatal stroke, coronary 
revascularization, or  unstable angina

Superiority of efpeglenatide versus placebo on time to the first occurrence of any of the 
following clinical events: new onset or progression to macro albuminuria (>300 mg/g) 
accompanied by a UACR value increase of ≥30% from Baseline, sustained ≥40% decrease
in eGFR from Baseline (for ≥30 days), chronic dialysis (for ≥90 days) , renal transplant, 
sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days) 
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9.4.2
Safety analyses
All safety analyses will be performed on the Safety Population. 
The observation period of safety data is divided into 3 main segments:

The pre-treatment period is defined as the time from informed consent up to the time of 
the first injection of IMP

The on-treatment period is defined as the time from the first injection of IMP up to 
30 days after the last injection of IMP

The post-treatment period is defined as the time starting 31 days after the last injection of 
IMP (after the on-treatment period)
The AE observations will be classified per the observation periods of safety data as defined above 
into:

Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period

Treatment-emergent AEs are AEs that developed or worsened or became serious during 
the on-treatment period

Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period.
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately.
In addition to the on-treatment period, all AEs, SAEs, AEs leading to permanent treatment 
discontinuation, and AEs leading to death will be summarized for the on-study period, which is 
defined as the time from randomization up to the day of recorded end of study or last contact.  
Table 8 - Safety analyses
Endpoint
Statistical Analysis Methods
AE
SAE
AE leading to 
treatment 
discontinuation
AE leading to death
AESI
AE requiring 
specific monitoring
All AEs will be coded to a lowest level term (LLT), preferred term (PT), high level term (HLT), and high level 
group term (HLGT) and associated SOC using the version of MedDRA currently in use by the Sponsor at 
the time of DB lock.
Adverse event incidence tables will be presented by primary SOC (sorted by internationally agreed order), 
HLGT, HLT and PT (sorted in alphabetical order) for each treatment group, showing the number (n) and 
percentage (%) of participants experiencing an AE.
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all TEAEs, all 
treatment emergent SAEs, all TEAEs leading to permanent treatment discontinuation, all TEAEs leading to 
death, all AESI, and AE requiring specific monitoring.
Adverse event incidence table for all types of TEAE will also be provided by treatment group in the subsets 
of participants on the background therapy of metformin + SGLT2, and on metformin + sulfonylurea.
Vital signs and 
laboratory data
ECG 
For quantitative safety parameters based on central laboratory/reading measurements, descriptive statistics 
will be used to summarize results and change from Baseline values by visit and treatment group. 
The incidence of potentially clinically significant abnormalities (PCSA), defined as abnormal values 
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Endpoint
Statistical Analysis Methods
considered medically important by the Sponsor according to predefined criteria/thresholds based on 
literature review, will be summarized at any time during the on-treatment period.
Results will be presented both in standard international and conventional US units
The incidence of Normal and Abnormal ECG status at any time during the on-treatment period will be 
summarized by treatment group whatever the Baseline level and according to Baseline status.
Exploratory
Will be described in the statistical analysis plan finalized before DB lock
HLGT: higher-level grouped term; HLT higher-level term; LLT: lower-level term; PT preferred term; SOC: system organ class; TEAE treatment-
emergent adverse event
9.4.3
Other analyses 
Exploratory analyses will be described in the statistical analysis plan finalized before DB lock.
9.5
INTERIM ANALYSES 
There is no interim analysis planned. 
9.5.1
Data Monitoring Committee (DMC)
See Appendix 1 (Section 10.1.4) for details. 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS
10.1.1 Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
-
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
-
Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
-
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The Investigator will be responsible for the following:
-
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
-
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2 Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 
21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
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Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant. 
A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within the screening window (ie within 1 week of the previous screening).
10.1.3 Data Protection

Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 

The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

Participants’ race and ethnicity (race: Asian, Black or African American, White, Other not 
reported, Unknown; ethnicity: Hispanic, Not Hispanic) will be collected in this study 
because these data are required by several regulatory authorities (eg, on African American 
population for US FDA). 

The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). 
They may be further processed if they have been anonymized.
10.1.4 Committees Structure
10.1.4.1 Steering Committee
The Steering Committee is responsible for providing study oversight. In this capacity, the 
Steering Committee shall address and resolve scientific issues encountered during the study. The 
Steering Committee is also responsible for ensuring accurate reporting of the study results.
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10.1.4.2 Data Monitoring Committee
An independent DMC with members who are independent from the Sponsor and the Investigators 
will meet on a regular basis and will be responsible for:

Review of accumulating clinical study safety data, and

Making a recommendation to the Sponsor regarding the study following each meeting
The DMC reviews and analyzes, on a regular basis, unblinded safety data throughout the study, as 
well as safety data from the other ongoing clinical studies conducted with efpeglenatide (a single 
DMC for the whole efpeglenatide program). Details describing the DMC processes and 
procedures are outlined in the DMC Charter. To maintain continuous blinding and study integrity, 
the analysis will be conducted by an independent statistician who will directly transfer data to 
DMC members, and measures will be taken to ensure the validity of the data.
10.1.4.3 Clinical Endpoint Committee
An independent CEC will be composed of experts in the field of cardiology, neurology, and 
gastroenterology (and other appropriate medical specialties as needed). This committee will be 
independent from the Sponsor and the Investigators, and will be implemented to review, assess 
and/or adjudicate all events of death, selected CV events (non-fatal MI, stroke, unstable angina 
leading to hospitalization, and heart failure leading to hospitalization), pancreatic events and other 
selected AEs (to be defined in the CEC charter). This review will be conducted in a blinded 
manner with regard to study treatment.
10.1.4.4 Independent Expert 
An independent ophthalmologist expert will review in a treatment-blinded manner all reported 
AEs suspected to be diabetic retinopathy to assess the presence of retinopathy and the relationship 
of reported AE to IMP.
Investigators are reminded that all patients should have eye examinations based on their 
retinopathy status, performed by a professional eye care provider according to International 
Council of Ophthalmology (ICO) guidelines (19) or local standards. Especially for patients at high 
risk, this should occur at minimum quarterly.
10.1.5 Dissemination of Clinical Study Data
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, European Union clinicaltrialregister (eu.ctr), and sanofi.com, 
as well as some national registries.
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
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publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com.
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials.  Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com.
10.1.6 Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 

The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor. 
10.1.7 Source documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in a separate study document.
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10.1.8 Study and Site Closure
The Sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the Investigator

Discontinuation of further study intervention development
10.1.9 Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.

The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS
The tests detailed in Table 9 will be performed by the central laboratory. 

Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be entered into 
the CRF.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations.
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Table 9 - Protocol-required safety laboratory assessments
Laboratory 
assessments
Parameters
Hematology
Platelet count
Red blood cell (RBC) count
White blood cell (WBC) count
Hemoglobin
Hematocrit
RBC indices:
Mean Corpuscular Volume 
(MCV)
Mean Corpuscular 
Hemoglobin (MCH)
%Reticulocytes
White blood cell (WBC) count with 
differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical chemistrya
Uric acid
Potassium
Aspartate 
aminotransferase (AST
Total bilirubinb
Glucose (non-fasting)
Sodium
Alanine aminotransferase
(ALT)
Creatinine
Amylase
Lipase
Calcitonin
Alkaline phosphatase
Estimated creatinine 
clearance
Lipid profile
Triglyceride(non-fasting)
Cholesterol:
Total cholesterol
Low-density lipoprotein cholesterol
High-density lipoprotein cholesterol
Anti-drug antibodies

Treatment boosted and treatment induced ADA

ADAs cross-reacting to endogenous glucagon

ADAs directed against the PEG linker of efpeglenatide
Routine urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, leukocyte

Microscopic examination (if blood or protein is abnormal)
Other urinalysis

Urinary albumin-to-creatinine ratio by spot urine
Other screening tests

Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only)

Serum human chorionic gonadotropin (HCG) pregnancy test (as needed for women of 
childbearing potential)c

Serology (hepatitis B surface antigen [HBsAg], and hepatitis C virus antibody) 
The results of each test will be transferred from Central Laboratory in the Clinical Database
NOTES :
a
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are given 
in Appendix 5 (Section 10.5). All events of ALT 3 × upper limit of normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or 
ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law) must 
be reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
b
In case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin
c
Urine pregnancy testing will be performed subsequent to Screening. If the urine test is positive, serum β-HCG should be tested for 
confirmation of the pregnancy
Investigators must document their review of each laboratory safety report.
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10.3
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
DEFINITION OF AE
AE definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE.
Events NOT meeting the AE definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.
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
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a) Results in death
b) Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c) Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d) Results in persistent disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e) Is a congenital anomaly/birth defect
f)
Other situations:
-
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
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the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
RECORDING AND FOLLOW-UP OF AE AND/OR SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the Investigator to review all
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.

The Investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative.

The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories:

Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Assessment of causality

The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.
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
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention
administration will be considered and investigated.

The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative.

The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

New or updated information will be recorded in the originally completed CRF.

The Investigator will submit any updated SAE data to the the Sponsor’s representative
within 24 hours of receipt of the information.

Please refer to Section 8.3.3 for more details.
REPORTING OF SAES
SAE reporting to the Sponsor’s representative via an electronic data collection tool

The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool.

If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper SAE data collection tool (see next section).

The site will enter the SAE data into the electronic system as soon as it becomes available.
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
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone.
-
Contacts for SAE reporting can be found in a separate study document.
10.4
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION
DEFINITIONS:
Woman of childbearing potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient. 
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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CONTRACEPTION GUIDANCE
Female participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10
during the treatment period and for at least 5 weeks after the last dose of study treatment.
In addition, WOCBP must refrain from donating ova for the duration of the study and at least 
5 weeks after last dose of study treatment.
Table 10 - Highly effective contraceptive methods
Highly effective contraceptive methods that are user dependenta
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation

Oralb

Intravaginal 

Transdermal
Progestogen only hormonal contraception associated with inhibition of ovulation

Oralb

Injectable
Highly effective methods that are user independenta

Implantable progestogen only hormonal contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used.
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant.
NOTES: 
a
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies. 
b
Pharmacokinetic drug interaction potential of oral hormonal contraception with the study treatment is low, but still unknown. Therefore, if the 
oral contraceptive cannot be replaced by another highly effective method of contraception, with a different route of administration, the 
hormonal contraception method must be supplemented with a male condom (for partner) during the treatment period and for at least 5 
weeks after the last dose of study treatment..
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PREGNANCY TESTING:

WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test.

Additional pregnancy testing should be performed as displayed in the SoA in Section 1.3
and as required locally.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected
COLLECTION OF PREGNANCY INFORMATION:
Male participants with partners who become pregnant 

The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive IMP.

After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be for at least one year following the estimated delivery date. 
Any termination of the pregnancy will be reported regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 

The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
be for at least one year beyond the estimated delivery date. Any termination of pregnancy 
will be reported, regardless of fetal status (presence or absence of anomalies) or indication 
for the procedure.

Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to
the study intervention by the Investigator will be reported to the Sponsor as described in
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 

Any female participant who becomes pregnant while participating in the study will
discontinue study intervention
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10.5
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Appendix 3 (Section 10.3) is met.
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Appendix 3 (Section 10.3) is met.
Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
Note:

“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening.

See Section X for guidance on safety reporting.

Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN.
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If any of the above conditions are met, the Investigator should take corrective measures to resolve 
and schedule an interim visit to evaluate the serum creatinine/GFR and the patient’s clinical status 
Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
INCREASE IN SERUM CREATININE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
investigational medicinal product by 
renal route
1.
Investigational medicinal 
product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
investigational medicinal product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
the beginning, then every week)
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1 week from the institution of corrective measures. Patients with a suspected renal event 
(reduction of eGFR) should have a repeat assessment of renal function 30 to 45 days following the 
onset of the event to confirm it is sustained. If acute renal failure is suspected, further clinical 
evaluation should be performed as per local standard of care, including confirmation of renal 
laboratory parameters, and consideration should be given to a nephrology referral. 
Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting adverse events in Appendix 3 (Section 10.3) is met.
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Appendix 3 (Section 10.3) is met.
If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie, stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE investigational 
medicinal product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
INCREASE IN CPK SUSPECTED TO BE OF NON-CARDIAC ORIGIN 
AND NOT RELATED TO INTENSIVE PHYSICAL ACTIVITY
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10.6
APPENDIX 6: MONITORING AND MANAGEMENT OF PARTICIPANTS WITH 
INCREASED LIPASE AND/OR AMYLASE, OR CALCITONIN
10.6.1 Monitoring of participants with increased lipase and/or amylase >2 ULN
GLP-1 RAs stimulate pancreatic beta-cell and suppress alpha-cell function. Some cases of acute 
pancreatitis have been reported with marketed GLP-1 RAs. Therefore participants enrolled in this 
study should be closely monitored for any suspected pancreatitis, eg, with symptoms and/or signs 
of acute abdominal distress or abnormal levels of pancreatic enzymes. Serum amylase and lipase 
concentrations are monitored routinely at Screening, Baseline and periodically during the study 
treatment period. 
In the presence of clinical signs and/or symptoms evocative of pancreatitis, eg, persistent 
abdominal pain, which can radiate to the back, often with characteristic positional features, with 
possible occurrence of nausea, vomiting, fever and leucocytosis, further measurement of amylase 
and lipase should be performed. The clinical signs and/or symptoms should be documented in the 
source data.
10.6.2 Elevation of amylase and/or lipase >2 x ULN without clinical signs and/or symptoms
In any case where amylase and/or lipase are >2 x ULN, a retest (centrally assessed as far as 
possible) must be performed as follows:

If value(s) is/are >2 to 3 x ULN: retest within 7 days,

If value(s) is/are >3 x ULN: retest within 48 hours,

If the value(s) remain(s) >2 x ULN upon retesting: amylase and/or lipase levels should be 
retested weekly until values are <2 x ULN.
In case a retest is >2 x ULN a gastroenterological evaluation and imaging (ultrasound and/or 
computed tomography [CT] or magnetic resonance imaging [MRI] with contrast, as appropriate) 
must be performed. The absence of clinical signs and/or symptoms should be documented in the 
source documents (if clinical signs and/or symptoms develop, please see Section 10.6.3 below).
Best clinical judgment is to be used when interpreting elevated serum amylase and lipase levels in 
asymptomatic participants. Temporary discontinuation of the IMP may be considered in these 
cases if deemed necessary by the Investigator.
10.6.3 Elevation of amylase and/or lipase >2 x ULN with clinical signs and/or symptoms.
In the presence of clinical signs and/or symptoms evocative of pancreatitis (as described above) 
associated with elevated amylase and/or lipase, treatment with the IMP should be promptly and at 
least temporarily discontinued pending further clinical evaluation and diagnosis confirmation. 
Clinical signs and/or symptoms are to be documented in the source data. A laboratory 
determination of amylase and lipase must be obtained at the time of the event and again within 
48 hours or earlier as clinically indicated. If the value(s) remain(s) >2 x ULN, then amylase and/or 
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lipase levels should be retested as described in Section 10.6.2 above, or more often if clinically 
indicated.
A gastroenterologic evaluation and imaging (ultrasound and/or CT or MRI with contrast, as 
appropriate) must be performed as clinically indicated and as per clinical practice and local 
guidelines. If a diagnosis of pancreatitis is confirmed, IMP should not be restarted and should be 
permanently discontinued. In both cases as described above under (1) and (2), all laboratory or 
clinical documentations are to be collected. If the retest confirms lipase and/or amylase values are 
>2 ULN , the event must be reported in the e-CRF on the AE form  and the specific 
complementary forms, using the appropriate verbatim: eg, “increased amylase and/or lipase” in 
case of isolated enzyme elevation, “suspected pancreatitis” in the presence of clinical signs 
evocative of pancreatitis if the diagnosis is suspected but cannot be confirmed or excluded, and 
“pancreatitis” if the diagnosis has been confirmed.
10.6.4 Management of participants with increased calcitonin values
During the course of the study if calcitonin value is found ≥20 pg/mL (5.9 pmol/L): 

A retest should be performed by the central laboratory within 7 days. 

The following is to be collected and recorded as soon as possible:
-
Conditions other than C cell disease which may increase calcitonin levels, such as: 
smoking status, treatment with proton-pump inhibitor (eg, omeprazole), autoimmune 
thyroid diseases (Hashimoto’s thyroiditis or Grave’s disease), differentiated thyroid 
cancer, hypercalcemia, hypergastrinemia, chronic renal insufficiency (not on dialysis), 
other neuro-endocrine tumors (lung small cell carcinoma, intestinal carcinoid), acute 
pulmonary inflammatory conditions, or sepsis
-
Personal and/or familial medical history in relation with thyroid or other endocrine 
diseases
-
Specific physical examination (neck, thyroid gland)
If the retest confirms that calcitonin value is ≥20 pg/mL: 

The event must be reported in the e-CRF on the AE form with all appropriate clinical and 
laboratory documentations. 

An ultrasound scan of thyroid should be performed and the participant may be referred to 
a Specialist if judged necessary.

The participant should continue to be followed according to protocol schedule (including 
planned calcitonin measurements). The AE form  should be updated with any new 
information collected during the follow up.

If calcitonin value ≥50 pg/mL (14.75 pmol/L) is found at any time during further follow 
up, the participant should be permanently discontinued from IMP and referred to a 
specialist. As far as possible, blood should be collected 1 to 2 weeks after IMP 
discontinuation and sent to the central laboratory for calcitonin measurement. As per 
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protocol, the participant should be followed according to study procedures up to the 
scheduled end of the study.
If at any time during follow-up calcitonin value ≥20 pg/mL increases by 20% or more between 
2 assessments (while remaining below 50 pg/mL), a repeated measurement should be performed 
earlier than scheduled in the protocol, ie, 1 month later. Once results are available, discussion with 
Sponsor representative should be initiated without delay for further guidance.
10.7
APPENDIX 7: GUIDANCE FOR THE FOLLOW-UP OF ACUTE WORSENING OF 
RENAL FUNCTION
Rapid change in renal function of greater than 30% as compared with the mean of the prior two 
study visits 

Evaluate if the patient is taking medications which alter serum creatinine such as: 
trimethoprim, fenofibrate, non-steroidal anti-inflammatory agents, cimetidine, 
cephalosporins, probenecid, aminoglycosides, amphotericin, ketoconazole, clofibrate, 
contrast agents

Evaluate if any of the following conditions are present that may alter serum creatinine:
-
Significant increase or decrease in BP due to changes in antihypertensive therapy or 
diuretic treatment
-
Plasma volume depletion or expansion
-
Flu-like symptoms
-
Infected urine
-
Obstructive uropathy
-
New onset or exacerbation of heart failure

If any of the above conditions are met, the Investigator should take corrective measures to 
resolve and schedule an interim visit to evaluate the serum creatinine/GFR and the 
patient’s clinical status 1 week from the institution of corrective measures. Patients with a 
suspected renal event (reduction of eGFR) should have a repeat assessment of renal 
function 30 to 45 days following the onset of the event to confirm it is sustained. If acute 
renal failure is suspected, further clinical evaluation should be performed as per local 
standard of care, including confirmation of renal laboratory parameters, and consideration 
should be given to a nephrology referral. 

Permanent discontinuation of IMP should be a last resort, and if IMP needs to be withheld, 
it should be done so temporarily when possible.
10.8
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS 
Not applicable.
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10.9
APPENDIX 9: ABBREVIATIONS
ADA:
anti-drug antibody
AE:
adverse event
AESI:
adverse event of special interest
ALP:
alkaline phosphatase
ALT:
alanine aminotransferase
AST:
aspartate aminotransferase
BP:
blood pressure
CABG:
coronary artery bypass graft
CAD:
coronary artery disease
CEC:
clinical endpoint committee
CFR:
Code of Federal Regulations
CI:
confidence interval
CIOMS:
Council for International Organizations of Medical Sciences
CONSORT:
Consolidated Standards of Reporting Trials
CT:
computed tomography
CV:
cardiovascular
CVD:
cardiovascular disease
CVOT:
cardiovascular outcome trial
DB:
database
DBP:
diastolic blood pressure
DMC:
Data Monitoring Committee
DME:
diabetic macular edema
DPP4:
dipeptidyl peptidase-4
ECG:
electrocardiogram
e-CRF:
electronic case report form
eGFR:
estimated glomerular filtration rate
EMA:
European Medicines Agency
FDA:
Food and Drug Administration
FSH:
follicle stimulating hormone
GCP:
good clinical practice
GI:
gastrointestinal
GLP-1:
glucagon-like peptide-1
HbA1c:
glycated hemoglobin A1c
HBsAg:
hepatitis B surface antigen
HCAb:
hepatitis C antibody
HCG:
human chorionic gonadotropin
HDL:
high density liporotein
HHF:
hospitalization for heart failure
HIPAA:
Health Insurance Portability and Accountability Act
HLGT:
high level group term
HLT:
high level term
HR:
heart rate
HRT:
hormonal replacement therapy
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IB:
investigator's brochure
ICF:
informed consent form
ICH:
International Conference on Harmonisation
IEC:
Independent Ethics Committee
IMP:
investigational medicinal product
IRB:
Institutional Review Board 
IRT:
interactive response technology
ITT:
intent-to-treat
IUD:
intrauterine device
IUS:
intrauterine hormone-releasing system
LDL:
low density lipoprotein
LLT:
lowest level term
MACE:
major adverse cardiac events
MCH:
mean corpuscular hemoglobin
MCV:
mean corpuscular volume
MDRD:
modification of diet in renal disease
MI:
myocardial infarction
MRI:
magnetic resonance imaging
MTC:
medullary thyroid cancer
NI:
noninferiority
NOAEL:
no observed adverse effect level
NPDR:
non proliferative diabetic retinopathy
NYHA:
New York Heart Association
PAD:
peripheral arterial disease
PCI:
percutanous coronary intervention
PCSA:
potentially clinically significant abnormalities
PDR:
proliferative diabetic retinopathy
PEG:
polyethylene glycol
pEOT:
premature end of treatment
PFS:
prefilled syringe
PT:
preferred term
QW:
once per week
R:
randomization
RA:
receptor agonist
RBC:
red blood cell
SAE:
serious adverse event
SBP:
systolic blood pressure
SC:
subcutaneous
SGLT2:
sodium-glucose linked transporter-2
SmPC:
summary of product characteristics
SoA:
schedule of activities
SOC:
system organ class
SUSAR:
suspected unexpected serious adverse reaction
T2DM:
type 2 Diabetes Mellitus
TEAE:
treatment-emergent adverse event
UACR:
urinary albumin-creatinine ratio
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UB:
upper bound
ULN:
upper limit of normal
US:
United States
WBC:
white blood cell
WOCBP:
woman of childbearing potential
10.10
APPENDIX 10: PROTOCOL AMENDMENT HISTORY
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
Amended protocol 01 (28 May 2018)
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
OVERALL RATIONALE FOR THE AMENDMENT
Health Authorities’ in Canada and Germany requested to update sections related to women of 
childbearing potential (WOCBP) participation, follow-up, and contraception. In addition, Sanofi 
uses this opportunity to edit other sections of the protocol, to update text with new available 
information, to align the procedures with those in other studies within the program and/or for 
better clarity. Main changes are listed below.
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Protocol amendment summary of changes table
Section # 
and Name
Description of Change
Brief Rationale
Section 5.1 
Inclusion 
Criteria and 
Section 10.4 
Appendix 4 
Contraceptive 
guidance and 
collection of 
pregnancy 
information
Clarification of the contraception requirements for 
male and woman of childbearing potential 
(WOCBP): contraception for male participants not 
required, ova donation restrictions added, change 
in contraceptive methods to be used for WOCBP, 
follow-up of pregnancy extended to one year
Efpeglenatide was not genotoxic, and a fertility and early 
embryonic development study in rats revealed no effect 
on male and female fertility and mating performance. 
Furthermore exposure at risk to induce embryo-fetal 
toxicity in female partners of male subjects taking 
efpeglenatide after transfer via seminal fluid can be 
excluded based on an exposure assessment performed 
according to methods proposed by Banholzer et al. (20) 
and an FDA guidance of 2015 (21) based on numerous 
parameters such as exposure at no observed adverse 
effect level (NOAEL) in embryo-fetal studies in two animal 
species, cumulated dose administered vaginally and 
resulting female exposure.  
Using worst case assumptions for these factors a safety 
margin of approximately 1800 between exposure at 
NOAEL in the most sensitive species and estimated 
exposure in females after contamination with 
efpeglenatide via seminal fluid was calculated. Therefore 
use of condoms to avoid this contamination of female 
partners of male subjects taking efpeglenatide is 
considered as not required in clinical trials.
WOCBP use contraception for the duration of the study 
and at least 5 weeks after last dose of study treatment, 
based on the reproductive toxicity profile of efpeglenatide. 
Since the potential fetal toxicity of efpeglenatide can 
extend to ova, WOCBP must refrain from donating ova for 
the duration of the study and at least 5 weeks after last 
dose of study drug (based on half-life of efpeglenatide). 
Contraceptive methods in Table 11 were updated based 
on the clarification that hormonal contraception drug 
interaction potential with the study treatment is low, but 
still unknown. Therefore, if the oral contraceptive cannot 
be replaced by another highly effective method of 
contraception, with a different route of administration, the 
hormonal contraception method must be supplemented 
with a male condom (for partner) during the treatment 
period and for at least 5 weeks after the last dose of study 
treatment. 
The section entitled, “Collection of pregnancy information” 
the duration of follow- up for the pregnancy was extended 
to one year to be consistent with the informed consent 
form (ICF)
Section 8.3.7 
Disease-
related events 
and other 
events not 
qualifying as 
AEs or SAEs
Clarification was added on reporting rules for the 
endpoints when they are considered per 
Investigators as Investigational Medicinal Product 
(IMP)-related
To clarify the rules of reporting of IMP-related endpoints to 
Sponsor
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Section # 
and Name
Description of Change
Brief Rationale
10.3 
Appendix 3: 
Adverse 
events: 
definitions 
and 
procedures 
for recording, 
evaluating, 
follow-up, and 
reporting
Lack of efficacy will not be reported as an adverse 
event (AE) but signs, symptoms and/or sequelae 
resulting from lack of efficacy will be reported if 
they fulfil the definition of an AE or serious adverse 
event (SAE)
Clarification done to comply with the Sponsor’s reporting 
standard
Section 5.1 
Inclusion 
Criteria and 
Section 5.2 
Exclusion 
Criteria
Clarifications on Inclusion Criterion I03 and 
Exclusion Criteria E09, E10, E12, and E14:
I03. Typo error corrected: 9 cardiovascular disease 
criteria instead of 8
E09. Exclusion of patients with hypersensitivity to 
any glucagon-like peptide-1 (GLP-1) receptor 
agonist (RA)
E10. Wording correction, as should state “…within 
6 months prior to randomization” rather than 
“screening”
E12. Clarifications added 
E14. Clarification that prior treatment with GLP1 
RAs is not allowed either alone or in combination
E17 and E21 were removed 
Clarifications for I03 and E10.
E09. Clarification added to exclude the hypersensitivity to 
any GLP-1 RA as well
E12 was amended to provide more details and clarify the
patients’ eligibility criteria.
E14 was amended to clarify that GLP-1 RAs either alone 
or in combination are forbidden as prior treatment. 
E17 was removed since this cardiovascular outcome trial 
(CVOT) is not a glycemic control trial: the addition of 
glucocorticoids will not affect a primary or secondary 
endpoint and therefore is not needed as an exclusion 
criterion. 
E21 was redundant with E24
Section 1.1 
Synopsis, 
Section 3 
objectives 
and 
Endpoints, 
and Section 
9.4.3 Other 
Analyses
Change in wording of anti-drug antibody endpoints 
and removal of percentages from endpoints
To align endpoints’ wording within the efpeglenatide 
program
Section 9.4.2 
Safety 
Analyses
All AEs, SAEs, AEs leading to permanent treatment 
discontinuation, and AEs leading to death will be 
summarized for the on-study period
Type of AEs to be summarized during the on-study period, 
as well as the definition, were clarified
Section 2.3 
Benefit/Risk 
Assessment
Section rearranged for better clarity; diabetic 
retinopathy complications removed from exceptions 
to the known adverse events profile of currently 
marketed GLP-1 RAs 
No case of diabetic retinopathy complication has been 
reported for efpeglenatide
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Section # 
and Name
Description of Change
Brief Rationale
Section 1.3 
Schedule of 
Activities 
(SoA) and 
Section 6.1 
Study 
intervention(s) 
administered
Allowing the combination of Visit 2 and Visit 3, as 
per Investigator’s judgment according to the 
patient’s medical profile; the minimal time window 
of 2 weeks between screening visit and 
randomization has been removed and replaced 
with a maximum time window of 3 weeks + 3 days
To allow, in some cases and as per investigator’s 
judgment, Visit 2 to be combined with Visit 3; clarification 
added for time window
Section 6.5 
Concomitant 
Therapy
Dosage information removed from list of 
information collected for concomitant medications
Treatment with GLP1 RAs is not allowed either 
alone or in combination
Additional GLP-1 RAs: added lixisenatide, 
albiglutide and semaglutide to the following 
sentence for completion: “Any GLP-1 receptor 
agonist, eg, exenatide, liraglutide, dulaglutide”
Other therapy (drugs with a narrow therapeutic 
window) were added
This information is not collected
To be consistent with E14
Lixisenatide, albiglutide, and semaglutide have been 
approved by the health authorities
To harmonize with the Investigator’s Brochure
Section 7.3 
Lost to Follow 
Up
Removed that unreachable patients are considered 
withdrawn from study
In accordance with the Sponsor’s management of lost to 
follow-up patients
Section 1.3 
Schedule of 
Activities 
(SoA) 
Clarification on note related to the ophthalmologic 
exam with fundoscopy
Monthly home urine pregnancy tests added
To clarify that documented ophthalmologic examination 
with fundoscopy is to be available within 6 months prior to 
randomization
To comply with Clinical Trial Facilitation Group 
recommendations related to pregnancy testing in clinical 
trials (22)
Section 
10.1.3 Data 
protection
Text related to participants race and ethnicity 
collection added
In compliance with privacy regulations and given that 
these data are collected in the study
Section 8.2.5 
Severe 
hypoglycemia 
and 
Section 11 
References 
New reference on hypoglycemia added
New reference available
Section 6.3 
Measures to 
minimize bias: 
randomization 
and blinding
“The bioanalyses will be unblinded” has been 
deleted
It is already mentioned in the paragraph above that only 
the Project Manager and lead scientist at Bioanalytical 
laboratory will have access to randomization code
Section 8.2.4 
Clinical safety 
laboratory 
assessments
Text on use of local laboratory results has been 
changed
Rewording  done to provide better clarity on recording of 
local laboratory results
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Section # 
and Name
Description of Change
Brief Rationale
Section 10.2 
Appendix 2: 
Clinical 
Laboratory 
Tests
The results of protocol-required safety laboratory 
assessments (done by the Central laboratory):
tests will be transferred from Central Laboratory in 
the Clinical Database
These results are not entered into the case report form 
(CRF)
Section 
10.1.4.1 
Steering 
Committee
Clarification on role of Steering Committee
Clarification
Section 
10.1.4.4. 
Independent 
Expert 
Committee
The word “Committee” was removed from the 
heading
A single independent expert will review
Throughout
Minor editorial and document formatting revisions
Minor, therefore have not been summarized
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11
REFERENCES
1. US Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry: Diabetes Mellitus —
Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. 2008 
Dec.
2. European Medicines Agency, 2015 Committee for Medicinal Products for Human Use 
(CHMP). Reflection paper on assessment of cardiovascular safety profile of medicinal 
products. 2016 Feb 25;EMA/CHMP/50549.
3. Plutzky J. The incretin axis in cardiovascular disease. Circulation. 2011 Nov 22;124(21):2285-
89.
4. Ryn D, Aacosta A. GLP-1 receptor agonists: Nonglycemic clinical effects in weight loss and 
beyond. Obesity. 2015 Jun;23(6):1119-29.
5. Sivertsen J, Rosenmeier J, Holst JJ, Vilsbøll T. The effect of glucagon-like peptide 1 on 
cardiovascular risk. Nat Rev Cardiol. 2012 Jan 31;9(4):209-22.
6. Investigator's Brochure, SAR439977, Ed. 8, 13 October 2017.
7. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. 
Liraglutide and cardiovascular outcomes in Type 2 Diabetes.  N Engl J Med. 2016 Jul 
28;375(4):311-22.
8. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in 
patients with Type 2 Diabetes and acute coronary syndrome. N Engl J Med. 2015 Dec 
3;373(23):2247-57.
9. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and 
cardiovascular outcomes in Type 2 diabetes.  N Engl J Med. 2016 Nov 10;375(19):1834-44.
10. Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of 
once-weekly exenatide on cardiovascular outcomes in Type 2 Diabetes. N Engl J Med. 2017 
Sep 28;377(13):1228-39.
11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, 
cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015 Nov 
26;373(22):2117-28.
12. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin 
and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017 Aug 
17;377(7):644-657.  doi: 10.1056/NEJMoa1611925. [Epub ahead of print]
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13. US Food and Drug Administration. FDA approves Jardiance to reduce cardiovascular death in 
adults with type 2 diabetes [cited 2016 Dec]. Available from: 
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm531517.htm.
14. Novo Nordisk. Victoza® (liraglutide) is approved in the US as the only type 2 diabetes 
treatment indicated to reduce the risk of three major adverse cardiovascular events [cited Sep 
2017]. Available from: http://press.novonordisk-us.com/2017-08-25-Victoza-R-liraglutide-is-
approved-in-the-US-as-the-only-type-2-diabetes-treatment-indicated-to-reduce-the-risk-of-
three-major-adverse-cardiovascular-events.
15. Boehringer Ingelheim International GmbH. Jardiance European Union Summary of Product 
Characteristics. October 2017.
16. Novo Nordisk A/S. Victoza European Union Summary of Product Characteristics. September 
2017.
17. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2005 May;28(5):1245-9.
18. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes A report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013 May;36(5):1384-95.
19. International Council of Ophthalmology. ICO Guidelines for Diabetic Eye Care [cited 2018 
Jan 10]. Available from: 
http://www.icoph.org/downloads/ICOGuidelinesforDiabeticEyeCare.pdf.
20. Banholzer ML, Wandel C, Barrow P, Mannino M, Schmitt G, Guérard M, et al. Clinical trial 
considerations on male contraception and collection of pregnancy information from female 
partners: update. Clin Transl Med 2016; 5:23.
21. US Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER). Guidance for Industry: Nonclinical Evaluation of 
Endocrine-Related Drug Toxicity. 2015 Sep.
22. Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. September 2014. 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed 
25 May 2018.
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFC14828 16.1.1 Amendment 02

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
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According to template: QSD-002643 VERSION 7.0 (20-FEB-2019) 
Page 1 
STATISTICAL ANALYSIS PLAN 
A Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study 
to Evaluate the Effect of Efpeglenatide on Cardiovascular Outcomes in Type 2 
Diabetes Patients at High Cardiovascular Risk  
EFC14828 (AMPLITUDE-O) 
SAR439977 (efpeglenatide) 
STATISTICIAN: 
 
DATE OF ISSUE: 12-Aug-2020 
Total number of pages: 
60 
NCT03496298


Statistical Analysis Plan  
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.2.3 
Tertiary/Exploratory objectives ......................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 10 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 10 
2.1.1 
Study completer: subjects completed study closeout visit (in person or by phone) or has 
died while in study  Demographic and baseline characteristics .................................................... 10 
2.1.2 
Prior or concomitant medications ................................................................................................... 12 
2.1.3 
Efficacy endpoints .......................................................................................................................... 13 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 14 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 14 
2.1.3.3 
Exploratory efficacy endpoint(s) ..................................................................................................... 15 
2.1.4 
Safety endpoints ............................................................................................................................ 15 
2.1.4.1 
Adverse events variables ............................................................................................................... 16 
2.1.4.2 
Deaths ............................................................................................................................................ 17 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 18 
2.1.4.1 
Vital signs variables ....................................................................................................................... 18 
2.1.4.2 
Electrocardiogram variables .......................................................................................................... 18 
2.1.5 
Immunogenicity endpoints ............................................................................................................. 19 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 19 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 21 


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2.2.2 
Analysis populations ...................................................................................................................... 21 
2.2.3 
Efficacy populations ....................................................................................................................... 21 
2.2.3.1 
Intent–to-treat population ............................................................................................................... 21 
2.2.4 
Safety population ........................................................................................................................... 22 
2.2.5 
ADA population .............................................................................................................................. 22 
2.3 
STATISTICAL METHODS ............................................................................................................. 22 
2.3.1 
Demographics and baseline characteristics .................................................................................. 23 
2.3.2 
Prior or concomitant medications ................................................................................................... 23 
2.3.3 
Extent of investigational medicinal product exposure .................................................................... 24 
2.3.3.1 
Extent of investigational medicinal product exposure .................................................................... 24 
2.3.4 
Analyses of efficacy endpoints ....................................................................................................... 24 
2.3.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 25 
2.3.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 30 
2.3.4.3 
Exploratory efficacy analyses ........................................................................................................ 30 
2.3.4.4 
Multiplicity issues ........................................................................................................................... 31 
2.3.5 
Analyses of safety data .................................................................................................................. 31 
2.3.5.1 
Analyses of adverse events ........................................................................................................... 32 
2.3.5.2 
Deaths ............................................................................................................................................ 35 
2.3.5.3 
Analyses of laboratory variables .................................................................................................... 36 
2.4.4.1 
Analyses of vital sign variables ...................................................................................................... 37 
2.4.4.2 
Analyses of electrocardiogram variables ....................................................................................... 38 
2.4.5 
Analyses of immunogenicity variables ........................................................................................... 38 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 38 
2.4.7 
Analyses of quality of life/health economics variables ................................................................... 38 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 39 
2.5.1 
General conventions ...................................................................................................................... 39 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 39 
2.5.3 
Missing data ................................................................................................................................... 39 
2.5.4 
Windows for time points ................................................................................................................. 42 
2.5.5 
Unscheduled visits ......................................................................................................................... 42 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 42 
2.5.7 
Statistical technical issues ............................................................................................................. 42 
3 
INTERIM ANALYSIS ..................................................................................................................... 43 
4 
DATABASE LOCK ........................................................................................................................ 44 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 45 
6 
REFERENCES ............................................................................................................................... 46 
7 
LIST OF APPENDICES ................................................................................................................. 47 


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APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 48 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 52 
APPENDIX C 
CALCULATION/DERIVATION DETAILS OF TIME-TO-EVENT EFFICACY/SAFETY 
ENDPOINTS .................................................................................................................................. 54 
APPENDIX D 
SAMPLE SAS® CODE FOR SUPPORTIVE ANALYSES FOR MISSING DATA OF 
PRIMARY EFFICACY ENDPOINT ................................................................................................ 57 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
BMI: 
body mass index 
BP: 
blood pressure 
CABG: 
coronary artery bypass graft 
CEC: 
Clinical Endpoint Committee 
CV: 
cardiovascular 
GI: 
gastrointestinal 
HbA1c: 
hemoglobin A1c 
hectic f: 
estimated glomerular filtration 
HHF: 
hospitalization for heart failure 
HLGT: 
high-level group term 
HLT: 
high-level term 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
LLT: 
lower-level term 
MACE: 
major adverse cardiac events 
MDRD: 
Modification of Diet in Renal Disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
Myocardial infarction 
NI: 
non-inferiority 
PCI: 
percutaneous coronary intervention 
PT: 
preferred term 
QW: 
once per week 
SGLT2: 
sodium-glucose linked transporter-2 
SOC: 
system organ class 
T2DM: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
UACR: 
urinary albumin creatinine ratio 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study 
in approximately 4000 Type 2 Diabetes Mellitus (T2DM) patients at high cardiovascular (CV) 
risk.  The study will consist of three periods: 
• A 2- to 3-week screening period. 
• A double-blind, placebo-controlled, multiple-dose treatment period, including up to 
8 weeks for dose titration. 
▪ If, at any time during the study, a participant does not tolerate the study treatment, the 
investigational medicinal product (IMP) may be temporarily discontinued or if 
medically necessary, permanently discontinued. 
▪ If a maximum of two consecutive doses are missed, the IMP can be restarted with the 
latest dose given; if three or more consecutive doses are missed, the IMP will be 
restarted using a new titration kit. 
▪ All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol. 
• A follow-up period of 6 weeks after the last dose of IMP. 
Patients who meet all eligibility criteria will be randomized centrally by an Interactive Response 
Technology (IRT) using a permuted-block randomization schedule with a fixed block size at a 
1:1:1 ratio to efpeglenatide 4 mg, efpeglenatide 6 mg or placebo.  Randomization will be stratified 
by the current or potential future use of a sodium-glucose linked transporter-2 (SGLT2) inhibitor 
(current use, potential future use, neither current nor potential future use). 
All randomized participants, including those who prematurely and permanently discontinued from 
IMP, will be followed from Randomization until the Study close-out visit or death, whichever 
comes first. A post-treatment safety follow-up visit 6 weeks after the last dose of IMP will be 
implemented for patients still on study treatment at the Study close-out visit. 
The study is event driven and will continue until 330 participants have at least one primary event 
(3-point major adverse cardiac events [MACE]) positively adjudicated by the Clinical Endpoint 
Committee (CEC). All randomized participants will be asked to return to the site for a study close-
out visit once the projected date of the required number of positively adjudicated events has been 
determined.  Approximately 4000 patients will be randomly assigned to study intervention to end 
up with an estimated total of 330 participants with at least one positively adjudicated 3-point 
MACE event. 


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1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to demonstrate that efpeglenatide (pooled 4 mg and 6 mg) is 
noninferior to placebo on 3-point MACE in T2DM patients with high CV risk. 
1.2.2 Secondary objectives  
• 
To demonstrate that efpeglenatide (pooled 4 mg + 6 mg) is superior to placebo on 3-point 
MACE in T2DM patients with high CV risk. 
• 
To demonstrate that efpeglenatide (pooled 4 mg + 6 mg) is superior to placebo on the 
expanded CV outcome in T2DM patients with high CV risk. 
• 
To demonstrate that efpeglenatide (pooled 4 mg + 6 mg) is superior to placebo on the 
composite outcome of new or worsening nephropathy in T2DM patients with high CV 
risk. 
• 
To assess the safety of efpeglenatide 4 and 6 mg once per week (QW), both added to 
standard of care in T2DM patients with high CV risk. 
1.2.3 Tertiary/Exploratory objectives  
• To compare efpeglenatide versus placebo on the occurrence of the following events in 
T2DM patients with high CV risk: 
- 
CV death; 
- 
Stroke (fatal and non-fatal); 
- 
Myocardial infarction (MI) (fatal and non-fatal); 
- 
All cause death; 
- 
Hospitalization for unstable angina; 
- 
Hospitalization for Heart Failure (HHF); 
- 
Coronary revascularization procedures (percutaneous coronary intervention [PCI] or 
coronary artery bypass graft [CABG]). 
• To compare efpeglenatide versus placebo on the following endpoints: 
- 
Change in hemoglobin A1c (HbA1c); 
- 
Change in body weight; 
- 
Change in blood pressure (BP); 
- 
Change in Urinary Albumin-Creatinine Ratio (UACR). 
• 
To compare efpeglenatide versus placebo on immunogenicity. 
 


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1.3 
DETERMINATION OF SAMPLE SIZE  
It is estimated that approximately 4000 participants are needed to obtain approximately 
330 participants with a positively adjudicated event for the primary composite cardiovascular 
endpoint (3-point MACE), based on the following trial design characteristics assumptions: 
• A recruitment period of approximately 12 months  
• Study duration is estimated to be approximately 24 months of follow-up after the last 
randomized patient, estimated follow-up ranging from 24 to 36 months 
• 2% annual early study discontinuation 
• Yearly event rate in placebo group: 4.4% for participants not using a SGLT2 inhibitor, and 
3.7% for participants using a SGLT2 inhibitor  
• Treatment effect of efpeglenatide compared to placebo: 15% risk reduction for participants 
not using a SGLT2 inhibitor, and a neutral effect for participants using a SGLT2 inhibitor 
• 20% of participants using a SGLT2 inhibitor at baseline, and additional 10% participants 
in placebo group and 5% participants in efpeglenatide group adding a SGLT2 inhibitor 
during the study period 
This will provide: 
• 90% power to demonstrate non-inferiority (NI) of efpeglenatide vs placebo with a 1.3 NI 
margin {upper bound of the 95% CI of the estimated hazard ratio <1.3} for the 3-point 
MACE (CV death, non-fatal MI or non-fatal stroke) 
• >99% power to demonstrate NI with a 1.8 margin 
1.4 
STUDY PLAN  
The following figure presents graphically the study design:  
Double-blind, placebo-controlled treatment period
Week: 
Visit:   
Baseline
-3
1
12
4
-1
2
Phone call visit
On site visit
Randomization
R
48
6
0
3
Study 
closeout
visita
3 weeks
7
60

8
Follow-up
period
Follow-up
visit
6 weeks
Efpeglenatide 4 mg; N ~ 1333
Efpeglenatide 6 mg; N ~ 1333
Placebo; N ~ 1333
72
9
2 mg
4 mg
2 mg 4 mg
6 mg
Placebo
Screening 
period
R
24
36

5
84

10
Onsite visits every 24 weeks until study
closeout; one phone visit is held between
2 consecutive onsite visits
4
8
 
1:1:1 randomization, stratified by the current or potential future use of SGLT2 inhibitor (Current use, Potential future use, Neither current nor 
potential future use). 
a All randomized patients will be asked to return to the study site for a study close-out visit when approximately 330 participants have at least one 
primary event (3-point MACE) positively adjudicated by the CEC 


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R: randomization; CEC: Clinical Endpoint Committee; SGLT2: sodium-glucose linked transporter-2  
The study flow chart is detailed in the protocol. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). 
The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section.  
The first patient was enrolled on 11 May 2018.  There is no planned interim analysis. 
Table 1 - Protocol amendment statistical changes  
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
1 
28-May-2018 
Type of AEs to be summarized 
during the on-study period, as well 
as the definition, were clarified 
All AEs, SAEs, AEs leading to permanent 
treatment discontinuation, and AEs leading 
to death will be summarized for the on-study 
period 
2 
30-Jul-2018 
To harmonize the anti-drug 
antibodies (ADA) endpoint with the 
other efpeglenatide Phase 3 clinical 
protocols 
 
Section 9.4.3 describes statistical 
analysis of secondary endpoints and 
the ADA endpoint has been moved 
to tertiary/exploratory endpoint 
Change of ADA objective/endpoint from 
secondary objective/endpoint to 
tertiary/exploratory objective/endpoint 
 
Removal of Table 9 describing the statistical 
analysis of ADA 
 
 
 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
Not applicable. 
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
Key definitions:  
Completion of Study: as study approaches to the end, the team will make prediction of time 
window when the target 330 first occurrence of 3-point MACE (positively adjudicated) can be 
achieved.  Once projected visit window is determined, the site will be notified of the time 
window. Following announcement of the project study close-out visit:  
1) for subjects remaining on IMP at announcement of project study close-out visit, sites 
will schedule a study close-out visit and an off-drug follow-up visit as per the time and 
events scheduled in protocol;  
2) for subjects that have prematurely and permanently discontinued IMP prior to 
announcement of the project study close-out visit but still in study at the 
announcement, sites will schedule a study close-out visit;  
3) for subjects that have prematurely and permanently discontinued study prior to 
announcement, sites will be required to make a final contact for efficacy outcome 
collection (if patients allow further contact by family member and health provider) or 
vital status check (if allowed by local law) as soon as possible after the announcement.  
Scheduled study-close out visit: a study visit window projected by the sponsor during which the 
sites are required to bring all patients back to site for study closeout. It is a fixed calendar time 
window.   For patients who already discontinued study prematurely, they’ll miss this visit and 
their efficacy events after this scheduled visit will not be included for efficacy analysis even 
positively adjudicate.  
Scheduled last study visit: later of study closeout visit or follow-up visit. That is, for patients still 
on IMP at study close-out visit, their scheduled last study visit will be follow-up visit; while for 
patients not on IMP at study close-out visit, study close-out visit will be their scheduled last study 
visit.   
End of study date: defined as date of last scheduled visit for those completed the study (follow-
up visit or study closeout visit if premature discontinued IMP) and the date collected on eCRF 
form ‘Completion of End of Study’ for those who did not complete study. If death is reason 
collected on the ‘Completion of End of Study’, date of death will be used 
2.1.1 Study completer: subjects completed study closeout visit (in person or by phone) 
or has died while in study  Demographic and baseline characteristics  
The baseline value (with the exception of serum creatinine and estimated glomerular filtration rate 
[eGFR]) is defined generally as the last available value prior to the first dose administration of 
double-blind IMP or the last available value on or before the date of randomization for patients 


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who were randomized but never exposed to IMP. For lab parameters, only central lab values 
should be used for baseline value derivation.  
For serum creatinine and eGFR, baseline is defined as the average of all central lab values before 
the first dose of the double-blind IMP for those randomized and exposed or before randomization 
for those who were randomized but never exposed to double-blind IMP.   
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the summary statistics in the safety and efficacy sections (Section 2.3.4 and Section 2.3.5).  
Demographic characteristics 
Demographic variables to be summarized are: 
• Age (years), 
• Age groups (<50, ≥50 and <65, ≥65 and <75, ≥75 years), 
• Sex (Male, Female), 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiple, Unknown), 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown), 
• Region (North America, Latin America, Europe, Other), 
• Baseline body mass index (BMI) (kg/m2), 
• Baseline BMI categories (<30, ≥30 to <40, ≥40 kg/m2), 
• Baseline body weight (kg), 
• Smoking status (never, current, former), 
• Alcohol habit (never, occasional, at least daily, at least weekly, at least monthly). 
Medical or surgical history 
Medical (or surgical) history includes general medical or surgical history.  This information will 
be coded using the version of Medical Dictionary for Regulatory Activities (MedDRA) currently 
in effect at Sanofi at the time of database lock. 
Disease characteristics at screening or baseline   
Specific disease history includes: 
• 
Duration of diabetes (years) derived as: (Date of informed consent - Date of diagnosis of 
diabetes + 1)/365.25, 
• 
Duration of diabetes categories (<10, ≥10 years), 
• 
Age at diagnosis of type 2 diabetes (years) derived as: Year of diagnosis of diabetes - Year 
of birth, 


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• 
Baseline HbA1c (%), 
• 
Baseline HbA1c categories (<8%, ≥8%), 
• 
Retinopathy history (Yes/No), 
• 
Baseline eGFR (mL/min/1.73m2), 
• 
Baseline eGFR categories (<15 mL/min/1.73m2 [End stage renal disease], ≥15 to 
<30 mL/min/1.73m2 [Severe decrease in GFR], ≥30 to <60 mL/min/1.73m2 [Moderate 
decrease in GFR], ≥60 to <90 mL/min/1.73m2 [Mild decrease in GFR], and 
≥90 mL/min/1.73m2 [Normal]), 
• 
Randomization strata of SGLT2 use (Current use, Potential future use, Neither current nor 
potential future use), 
• 
Use of SGLT2 at baseline (yes, no), 
• 
History of heart failure.  
The following summary will also be provided: 
• Baseline Serum creatinine (µmol/L), 
• Baseline Systolic blood pressure (mmHg), 
• Baseline Diastolic blood pressure (mmHg), 
• Baseline Heart rate (beats per min), 
• Baseline UACR (mg/g), 
• Baseline lipid profile (total cholesterol, HDL, LDL, triglycerides), 
• Patients with at least 1 CV risk factor at screening or baseline, 
• History of cardiovascular disease (CVD) (e.g. Coronary artery disease [CAD], 
cerebrovascular disease, and peripheral vascular disease), 
• CV risk factors. 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) that the participant is receiving at the time of enrollment or during the study 
must be recorded in the corresponding case report form page. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 


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Medications will be classified into the following 3 groups: 
• Prior medications are those the patient used prior to first IMP intake.  Prior medications 
can be discontinued before first administration or can be ongoing during treatment phase.   
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMP(s), from first dose to the end of treatment + 30 days (+ 7 days for antidiabetic drugs).  
A given medication can be classified both as a prior medication and as a concomitant 
medication.  Concomitant medications do not include medications started during the 
posttreatment period (as defined in the observation period in Section 2.1.4).  
• Posttreatment medications are those the patient took in the period running from the 31st 
day (8 days for antidiabetic drugs) after the last injection of IMP up to the end of the study. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
An independent Clinical Endpoint Committee (CEC) will review and adjudicate all events of 
death and selected CV events (MIs, strokes, unstable angina requiring hospitalization, 
hospitalization for heart failure (HHF), and coronary revascularization) in a blinded manner.  Only 
events positively adjudicated by the CEC will be included for main efficacy analysis, unless 
otherwise specified.   
All randomized patients (irrespective of whether they experienced efficacy event[s] or whether 
they permanently discontinued double-blind treatment) will be followed from randomization until 
the planned last study visit (follow-up visit or study closeout visit for patient premature 
discontinued IMP). All events occurring on or after randomization and up to patient’s end of study 
date will be included, unless otherwise specified below. 
For positively adjudicated efficacy endpoint events with onset date after the patient’s end of study 
date:  
 
1. For patients who prematurely discontinued study, these events will be included in efficacy 
analysis if the events occur on or before the scheduled study-close out visit. Otherwise, 
these events will be listed as applicable and not be included in primary efficacy analysis   
2. For study completers, these events will be included in efficacy analysis if the 
proceeding/related event onset date is on or before the patient’s scheduled last study visit. 
Otherwise, these events will be listed separately as applicable and not be included in 
primary efficacy analysis  
 
For example, for a CV death, if the onset date of its preceding fatal stroke is before the 
patient’s follow-up visit and the CV death date is after follow-up visit (before data base 
lock (DBL) date), this CV death will be included in efficacy analysis if adjudicated as 
cardiovascular death.  
 


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Any endpoint events reported in the database, but not listed above, will not be included in the 
efficacy analysis.  
2.1.3.1 Primary efficacy endpoint(s)  
The primary efficacy endpoint is: 
• 
Time to the first occurrence of any of the following 3-point MACE events: 
- 
CV death 
- 
Non-fatal MI 
- 
Non-fatal stroke 
The death events adjudicated by CEC as ‘undetermined death’ will be considered as CV death and 
included in efficacy analysis.  
2.1.3.2 Secondary efficacy endpoint(s)  
• 
Time to first occurrence of non-fatal stroke and death 
• 
Time to the first occurrence of any of the following expanded CV events: 
- 
CV death 
- 
Non-fatal MI 
- 
Non-fatal stroke 
- 
Coronary revascularization 
- 
Hospitalization for unstable angina  
• 
Time to the first occurrence of any of the following new or worsening nephropathy: 
- 
New onset or progression to macro albuminuria (>300 mg/g) accompanied by an 
UACR value increase of ≥30% from Baseline 
- 
Sustained ≥40% decrease in eGFR from Baseline (for ≥30 days) 
- 
Chronic dialysis (for ≥90 days) 
- 
Renal transplant 
- 
Sustained eGFR <15 mL/min/1.73 m2 (for ≥30 days) 
Low eGFR value and 40% eGFR decrease from baseline will be captured from dedicated eGFR 
page “Renal event-eGFR Decrease”. Participants with a suspected renal event (reduction of 
eGFR) should have a repeat assessment of renal function 30 to 45 days following the onset of the 
event to confirm it is sustained. For UACR increase, it will be captured and reported by lab. 
Chronic dialysis and renal transplant will be recorded in eCRF procedure pages: “Renal Event – 
Dialysis Procedure” and/or “Other Procedures”.    


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2.1.3.3 Exploratory efficacy endpoint(s)  
The exploratory efficacy endpoints are: 
• 
Time to CV death 
• 
Time to first occurrence of Stroke (fatal and non-fatal)  
• 
Time to first occurrence of MI (fatal and non-fatal) 
• 
Time to all cause death 
• 
Time to first occurrence of hospitalization for unstable angina 
• 
Time to first occurrence of HHF 
• 
Time to first occurrence of coronary revascularization procedures (PCI or CABG) 
• 
Changes from Baseline to scheduled visits per protocol in: 
- 
HbA1c  
- 
Body weight 
- 
BP 
- 
UACR 
- 
Heart rate  
2.1.4 Safety endpoints  
The safety endpoints include the reported adverse events (AE), hypoglycemia and other safety 
information, such as clinical laboratory data, vital signs, and electrocardiogram (ECG). 
Observation period  
The observation period will be divided into 3 periods: 
• The pre-treatment period or screening period is defined as the time from signed informed 
consent up to the time of first injection of the double-blind IMP 
• The treatment-emergent adverse event period (on-treatment period) is defined as the time 
from the first injection of the IMP to the last injection of the IMP + 30 days (or +7 days for 
hypoglycemia). 
• The posttreatment period is defined as the period after the end of the treatment-emergent 
adverse event period. 
The on-study observation period/on-study is defined as the time from first IMP until the end of 
(the) study date (defined as the last scheduled visit for those who completed the study and the 
study discontinuation date collected on eCRF form ‘Completion of End of Study’ for those who 
did not complete the study. If death is reason collected on the ‘Completion of End of Study’ form, 
date of death will be used).  
The post-study observation is defined as anything after the on-study observation period.   


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2.1.4.1 Adverse events variables  
Adverse event classification  
The AE observations will be classified per the observation periods of safety data as defined above 
into: 
• 
Pre-treatment AEs are adverse events that developed or worsened or became serious 
during the pre-treatment period 
• 
Treatment-emergent AEs (TEAEs) are adverse events that developed or worsened or 
became serious during the on-treatment period 
• 
Post-treatment AEs are adverse events that developed or worsened or became serious 
during the post-treatment period 
• 
On-study AEs are adverse events that developed or worsened or became serious during 
the on-study period 
All AEs (including SAEs), AEs of special interest (AESI) and AEs requiring specific monitoring 
(AERSM) will be coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), 
high-level group term (HLGT), and associated primary system organ class (SOC) using the 
version of MedDRA currently in effect at Sanofi at the time of database lock. 
AESI include the following terms: 
• 
Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP 
• 
Symptomatic overdose (serious or nonserious) with IMP 
• 
alanine aminotransferase (ALT) ≥3 upper limit normal (ULN) (if baseline ALT <ULN) Or 
ALT ≥2 times the baseline value (if baseline ALT ≥ULN) 
AERSM include the following terms: 
• 
Severe gastrointestinal (GI) events 
• 
Severe hypoglycemia 
• 
Pancreatic events (including abnormal values of pancreatic enzymes, pancreatitis and 
pancreatic neoplasm) 
• 
Calcitonin increase >5.9 pmol/L (20 pg/mL) and thyroid C-cell neoplasm 
• 
Acute renal failure 
• 
Diabetic retinopathy complications 
• 
Severe injection site reaction 
• 
Severe allergic reactions 
• 
Severe immune complex disease 
The CEC will review pancreatic events in a blinded manner.  


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The criteria of AESI and AERSM are defined in below Table 2.  
Table 2 - Criteria for AESI and AERSM  
AE Grouping 
Criteria 
AESI 
 
Pregnancy 
“Pregnancy” checked 
Symptomatic Overdose 
“Overdose” checked and symptomatic (AEOVSYMP) = ”Yes” 
                ALT ≥3 ULN (if baseline ALT <ULN) Or ALT ≥2   
                times the baseline value (if baseline ALT  
              ≥ULN) 
“ALT Increase” checked and Yes to the question “Is the event an 
AESI?” in eCRF form “Adverse Events” 
AERSM 
 
Severe GI events 
AE severity= “severe” using Gastrointestinal disorders 
CMQ 
Severe hypoglycemia 
Any hypoglycemia event which either required assistance 
(from hypoglycemia page) or missed answering 
‘Assistance Required’ but with at least one of the 4 
symptoms of ne of the 4 symptoms (ie, coma, seizure, 
loss of consciousness, and confusion) 
Pancreatic events 
cases reported in pancreatic specific eCRF page or AE 
with category = “Pancreatic neoplasm” selected 
Calcitonin and thyroid C-cell neoplasm 
Using Calcitonin increase CMQ 
Using Medullary thyroid cancer CMQ 
Acute renal failure 
Using Acute renal failure Narrow CMQ 
Diabetic retinopathy complications 
AE category = ”Diabetic Retinopathy” 
Severe injection site reaction 
Intensity = "Severe" + Using Injection site reaction_ CMQ 
Severe allergic reactions 
Intensity = "Severe" + CMQs for anaphylactic reaction, 
angioedema, severe cutaneous adverse reaction, 
anaphylactic/anaphylactoid shock conditions (under SMQ 
"Shock"), and hypersensitivity 
Severe immune complex disease 
Intensity = "Severe" using Immune complex disease 
CMQ 
 
2.1.4.2 Deaths  
The deaths observation period is per the observation periods defined above.  
• Death on-treatment:  deaths occurring during the on-treatment period  
• Death on-study:  deaths occurring during the on-study observation period 
• Death poststudy:  deaths occurring after the on-study observation period 


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2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis (including hematology, clinical chemistry, and 
lipids) and urinalysis.  Clinical laboratory values after conversion will be analyzed in standard 
international units and international units will be used in all listings and tables.  Additional results 
using conventional units will be presented as necessary.  
Blood samples for clinical laboratories will be collected as described in the study flow chart in the 
protocol.  The laboratory parameters will be classified as follows: 
• Serum hematology  
- 
Red blood cells and platelets:  platelet count, red blood cell count, hemoglobin, 
hematocrit  
- 
White blood cells:  white blood cell count, differential count (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) 
• 
Serum clinical chemistry  
- 
Pancreatic enzymes: Amylase, Lipase;  
- 
Electrolytes:  potassium, sodium;   
- 
Renal function:  creatinine, eGFR (calculated by the central laboratory using the 
Modification of Diet in Renal Disease (MDRD) formula), UACR;  
- 
Liver function:  alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
alkaline phosphatase (ALP), total bilirubin (TB), Lactic acid dehydrogenase (LDH)  
- 
Calcitonin 
• Lipid profile  
- 
Total cholesterol, high-density lipoprotein cholesterol (HDL-C), Low-density 
lipoprotein cholesterol (LDL-C) (calculated by Friedwald formula), Non-HDL-C 
(calculated as the difference between TC and HDL-C), Triglycerides (TG)  
Technical formulas are described in Section 2.5.1. 
2.1.4.1 Vital signs variables  
Vital signs include: heart rate and blood pressure (systolic and diastolic), all in a seated position.   
2.1.4.2 Electrocardiogram variables  
12-lead ECGs performed locally at the Investigator site.  ECG assessments will be described as 
normal or abnormal.  


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2.1.5 Immunogenicity endpoints   
Serum samples are collected to assess the Anti-drug antibody (ADA) status (positive/negative) at 
baseline.  The titer of confirmed positive samples will be reported. Cross-reactivity of confirmed 
positive samples to endogenous GLP-1 (positive/negative), endogenous glucagon 
(positive/negative), neutralizing capacity of ADAs, and presence of anti-polyethylene glycol 
(PEG) antibodies (positive/negative) will also be evaluated in serum. Below are some important 
definitions needed for ADA analysis.  
 
Treatment induced ADAs: ADAs developed de novo (seroconversion) following administration of 
the biotherapeutic (i.e., formation of ADAs any time after the initial drug administration in a 
subject without pre-existing ADAs). If the baseline ADA sample is missing or non-reportable and 
at least one reportable ADA sample is available during the treatment (including follow-up period) 
the baseline sample will be considered as “negative” for data analysis. This is considered being a 
conservative approach for ADA assessment. 
Treatment boosted ADA: Pre-existing ADAs that were boosted to a higher level following 
administration of efpeglenatide (i.e., any time after the initial drug administration) the ADA titer 
is significantly higher than the baseline titer.  
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who signed the informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used.  
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
• 
Screened patients 
• 
Screen failure patients and reasons for screen failure 
• 
Nonrandomized but treated patients, if any 
• 
Randomized patients 
• 
Randomized but not treated patients 
• 
Randomized and treated patients 
• 
Patients who did not complete the treatment as per protocol (i.e. those not completed 
treatment and their main reason for premature end of treatment is not death per ‘treatment 
status’ eCRF) 


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• 
Patients who discontinued the treatment by main reason for permanent treatment 
discontinuation (Note: patients who died while on treatment will be considered as 
completed treatment) 
• 
Patients who completed the study per protocol (i.e. subject status is death or completed on 
the ‘Completion of end of study’ eCRF form) 
• 
Patients who did not complete the study per protocol and the reasons for study discontinuation 
• 
Patient vital status at last study contact (alive, dead) 
• 
Patient vital status at planned study close out visit (alive, dead, unknown) 
For all categories of patients (except for the screened, screen failure and nonrandomized but 
treated categories) percentages will be calculated using the number of randomized patients within 
each treatment group as the denominator.  Reasons for treatment discontinuation will be supplied 
in tables giving numbers and percentages by treatment group. Patients who prematurely and 
permanently discontinue from treatment and/or study for other reasons will also be listed. A 
summary of screened, screen failed, randomized, discontinued treatment and study will also be 
provided by region, country and site. 
Number (%) of patients who prematurely discontinued the study will further be summarized 
according to whether or not the patients had either primary efficacy endpoint confirmed by the 
CEC prior to study discontinuation.  
Kaplan-Meier (KM) plots/estimates of the cumulative incidence of prematurely permanent 
treatment discontinuation due to any reason (note: deaths on treatment will be considered 
completers), or due to AE will be provided on the randomized population.  Randomized not 
treated patients will be considered as a treatment discontinuation at Day 1 (day of randomization). 
All treatment completers, including patients who died while on-treatment, will be considered as 
right-censored at last IMP administration date (death date will be used for patients who died  
while on-treatment when the last IMP date is incomplete or missing). 
The duration of study participation will be summarized using mean, SD, median, minimum and 
maximum.  Study duration (days) is defined as date of study completion/ study 
discontinuation/death date – date of randomization + 1.   
All critical or major deviations will be summarized in tables giving numbers and percentages of 
patients with deviations by treatment group in ITT population, including the critical or major 
protocol deviations due to COVID-19 impact.  Listing of participants with at least one critical or 
major deviation (including deviation due to COVID-19) will be provided.  
Additionally, the following analysis populations will be summarized by treatment group.  
• 
Randomized population 
• 
Efficacy population: intent-to-treat (ITT) population  
• 
Safety population 
• 
ADA population 


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2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, or c) a patient is randomized twice. 
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately.  
2.2.2  Analysis populations  
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
Patients treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.  The safety experience of patients treated and not randomized 
will be reported separately, and these patients will not be in the safety population. 
2.2.3 Efficacy populations  
The efficacy analysis population will be the ITT population. 
2.2.3.1 Intent–to-treat population  
The ITT Population is defined as: 
• All randomized participants irrespective of compliance with the study protocol and 
procedures. Participants will be analyzed according to the treatment group allocated by 
randomization.  


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2.2.4 Safety population  
The Safety Population is defined as:  
• All randomized participants who have received at least 1 dose of double-blind treatment, 
regardless of the amount of treatment administered. Participants will be analyzed 
according to the treatment actually received. 
In addition:  
• Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately. 
• For participants receiving 1 or more injections of efpeglenatide during the trial, regardless 
of being assigned to the efpeglenatide groups or not, the treatment group allocation for as-
treated analysis will be included in the efpeglenatide dose group that they are exposed for 
longer duration (by counting the number of kits received). In case of tie, highest dose 
group will be used.   
• Participants, who prematurely and permanently discontinued study treatment during the 
titration phase will be summarized in their planned treatment group for as-treated analysis. 
• Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population in their planned treatment group. 
• Randomized patients will be excluded from the safety population only if there is 
documented evidence (i.e., all study dates recorded as no medication taken) that patients 
have not taken the study treatment. If a patient is dispensed double-blind IMP and is lost to 
follow-up without any documented evidence, the patient will be considered exposed. 
2.2.5 ADA population  
ADA population is defined as: 
• All participants from the safety population with at least 1 post-baseline valid ADA sample 
after study treatment (efpeglenatide) administration. 
2.3 
STATISTICAL METHODS  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group.  Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group.  
Unless otherwise specified, all descriptive summary will be by treatment groups (4 mg 
efpeglenatide, 6 mg efpeglenatide, pooled 4 mg+6 mg efpeglenatide, placebo, and all (if needed)). 
Only pooled efpeglenatide treatment group (4 mg + 6 mg efpeglenatide) will be compared with 
placebo for formal statistical hypothesis testing.  


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2.3.1 Demographics and baseline characteristics  
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.   
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups using descriptive statistics.  
All reported medical and surgical history will be presented by primary SOC and HLT. The tables 
will be sorted by SOC internationally agreed order and decreasing frequency of HLT based on the 
overall incidence across treatment groups.  
In addition, medical history of specific interest (cancer [any], fracture [any], hypo or hyper 
thyroidism, thyroidectomy, cholelithiasis, cholecystectomy, diabetic nephropathy, TIA [transient 
ischemic attack], atrial fibrillation, hypertension, heart failure, hyperlipidemia, cardiovascular 
disease history and CV risk factors, retinopathy history) will be presented by treatment group.. 
P-values on demographic and baseline characteristic data will not be calculated.  
2.3.2 Prior or concomitant medications  
The prior and concomitant medications as described in Section 2.1.1 will be presented for the 
randomized population.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 3 
digits of the ATC class (therapeutic category).  All ATC codes corresponding to a medication will 
be summarized, and participants will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication. Therefore, participants may be counted several times for the 
same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment groups.  In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant and posttreatment medications will be sorted by decreasing frequency 
of ATC followed by all other therapeutic classes based on the incidence in the efpeglenatide group 
(pooled 4 mg + 6 mg groups). In case of equal frequency regarding ATCs (anatomic or 
therapeutic categories), alphabetical order will be used.  
These prior and concomitant medications will be summarized using ATC code by therapeutic 
subgroup (2nd ATC level), pharmacological subgroup (3rd ATC level) and chemical subgroup 
(4th ATC level).  Patients will be counted once in each ATC level linked to the medication; 
therefore patients may be counted several times for the same medication. The numbers and 
percentages of patients in each level will be presented by treatment group. 


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Medications will also be summarized by special interest, i.e., glucose lowering medication, 
antihypertensive medication, anti-platelet, and statins by treatment group.  
In addition, the following summaries will also be provided:  
• 
Number (%) of patients taking SGLT2 at baseline (yes, no) by randomization strata of 
SGLT2 use. 
• 
Number (%) of patients taking SGLT2 during the study (yes, no) by randomization strata 
of SGLT2 use. 
• 
Number (%) of patients taking metformin + SGLT2 at both baseline and during the study 
• 
Number (%) of patients taking metformin + sulfonylurea at both baseline and during the 
study 
2.3.3 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed and summarized by actual treatment within the 
safety population (See Section 2.3.2). 
2.3.3.1 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed in the safety population by duration of IMP exposure 
and by category.  
Duration of IMP exposure is defined as last dose date – first dose date + 7 day, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 calculation in case of missing or 
incomplete data).   
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum).  In addition, duration of treatment exposure will 
also be summarized by numbers and percentages for each category and cumulatively. Following 
are the categories of exposure-range (in months): <3 months, >3 to 6 months, >6 to 12 months, 
>12 to 18 months, >18 to 24 months, > 24 to 36 months, > 36 months.   
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years.  
Percentage of injection taken will be summarized, calculated as (total number of planned 
injections – number of missed injections)/total number of planned injections*100 during treatment 
period.   
2.3.4 Analyses of efficacy endpoints  
Unless otherwise specified, all efficacy analyses will be performed on the ITT population and will 
include all efficacy endpoint events positively adjudicated by the CEC, and as reported by 
investigator for renal events, occurring on or after randomization up to the scheduled last study 


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visit, inclusive, even after the patient has prematurely and permanently discontinued the study 
treatment. For details of what efficacy events will be included, please refer to Section 2.1.3. 
2.3.4.1 Analysis of primary efficacy endpoint(s)  
2.3.4.1.1 Statistical Hypotheses  
The statistical hypothesis for the primary endpoint of 3-point MACE is to test that efpeglenatide is 
noninferior (1.8 and 1.3 margin) to placebo at the two-sided 5% alpha level: 
• H0: Hazard ratio of efpeglenatide (pooled 4mg and 6mg groups) versus placebo ≥1.8 vs. 
Ha: Hazard ratio of efpeglenatide versus placebo <1.8 
and  
• H0: Hazard ratio of efpeglenatide (pooled 4mg and 6mg groups) versus placebo ≥1.3 vs. 
Ha: Hazard ratio of efpeglenatide versus placebo <1.3 
The time to the first occurrence of the composite 3-point MACE endpoint (CV death, non-fatal 
MI, non-fatal stroke) will be analyzed using a Cox proportional hazards model with treatment 
(efpeglenatide 4 mg, efpeglenatide 6 mg, placebo), region (Norther America, Latin America, 
Europe, other), and randomization stratum of use of an SGLT2 inhibitor (current use, potential 
future use, neither current nor potential future use) as the factors. The analyses will be performed 
by including only events positively adjudicated by the CEC. Participants who receive either 4 mg 
or 6 mg of efpeglenatide will be combined as one efpeglenatide treatment group when making 
comparisons using appropriate contrast for the purposes of the primary analysis. The hazard ratio 
between pooled efpeglenatide and placebo will be estimated along with the associated 2-sided 
95% CI. The NI with the 1.8 and 1.3 margin will be demonstrated on the primary endpoint if the 
upper bound of the 2-sided 95% CI is less than 1.8 and 1.3, respectively. 
The time to event will be calculated as date of event as determined by the CEC (or date of 
censoring) – randomization date +1.   
2.3.4.1.2 Censoring rule  
 
Patients will be right-censored at the last date with information available on the CV outcomes if 
they have not experienced any positively-adjudicated component of the primary composite CV 
events on or before their end of study visit. Specifically, the censoring date is defined as follows: 
• 
Patients who completed the study will be censored at their scheduled last study visit date 
(study close-out visit date or final follow-up visit date) 
• 
Patients who died before completing or discontinuing the study (ie, death reported on the 
Completion of End of Study form) will be censored at their date of non-CV death 


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• 
Patients who discontinued the study will be censored at their later of study discontinuation 
date or latest date with cardiovascular efficacy endpoint information (MI/UA, heart failure, 
cerebrovascular event, admission to hospital/emergency room, coronary procedure, or 
cardiac biomarkers as collected in eCRF) collected. For more details of censoring rule, 
please refer to Appendix C.  
Kaplan-Meier curves of the cumulative incidence rate will be provided by treatment groups over 
on-study efficacy period (from randomization to end of study date). The incidence rate per 100 
patient-years (calculated by 100 * number of patients with events / sum of time at risk (days) over 
all patients/365.25) will be reported.  For patients with an event, patient-year is time from 
randomization to first event; for patient without any event, patient-year is from randomization to 
censoring date.  
Underlying assumptions of the Cox proportional hazards model will be checked by visual 
inspection of the Kaplan-Meier plots (log(-log(survival) vs log(survival time)). 
Individual components of the primary endpoints will be analyzed using the same Cox proportional 
hazards model described above.  Censoring rules described above will be used, and for 
components other than CV death, patients who died before completing or discontinuing the study 
will be censored at date of death (i.e. CV or non-CV death). See Appendix C for specific 
censoring rules.  
2.3.4.1.3 Sensitivity analysis  
• 
The primary analysis of the primary endpoint will be repeated by censoring the events at 
the time a participant starts treatment with a SGLT2 inhibitor (for participants who were 
not receiving a SGLT2 inhibitor at baseline) or stops treatment with a SGLT2 inhibitor 
(for participants who were already receiving an SGLT2 inhibitor at baseline). 
• 
The primary analysis of the primary endpoint will be repeated using the ITT analysis set, 
by excluding deaths adjudicated as ‘undetermined cause of death’ by the CEC.  
• 
The primary analysis of the primary endpoint will be repeated by including only events 
from randomization to last IMP administration date + 30 days or patient’s last study visit 
date, whichever is earlier. For patient not having a primary endpoint during this period, the 
patient will be right-censored at the earlier date of last IMP administration date + 30 days, 
and patient’s censoring date defined above.    
• 
If discrepancy in stratum assignment between IRT and eCRF occurred in more than 5% of 
patients, the primary analysis will be repeated using the actual use of SGLT2 inhibitor at 
baseline (yes, no). 
Assessment of missing data 
For patients who discontinued study but no MACE event was positively adjudicated by scheduled 
study closeout visit, the missing data are events that may occur after a patient is censored (the later 
of the patient’s study discontinuation date and the last date they have information on CV efficacy 
endpoint for patients who discontinued the study).  


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Reasons for censoring (including non-CV death, completed study, and study discontinuation 
reasons) will be summarized. For patients who discontinued the study, the time from censoring 
date to planned study close-out visit date will be summarized to show the magnitude of missing 
information.  
Subjects prematurely and permanently discontinuing IMP, for other reason than death, prior to 
study end could have a different event and hazard rate from those who stay on IMP throughout the 
study, and their corresponding dropout could be considered informative. This subgroup can be 
divided into subjects with information and subjects with missing information regarding primary 
MACE endpoints, see figure below.  
Diagram showing subjects divided into subgroups related to missing information about MACE. 
 
Subjects with information related to the MACE endpoint events (either discontinued study but 
have MACE prior to scheduled study closeout visit, or completed the study) will be used to 
impute data in subjects without MACE endpoints (discontinued study and no MACE event 
reported through third party data by scheduled study closeout visit). Subjects who developed 
MACE prior to the IMP discontinuation are included for imputation and their time to MACE data 
will be used for the imputation modeling. With these subjects included, the model estimate of 
hazard should fully reflect the potential hazard of the subjects with missing outcome. More 
specifically, subjects from below scenarios 2 and 3 will be used to impute the missing data of 
scenario 4 of the same treatment arm:  


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Note:  
1. SCV: study close-out visit;  
2. MACE censoring date of scenario 4 is the later of study discontinuation date or latest 
date with CV event information collected   
The following supportive analyses will be performed to evaluate how the primary efficacy results 
could be influenced by different assumptions about the missing data.  In particular, a 4-step 
approach will be used: 
- 
Step 1: For each arm, the hazard rate after treatment discontinuation will be generated 
from the posterior distribution of the parameters in the exponential survival function in 
subjects who have discontinued treatment but either have MACE event prior to 
scheduled study closeout visit or have completed study. 
Note: the Kaplan-Meier curve based on observed pooled data is nearly a straight line, 
so constant hazard rate is assumed. So exponential survival function is used for hazard 
rate for each arm.  
- 
Step 2: The missing event date of scenario 4 will be imputed multiple times by the 
samples of the hazard rate generated in Step 1. The imputed event date will be 
censored by the planned study close-out visit date if the imputed event date is after the 
study close out visit date. 


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- 
Step 3: In each imputation, the imputed dataset will be analyzed by the same Cox 
proportional hazards model as the primary analysis. 
- 
Step 4: The results of the above analyses will be combined using Rubin’s formula 
• 
A tipping point analysis will be performed, where time to events will be imputed by using 
the same multiple imputation method as described above (step 1-4) and vary the hazard 
rates for subjects not complete study and have missing MACE event. The goal of the 
analysis is to find the scenarios where the result from the primary endpoints analyses will 
be “tipped”, i.e., the conclusion of non-inferiority will change. More specifically, a grid-
search with hazard rates for the efpeglenatide group increased by an increment (e.g. 1, 1.1, 
1.2, 1.3, 1.4, 1.5, 1.6, …) will be implemented to explore the plausibility of missing data 
assumptions. A proper range of the hazard rates will be searched to estimate the point 
where the upper bound of 95% CI for the hazard ratio exceeds 1.3, and 1.8 respectively, 
when the corresponding comparison fails to declare statistical significance for non-
inferiority.  
SAS pseudo-codes is provided in Appendix D. 
2.3.4.1.4 Subgroup Analysis  
Subgroup analyses will be conducted for the primary endpoint for the following factors:  
Key subgroup analyses:  
• 
Age (< median age value, ≥ median age value) 
• 
Sex (male, female) 
• 
Race (White, Black or African American, Asian, and Other (American Indian or Alaska 
native + Not reported + Unknown + multiple). 
• 
Region (North America, Latin America, Europe, other)  
• 
Use of SGLT2 at baseline (Yes, No) 
• 
Baseline BMI categories (<median BMI value, ≥ median BMI value) 
• 
Duration of diabetes (< 10, ≥10 years) 
• 
Baseline HbA1c categories (<8%, ≥8%) 
• 
Baseline eGFR categories (<median eGFR value, ≥ median eGFR value) 
• 
Baseline metformin use (Yes, No) 
• 
History of CV disease (CVD) (yes, no) 
Other subgroup analyses:  
• 
Age (<65, ≥65 and <75, ≥75 years)  
• 
Randomization strata of SGLT2 use (Current use, Potential future use, Neither current nor 
potential future use) 
• 
Baseline BMI categories (<30, ≥30 to <40, ≥40 kg/m2) 


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• 
Ethnicity (Hispanic, not Hispanic) 
• 
Baseline eGFR categories (< 30 mL/min/1.73m2, 30 to <60 mL/min/1.73m2, 60 to 
<90 mL/min/1.73m2, ≥90 mL/min/1.73m2) 
Each of these factors will be analyzed statistically using a Cox proportional hazard model 
including the effects of the primary analysis model and effects for subgroup and subgroup-by-
treatment interaction.  The incidence rate, estimated hazard ratios between pooled efpeglenatide 
and placebo, and associated 95% confidence intervals will be calculated within each of the 
subgroups generated by these analyses.  Subgroup by treatment interaction p-values will be 
reported, and results will be plotted using forest plot. 
2.3.4.2 Analyses of secondary efficacy endpoints  
If the NI with the 1.8 and 1.3 margin is demonstrated on the primary endpoint, the superiority of 
pooled efpeglenatide vs placebo for the primary endpoint will be tested in a hierarchical order. 
The superiority will be claimed if the UB of the 2-sided 95% CI of hazard ratio is less than 1. The 
nominal p-value using the log-rank test (stratified by randomization stratum of use of an SGLT2 
inhibitor) will also be calculated. 
The secondary time to event endpoints will be analyzed using the same Cox proportional hazards 
model as used for the analysis of primary endpoint described above. The analyses will be 
performed by including events positively adjudicated by the CEC for cardiac events, and events as 
reported by investigator for renal events. The hazard ratios between pooled efpeglenatide and 
placebo will be estimated along with the associated 2-sided 95% CIs. See Appendix C for the 
censoring rule. 
Kaplan-Meier curves of the cumulative incidence rates will be provided by treatment groups. The 
incidence rate per 100 patient-years will be reported. The p-value using the log-rank test (stratified 
by randomization stratum of use of an SGLT2 inhibitor) will also be calculated.  
Individual components of the secondary endpoints will be analyzed using the same Cox 
proportional hazards model described above.   
In addition, the total number of events sent for adjudication and positively adjudicated will be 
summarized as well as the concordance rate between investigator opinion and adjudication by the 
CEC for each cardiac event type.  
2.3.4.3 Exploratory efficacy analyses  
Time to event endpoints will be analyzed using the same model described for the secondary 
primary endpoints. 
For continuous efficacy endpoints, summary statistics at scheduled visits using observed data will 
be provided for each treatment group. The summary will include the number of observations, 
mean, SD, SE, minimum, median, and maximum. Graphical presentations will be used to examine 
trends over time using mean values (±SE) and mean changes from baseline (±SE) at each 
scheduled visit.  


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In addition, Kaplan-Meier plot of time to initiation of SGLT2 use will be provided.  See  
Section 2.5.3 for handling missing medication dates. Patients on SGLT2 at baseline will be 
censored at randomization. Patients who never start SGLT2 will be censored at the patients of end 
of study date (refer to Section 2.1.4).  
2.3.4.4 Multiplicity issues  
A hierarchical testing procedure will be used to strongly control the overall Type-1 error rate at 
2-sided 0.05 (0.025 for 1-sided).  
The primary hypotheses will be tested first with below fixed sequence, each at alpha=0.05 
(2-sided) level: 
1. Non-inferiority of efpeglenatide (pooled 4 mg + 6 mg) versus placebo on 3-point MACE 
with NI=1.8 
2. Non-inferiority of efpeglenatide (pooled 4 mg + 6 mg) versus placebo on 3-point MACE 
with NI=1.3 
If the hypotheses above are statistical significant, the secondary hypotheses will be tested in below 
fixed sequence with each testing at significance level of 0.05 (2-sided) to continue to control the 
overall family-wise error rate at 0.05 (2-sided): 
• 
Superiority for 3-point MACE 
• 
Superiority for expanded MACE 
• 
Superiority for the new or worsening nephropathy 
Inferential conclusions about successive secondary hypotheses require statistical significance of 
the prior one. No further multiplicity adjustments will be made for other efficacy endpoints or 
subgroup analyses for which nominal p-values may be provided for descriptive purpose only. 
2.3.5 Analyses of safety data  
The summary of safety results will be presented by treatment group. All safety analyses will be 
performed on the safety population. The AE analysis will exclude the CV events reported and 
final diagnosed as CV events by investigator and also positively adjudicated as CV events by 
CEC.   
In addition to the on-treatment period, all AEs, SAEs, AEs leading to permanent treatment 
discontinuation, and AEs leading to death will be summarized for the on-study period as defined in 
Section 2.1.4.   


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General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.2.4, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (e.g., exposed but not 
randomized) will be listed separately 
• For WBC and differential counts, the baseline is defined as the last available value before 
the first injection of IMP where no differential component is missing.   
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA version dated May 2014 [Appendix A]) 
• PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the on-treatment PCSA percentage 
• The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter during the on-treatment period 
by treatment group in the safety population. 
• For laboratory and vital sign parameters defined as efficacy endpoints, descriptive 
statistics and graphs will be provided in the efficacy section only, and PCSAs summaries 
will be provided in the safety section. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group.  Summaries will include the last on-treatment value. The last on-
treatment value is defined as the value collected on the same day/time of the last injection 
of IMP.  If this value is missing, this last on-treatment value will be the closest value prior 
to the last injection of IMP.  
• The analysis of the safety variables will be essentially descriptive, and no statistical 
hypothesis testing is planned.   
2.3.5.1 Analyses of adverse events  
Generalities 
The primary focus of AE reporting will be on TEAEs.  Pretreatment and posttreatment adverse 
events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 


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determine it is pretreatment or posttreatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by SOC and PT, sorted in alphabetical order for each 
treatment group, the number (n) and percentage (%) of patients experiencing an adverse event.  
Multiple occurrences of the same event in the same patient will be counted only once in the tables 
within a treatment phase.  The denominator for computation of percentages is the safety 
population within each treatment group. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment).  For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs will define the presentation order for all other tables 
unless otherwise specified.  Sorting will be based on incidence in the pooled efpeglenatide group. 
Analysis of all TEAEs 
The following TEAE summaries will be generated for the safety population. 
• Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to permanent treatment discontinuation 
- 
TEAE leading to death 
- 
Serious TEAE leading to permanent treatment discontinuation  
• All TEAEs by primary SOC and PT, sorted by the internationally agreed SOC order and 
by decreasing incidence of PTs within each SOC. This sorting order will be applied to all 
other tables by SOC and PT, unless otherwise specified. 
• All TEAEs related to IMP by primary SOC, and PT  
• All TEAEs by maximal severity, presented by primary SOC and PT 
• Common TEAEs (e.g., PTs ≥2% in any treatment group) by primary SOC, and PT   
• Common TEAEs (e.g., PTs ≥5% in any treatment group) by primary SOC and PT and by 
intrinsic factors: age group (<50, ≥50 to <65, ≥65 to <75, ≥75 years), sex (Male, Female), 
race (White, Black or African American, Asian, Other), and any pertinent subgroups as 
appropriate.  
• All TEAEs by primary SOC and PT and by subgroup BMI (<30, ≥ 30 to <40, ≥40 kg/m2)  
• All TEAE by primary SOC and PT and by anti-efpeglenatide antibody status (positive, 
negative) 
• Kaplan-Meier plot, for the time to first onset of the following PTs: nausea, vomiting and 
diarrhea 


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• The frequency of TEAEs over time will be provided for nausea, vomiting and diarrhea, 
using 3-month time intervals, i.e., [0-3] month, (3-6] month, (6-9] month, (9-12] month, 
etc. In each time interval, the numerator in the calculation of percentages will be the 
number of participants with at least 1 TEAE occurring in this time interval. Two types of 
analyses will be included:  
• 
(1) only the first event will be counted for each participant and all recurrent events will 
not be included, and the denominator for the calculation of percentages will be the 
number of participants at risk at the beginning of the time interval who did not 
experience a first event in the preceding intervals; 
• 
(2) the recurrent events in subsequent intervals will be counted once for each 
participant in the numerator of the corresponding interval, and the denominator for the 
calculation of percentages will be the number of participants at risk at the beginning of 
the time interval.  
A histogram of the frequency over time (by 3-month intervals) will also be presented 
as appropriate. 
Analysis of all treatment emergent SAEs 
• All serious TEAEs by primary SOC and PT  
• All serious TEAEs related to IMP by primary SOC and PT  
Analysis of all TEAEs leading to permanent treatment discontinuation 
• All TEAEs leading to permanent treatment discontinuation by primary SOC, HLGT, HLT, 
and PT  
• All TEAEs leading to permanent treatment discontinuation by primary SOC and PT 
Analysis of on-study AEs 
• All the analyses in above categories, including AEs, SAEs, AEs leading to permanent 
treatment discontinuation, and AEs leading to death will be summarized for the on-study 
period by SOC and PT.   
Analyses of events of special interest and events requiring specific monitoring 
Unless otherwise specified, AESI and AERSM will be summarized during the TEAE period by 
prespecified- grouping (AE category of interest) and PT, showing the number (%) of participants, 
sorted by decreasing frequency of PT. 
Severe hypoglycemia 
The severe hypoglycemia will be analyzed on TEAE period.  
The following analysis will be provided for severe hypoglycemia:  
• 
Number (%) of patients with at least one severe hypoglycemia 
• 
Number of events per 100 patient-years of total IMP exposure. 


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Pancreatic events  
The Pancreatic events will be reviewed, assessed and/or adjudicated by CEC.  
The following analysis will be provided for positively adjudicated events during the TEAE period: 
• The number (%) of patients with at least one positively adjudicated pancreatitis by type: 1) 
acute pancreatitis, 2) acute on chronic pancreatitis, 3) chronic pancreatitis, 4) unknown 
pancreatitis; 
• The number (%) of patients with at least one positively adjudicated pancreatic neoplasm 
by type: 1) malignant - confirmed, 2) Malignant - probable, 3) Benign. 
Analysis of pretreatment and posttreatment adverse events  
• All pretreatment AEs by primary SOC and PT, showing the number (%) of patients with at 
least 1 pretreatment adverse event 
• All posttreatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 posttreatment adverse event 
• All posttreatment SAEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 posttreatment serious adverse event 
Listing 
Supporting AE listings will be provided for SAEs, AESIs, deaths, severe hypoglycemia, 
pancreatic events and AEs leading to treatment discontinuation and/or death. 
These listing sorted by treatment, participant identification, onset date, will include the following 
information: treatment, participant identification, country, age, gender, race, BMI, primary SOC, 
PT, reported term, onset date, study day (relative day to the start date of IMP), AE duration, 
duration of exposure, intensity, corrective treatment, action taken with IMP, date of treatment 
discontinuation (if relevant), relationship to IMP/NIMP/study procedures, outcome, date of death 
if any, seriousness, seriousness criteria, and AE status. 
Similar to AE listing, listing for all adjudicated AEs will be provided plus adjudication outcome. 
2.3.5.2 Deaths  
The following summaries of deaths will be generated for the safety population.  
• 
Number (%) of patients who died by study period (on-study, on-treatment, post-study) 
• 
Deaths in nonrandomized patients or randomized but not treated patients 
• 
Primary cause of death as adjudicated by CEC (by 3 major categories of causes [i.e., 
cardiovascular, non-cardiovascular, and undetermined], and by additional subcategories 
per CEC charter). 
• 
Primary cause of death as reported by the investigator. 


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• 
Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC and PT 
showing number (%) of patients sorted by internationally agreed SOC order, with PT 
presented in alphabetical order within each SOC.  
• 
TEAEs leading to death (death as an outcome on the adverse event case report form page 
as reported by the Investigator) by primary SOC and PT  
• 
Number (%) of patients with AEs leading to death by primary SOC and PT during the on-
study period 
2.3.5.3 Analyses of laboratory variables  
This section will be organized by biological function as specified in Section 2.1.4.3. 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all protocol-required laboratory variables (central laboratory values, changes from 
baseline and/or percent change from baseline [e.g., lipid parameters, albumin, total protein, 
hemoglobin, hematocrit]) will be calculated for each visit or study assessment (baseline, each 
post-baseline time point, last on-treatment value) by treatment group. For selected laboratory 
parameters (eg, ALT, AST, and ALP), descriptive statistics will also be summarized by upper 
limit of normal (ULN) values. Graphical presentations will be used to examine trends over time 
using mean (±SE) and/or mean change from baseline (±SE) at scheduled visits. Results will be 
presented in standard international unit. 
The incidence of PCSAs (list provided in Appendix A) at any time during the treatment-emergent 
adverse event period will be summarized by biological function and treatment group whatever the 
baseline level and/or according to the following baseline status categories:  
• 
Normal/missing 
• 
Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided as necessary. For calcitonin, no PCSA criterion is defined. Similar summaries 
will be provided using the pre-defined categories: ≤ULN, >ULN - 20 ng/L, ≥20 - <50 ng/L, and 
≥50 ng/L (Note that ng/L is the standard international unit and is equivalent to pg/mL).   
All measurements collected during the On-treatment period, including values from unscheduled 
visits, will be considered for the PCSA summaries. However, when several measurements are 
performed on the same date and at the same time for a given laboratory test, the central laboratory 
value will be selected over the local lab value. These summaries will include patients in the safety 
population who have at least 1 assessment performed during the On-treatment period. When a 
PCSA definition involves a change from baseline value, patients must also have a baseline value 
to be included in the summaries, and when required by the definition of the abnormality, patients 
must also have available laboratory normal ranges.  


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For some parameters, such as liver enzymes, the lower limit of normal (LLN) is not considered 
clinically relevant, and values below this limit are considered normal. When there are multiple 
PCSA criteria for a specific parameter (eg, ALT), the participant will be counted once during the 
On-treatment period for the specific parameter in question under the worst/maximum PCSA 
category. 
Elevation of liver parameters will be summarized by treatment group in safety population. 
For PCSA, both central and local lab data will be used, though centralized data will be used 
preferentially to the local measures in the analysis when several measurements are performed on 
the same date and at the same time for a given laboratory test. 
A listing of patients with at least 1 on-treatment PCSA (or out of normal range when no PCSA 
criteria is defined) will be provided (except for mild and moderate eGFR decreases) and will 
display the entire patients’ profile across time for all parameters belonging to the corresponding 
biological function. Individual data listings will include flags when applicable: 
• 
Baseline values will be flagged “B”. 
• 
Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and LLN. Baseline, last on-treatment value, and individual data will be flagged “L” 
if the value is below the LLN and will be flagged “H” if it is above the ULN. 
• 
Laboratory PCSA criteria will be used for the corresponding laboratory parameters. Values 
reaching a PCSA limit will be flagged (+, ++, -, or -- depending upon the direction and 
level of the abnormality). Flags for WBC and differential counts will be determined using 
data expressed in international units. 
For parameters whose PCSA criteria are multiples of the ULN, the parameter’s value will also be 
expressed as a multiple of the ULN in the individual data provided. 
2.4.4.1 Analyses of vital sign variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital sign variables (values and change from baseline) will be calculated for each 
scheduled visit (baseline, each post-baseline time point, last on-treatment value) by treatment 
group.   
The incidence of PCSAs at any time during the On-treatment period will be summarized by 
treatment group irrespective of the baseline level and/or according to the following baseline status 
categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 


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A listing of patients with at least 1 post-baseline PCSA will be provided and will display the 
patient’s profile over time of all vital sign parameters. Individual data listings will include the 
following flags: 
• 
Baseline values will be flagged “B”, 
• 
Parameter values reaching a PCSA limit will be flagged (‘+’ or ‘-’ depending on the 
direction). 
2.4.4.2 Analyses of electrocardiogram variables  
The frequency and percentage of 12-lead ECG interpretation (normal, abnormal) will be provided 
at each scheduled visit by treatment group. 
2.4.5 Analyses of immunogenicity variables  
An anti-drug antibody positive participant is defined as a participant with at least one treatment-
induced or treatment-boosted ADA-positive sample at any time. 
Summaries of ADA data will be provided for participants treated with efpeglenatide only. All 
summaries related to kinetics of ADA response (ADA status and magnitude, ADA attributes, 
participant status, ADA incidence) will be descriptive; no statistical significance tests will be 
performed on ADA data. The incidence of ADA status (positive/negative/inconclusive) will be 
summarized by visit, treatment, and individual titer for the ADA population. Incidence of 
treatment induced and treatment-boosted (treatment emergent) ADA during on-study period will 
be summarized by treatment. Incidence of participants with ADA cross-reactivity to endogenous 
GLP-1 (positive/negative), and to endogenous glucagon (positive/negative) will be summarized 
by visit and treatment. Incidence of participants with ADA directed against PEG linker, HMC001 
moiety and exendin-4 moiety (positive/negative), will be summarized by visit and treatment. 
Analysis will be conducted as appropriate to assess the relationship with hypersensitivity 
reactions. 
Incidence of participants with neutralizing antibodies against efpeglenatide and against 
endogenous GLP-1 and Glucagon will be summarized by visit and treatment. 
ADA data from unscheduled visits (due to SAE for example) will not be included in summary and 
will be presented only in ADA values listing. 
2.4.6 Analyses of pharmacokinetic variables  
Not applicable. 
2.4.7 Analyses of quality of life/health economics variables  
Not applicable.  


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2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Demographic formulas 
The participant’s duration of diabetes (years) is calculated using the date of informed consent and 
the date of diabetes diagnosis. 
If date of diabetes diagnosis is a complete date, then the duration of diabetes is (date of informed 
consent - date of diabetes diagnosis + 1) / 365.25. If date of diabetes diagnosis is a partial date: 
a) year and month are not missing, but day is missing, then day = 01 
b) year is not missing, but month and date are both missing, then month = January and 
day = 01. 
Renal function formulas  
The estimated GFR (mL/min/1.73 m2) will be calculated using the 4 variable MDRD formula:  
Standard unit: eGFR (mL/min/1.73 m2) = 175 x [Serum Creatinine (µmol/L)/88.4]-1.154  
x Age (year)-0.203 x 1.212 (if Black) x 0.742 (if female) 
Conventional unit: eGFR (mL/min/1.73 m2) = 175 x Serum Creatinine (mg/dL)-1.154  
x Age (year)-0.203 x 1.212 (if Black) x 0.742 (if Female) 
Laboratory safety variables 
For data below the lower limit of quantification (LLOQ) / limit of linearity, half of the lower limit 
value (i.e., LLOQ/2) will be used for quantitative analyses. For data above the upper limit of 
quantification (ULOQ) / limit of linearity, the upper limit value plus a unit value based on the 
digit of the variable following the sponsor’s standard convention (i.e., ULOQ+0.01 if the digit is 2 
for the parameter) will be used for quantitative analyses. Note: this rule not applicable to UACR.  
2.5.2 Data handling conventions for secondary efficacy variables  
Rules defined for the primary efficacy variable will apply to time-to-event of secondary efficacy 
variables.  
2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 


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Derived variables will be considered missing if any of the original variables required to calculate 
them are missing. For example, if either a baseline assessment or an endpoint assessment is 
missing for a particular patient, then change from baseline at endpoint will be missing. Depending 
upon the assessment, analyses may not include all patients in the analysis population, because 
certain patients in the intended population may have missing data. 
Handling of computation of treatment duration if IMP end of treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment case report form page.  If this date is 
missing or a partial date, the exposure duration should be left as missing.  
Handling of medication missing/partial dates 
In general, no imputation of medication start/end dates or times will be performed.  If a 
medication date or time is missing or partially missing and it cannot be determined whether it was 
taken prior or concomitantly or at baseline, it will be considered a prior, concomitant, baseline, 
and post-treatment medication. 
For partial start and stop dates for SGLT2 concomitant or post-treatment medications, the 
following imputation rules apply: 
• 
If the day of the start date is missing the start date is set to 15th of the month  
• 
If the day and month of the start date are missing, then the start date is set to 15th June of 
the year. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial AE/hypoglycemia onset dates and times will be imputed so that if the partial 
AE/hypoglycemia onset date/time information does not indicate that the AE/hypoglycemia started 
prior to treatment or after the TEAE period, the AE/hypoglycemia will be classified as 
treatment-emergent.  No imputation of AE end dates/times will be performed.  These data 
imputations are for categorization purpose only and will not be used in listings.  No imputation is 
planned for date/time of AE resolution. 
Handling of adverse events/hypoglycemia when date and time of first IMP administration is 
missing 
When the date and time of the first IMP administration is missing, all AEs/hypoglycemia that 
occurred on or after the day of randomization should be considered as TEAEs.  The exposure 
duration should be kept as missing. 
Handling of adverse events/hypoglycemia when IMP end of treatment date is missing 
For the purpose of defining TEAE period, the date of the last administration of double-blind IMP 
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If the date of last administration reported on the e-CRF “Treatment Status” page is  
• 
Partially missing, it will be imputed with a date as late as possible before or on the date of 
death, if the end of treatment reason was death or study discontinuation date if available on 
the eCRF “Completion of End of Study” or study close-out visit date for patients who 
completed the study.  
• 
Completely missing, it will be imputed with the date of death, if the end of treatment 
reason was death or study discontinuation date if available on the eCRF “Completion of 
End of Study” or study close-out visit date for patients who completed the study. 
If the study discontinuation date on eCRF “Completion of End of Study” page is  
• 
Partially missing, it will be imputed with a date as late as possible. 
• 
Completely missing, all adverse events occurred on or after the first administration of 
double-blind IMP will be considered as treatment emergent adverse events. 
Handling of missing assessment of relationship of adverse events to IMP  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered.  If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   


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Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with a reference identification number that links the new record to the original 
record. An AE that worsened or became serious will be considered a new recurring AE in the 
summary of recurrent events or in the summary of events by time intervals. 
2.5.4 Windows for time points  
Time windows will not be applied to visits.  Nominal visits will be used for descriptive statistics.  
Display of safety data by visit (laboratory variables and vital signs) 
Descriptive statistics (N, mean, SD, minimum, median, maximum) of quantitative laboratory 
variables and vital signs (observed data and change from baseline) during the TEAE period for all 
scheduled visits as per protocol will be provided (i.e., only including participants having non-
missing assessments at a nominal visit). Summaries showing data by visit will be presented 
according to the visit number and labeled with the targeted approximate month. 
As specified in the study protocol, laboratory data from scheduled visits are reported by central 
laboratories. When both central and local laboratories report values from the same blood sample 
(ie, sample collected at the same date and time), only measurements from the central laboratory 
will be included in the analyses. When only local laboratory results are reported and central 
laboratory results are unavailable, the local results will not be used in the efficacy analyses. In the 
safety analyses, local results will only be used in the PCSA summary if they are accompanied by a 
local laboratory normal range. 
When a participant has more than 1 measurement from the central laboratory for the same 
laboratory parameter on the same date, the average of the measurements will be used. For the 
same laboratory parameter, if a participant has more than one measurement on different dates for 
the same scheduled visit, the value closest to the scheduled visit will be used for the scheduled 
visit. When the values for the same scheduled visit are equidistant, the last value should be used 
for the scheduled visit. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will not be included in the 
by-visit summaries, but will be used for computation of baseline, last on-treatment value, and PCSAs. 
2.5.6 Pooling of centers for statistical analyses  
Center will not be included in the statistical models for efficacy analyses. However, all centers within 
a region will be pooled, and region will be included as a fixed factor in a parametric statistical model 
(e.g., Cox proportional hazards model, etc.) for primary and secondary efficacy endpoints.  
2.5.7 Statistical technical issues  
None. 


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3 
INTERIM ANALYSIS  
No interim analysis is planned. 
 


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4 
DATABASE LOCK  
The database is planned to be locked approximately 4 to 6 weeks after the last patient last visit. 


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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be performed by using SAS® version 9.4 or higher. 
 


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6 
REFERENCES  
Not applicable. 
 


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7 
LIST OF APPENDICES  
 
Appendix A: 
Potentially clinically significant abnormalities (PCSA) criteria 
Appendix B: 
Summary of statistical analyses  
Appendix C: 
Calculation/Derivation details of time-to-event efficacy/safety endpoints 
Appendix D: 
Sample SAS® code for supportive analyses for missing data of primary efficacy 
endpoint 
 
 
 


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Appendix A 
Potentially clinically significant abnormalities criteria  
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From 30 May 21, 2014) 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not 
in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in ULN, not 
in IU/L.  
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in ULN, not 
in IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L or mg/L. 
Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, 
whatever the interval between measurements. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one 
mentioning zero can be deleted. 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From 30 May 21, 2014) 
Parameter 
PCSA 
Comments 
CLcr (mL/min) 
(Estimated creatinine 
clearance based on the 
Cockcroft-Gault 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
eGFR (mL/min/1.73 m²) 
(Estimate of GFR 
based on an MDRD 
equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with impaired renal 
function-study design, data analysis, and impact on 
dosing and labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L (Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential count 
available. 
Lymphocytes 
>4.0 Giga/L 
 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From 30 May 21, 2014) 
Parameter 
PCSA 
Comments 
Neutrophils 
<1.5 Giga/L (Non-Black); <1.0 Giga/L (Black) 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 17th Ed., 
2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from baseline are 
more relevant than based on absolute value. Other 
categories for decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for particular drug 
development, the analysis is redundant with that of 
Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on drug-induced 
blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 bpm 
≥120 bpm and increase from baseline≥20 bpm 
To be applied for all positions (including missing) 
except STANDING. 
SBP 
≤95 mmHg and decrease from baseline ≥20mmHg 
≥160 mmHg and increase from baseline ≥20 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 mmHg 
≥110 mmHg and increase from baseline ≥10 mmHg 
To be applied for all positions (including missing) 
except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
Ref.: ICH E14 guidance (2005) and E14 Q&A 
(2012), and Cardiac Safety Research Consortium 
White Paper on PR and QRS (Nada et al. Am Heart 
J. 2013; 165(4) : 489-500) 


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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
(From 30 May 21, 2014) 
Parameter 
PCSA 
Comments 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20 bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20 bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
>220 ms 
>220 ms and increase from baseline ≥25% 
>240 ms 
>240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA 
categories to be identified in individual 
subjects/patients listings. 
 
 


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Appendix B 
Summary of statistical analyses  
 
EFFICACY ANALYSIS 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoints 
Time to first occurrence of CV 
death, non-fatal MI, non-fatal 
stroke (non-inferiority) 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
Yes 
sensitivity analyses 
(see  
Section 2.3.4.1.3) 
Yes Subgroups: 
age, sex, race etc. 
(see  
Section 2.3.4.1.3) 
No 
Secondary endpoints 
Time to first occurrence of CV 
death, non-fatal MI, non-fatal 
stroke (superiority) 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
Same as primary 
endpoint 
Above 
No 
Time to first occurrence of CV 
death, non-fatal MI, non-fatal 
stroke, coronary 
revascularization, 
hospitalization for unstable 
angina 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
No 
No 
No 
Time to first occurrence of New 
onset or progression to macro 
albuminuria (>300 mg/g) 
accompanied by a UACR value 
increase of ≥30% from 
Baseline,  
Sustained ≥40% decrease in 
eGFR from Baseline (for 
≥30 days), Chronic dialysis (for 
≥90 days), Renal transplant, 
Sustained eGFR 
<15 mL/min/1.73 m2 (for ≥30 
days)  
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors  
 No 
No 
No 
 
 
 
 
 
 
Exploratory endpoints 
 
 
 
 
 
Time to stroke or death 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
No 
No 
No 
Time to Death 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
 No 
No 
No 
Time to stroke 
ITT 
Cox proportional 
hazards model with 
No 
No 
No 


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Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
treatment, region, and 
stratification as fixed 
effect factors 
Time to CV Death 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
 No 
No 
No 
Time to MI 
ITT 
Cox proportional 
hazards model with 
treatment, region, and 
stratification as fixed 
effect factors 
 No 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
ITT= Intent-to-treat 
 
SAFETY ANALYSES 
Endpoint 
Analysis 
population 
Primary analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Adverse events 
Safety 
Follow safety guidelines 
No 
By intrinsic 
factors  
See AESI and 
AERSM section 
Clinical laboratory data 
Safety 
Follow safety guidelines 
No 
No 
No 
Vital signs 
Safety 
Follow safety guidelines 
No 
No 
No 
Hypoglycemia 
Safety 
Follow safety guidelines 
No 
By intrinsic 
factors  
See analysis of 
hypoglycemia section 
Anti-drug Antibody 
 
Safety 
Follow safety guidelines 
No 
No  
See analyses of 
immunogenicity 
variables 
 section 


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Appendix C 
Calculation/Derivation details of time-to-event efficacy/safety 
endpoints  
 
This section describes the calculation of the time to event and the time that patients without event 
and were in the study (under risk).  
For patients with an event, the time to event is calculated as:  
Date of event – start date + 1 
For patients without an event, the time at risk is calculated as:  
Date of censoring – start date + 1 
For specific analysis, events that occur any time during the data period of the corresponding 
analysis will be considered as eligible events.  
Start date  
In general, the start date of an efficacy event will be the date of randomization unless otherwise 
specified. However, the date of first IMP taken will be used as the start date for the analysis 
(analyzed as occurrence of and time to first event) of following events:  
• AE (including AE, AESI, AERSM) 
Onset of event (date of event)  
If the event is adjudicated, the date of event will always be the date determined by the CEC 
adjudication even it is different from the investigator reported date.   
 
For composite outcomes, e.g. time to CV death, non-fatal MI and non-fatal stroke, the earliest 
onset date of each individual component will be used.  
 
For the analysis of the endpoints ‘time to CV death’ and ‘time to all-cause death’, the time to 
death rather than time to the first onset of the fatal event will be used. 
 
Handling of missing or incomplete event dates  
If the onset dates (adjudicated by CEC) of time-to-event endpoints is completely missing, then use 
investigator reported onset date given this investigator date is complete and available. If the onset 
dates (adjudicated by CEC) is partial missing, then if the partial available dates be consistent with 
the investigator dates, use investigator date given it is more complete. And impute any remaining 
missing onset dates using following algorithm.   
• If only month of the event is known, then the 15th day of this month will be imputed for a 
missing day and year of the start date will be imputed as the year, or  


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• If only the year of the event is known, then 15th of June will be imputed for the missing 
day and month, or  
If the resulting imputed dates are prior to the randomization date, imputed date will be reset to the 
randomization date. For non-death event, no imputation will be made for completely missing date. 
For death, the impute date be the latest of all imputed event dates and patient’s last trial contact 
date.  
Censoring 
The underlying rule for censoring is that the censoring date should be the last date the patient is 
known to be free of the event endpoint (free of each component for composite endpoint) on or 
before study close-out visit.   
a. General censoring rule for primary MACE efficacy endpoint:  
For patients who have no primary MACE endpoints, they will be censored using the following 
rules: 
• Patients who completed the study and not died before the study completion will be 
censored at their study close-out visit date or follow-up visit date.  
 
Note: If there are CV events happening after the patient’s study close-out visit date and the 
event’s proceeding/related event’s onset date is on or before the study close-out visit date, 
in this case, this CV events will be included in efficacy analysis if it positively 
adjudicated. The patient will still be censored at study close-out visit date if these events 
not adjudicated positively.  
 
For example, for a CV death, if the onset date of its proceeding fatal stoke is before the 
patient’s study close-out visit date and the CV death date is after study close-out visit date 
(before DBL date), this CV death will be included in efficacy analysis if positively 
adjudicated as CV death. 
 
Another example, for a HHF, if the onset date of its proceeding HF is before study close-
out visit date and its resulted hospitalization is after study close-out visit date, this HHF 
will be included in efficacy analysis if positively adjudicated. Otherwise, the patient will 
be censored at study close-out visit date if the HHF is not positively adjudicated.  
 
• Patients who died before study close-out (i.e. Death reported on the ‘Completion of End of 
Study’) will be censored at their date of Non-CV death  
 
• Patients who discontinued the study will be censored at their later of study discontinuation 
date or latest date with cardiovascular efficacy endpoint information (MI/UA, heart failure, 


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cerebrovascular event, coronary procedure, admission to hospital/emergency room, or 
cardiac biomarkers as collected in eCRF) collected. 
 
More specific: If there are events happening after the patient’s study discontinuation date 
and the events are not positively adjudicated, the latest date of these events will be the new 
censored date of the patient.  
b. Specific censoring rule for all-cause mortality 
Patients who did not die will be censored at the latest date of:  study close-out visit date, date of 
vital status (if alive), or date last known to be alive (if LTFU). Usually, this is the date of ‘Date of 
last available information’ in ‘Subject Status’ form for patient alive at that date.  
c. Specific censoring rule for composite renal endpoints 
Patients without the event will be considered censored at their latest of last laboratory sample date 
where eGFR/UACR results are available and patient’s last visit date. If a patient doesn’t have the 
eGFR/UACR measurements after a certain timepoint, but a dialysis procedure not meeting the 
definition of chronic occurs after the last eGFR/UACR measurement and last visit date, the 
patient will be censored at the last start date of dialysis.  
Patients without laboratory measurement at either baseline or post-baseline will be censored at 
Day 1.  
d. Specific censoring rule for eGFR (UACR) endpoint only  
Patients without an event will be considered censored at the earlier of their last laboratory sample 
date where eGFR (UACR) results are available. 
Patients without laboratory measurement at either baseline or post-baseline will be censored at 
Day 1.  
e. Censoring for severe hypoglycemia or AE (as part of general AE analysis)  
 
To keep the analysis of severe hypoglycemia consistent with the overall AE analysis, for AE, a 
patient without an adverse event will be considered censored at the date of last IMP taken + 30 
days or date of death, if earlier. For severe hypoglycemia, a patient without a severe 
hypoglycemia will be considered censored at the date of last IMP taken + 7 day or date of death, 
whichever earlier.  


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Appendix D 
Sample SAS® code for supportive analyses for missing data of 
primary efficacy endpoint  
 
* VARIABLES;  
* cnsrn -  censoring indicator, cnsrn=1-cnsr with 1=event, 0=censor; 
* adt -  event or censoring date; 
* rfstdt – randomization date  
* EOSSTT – whether patients completed or discontinued from study;  
* EOTSTT – weather patients either completed or discontinued from treatment; 
* TRTEDT– treatment end date;* armn – treatment arm, 0 for control; 
* planned_closeout_date – planned closeout visit date for patients without closeout visit 
 
data sce1 sce2 sce3 sce4; 
 
set &data; 
 
aval_trted= adt-trtedt+1 ; 
     
     ** subjects are treatment completer**;       
    if EOTSTT ^='DISCONTINUED' THEN output sce1; 
     *** 2a: subjects with MACE before IMP discontinuation; 2b: 
subjects with first MACE after IMP disct and study completer ***;  
    if (EOTSTT='DISCONTINUED' and CNSRN=1 and ADT<=TRTEDT ) OR 
(EOTSTT='DISCONTINUED' and CNSRN=1 AND ADT>=TRTEDT and 
EOSSTT^="DISCONTINUED")   then output sce2;  
     *** subjects discontinued IMP and study, 3a: first MACE after 
pEOS, 3b: first MACE after pEOS ***/; 
    if EOTSTT='DISCONTINUED' AND EOSSTT = 'DISCONTINUED' AND  CNSRN=1 
AND ADT>=TRTEDT  then output sce3; 
     **** 4: subjects of discontinued treatment and study without MACE 
by study closeout visit ****; 
    if EOTSTT='DISCONTINUED' AND EOSSTT='DISCONTINUED' and CNSRN=0   
THEN OUTPUT SCE4;  
  run; 
   
   *** combine scenario 2 and 3 to estimate hazard rate **;  
    data pattern1; 
      set sce2 sce3; 
    run;  
 
    proc sort data=pattern1; 
 
  by armn; 
run; 
ods output  PosteriorSample = PostSamp; 
    proc phreg data = pattern1; 
         model aval_trted*cnsrn(0)=; 
    ** Number of imputation times = nmc/thinning = 100 times; 
         bayes seed=14828 piecewise=hazard (ninterval=1 prior=gamma) 
nbi =2000 thinning=10 nmc=1000;  
         by armn;    


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     run; 
 
    /*proc print data=postsamp;    
      run; */ 
 
    proc sort data=postsamp; 
         by armn; 
    run;  
 
   data parout; 
      retain _imput_ ; 
 
    set PostSamp; 
 
    by armn;  
 
     if first.armn then 
 
     _imput_=0; 
 
       _imput_ =_imput_ +1; 
    run; 
 
 
   DATA PATTERN2; 
       SET SCE4; 
   RUN;  
 
   proc sort data=PATTERN2; 
      by armn; 
   run; 
 
  proc sql; 
     create table pattern2_a as 
 
   
 select * 
 
 
 
from pattern2 as r full join parout as l 
 
 
 
 
on r.armn=l.armn; 
    quit; 
***********************************************************; 
   data tempdata; 
   
  set  pattern2_a; 
 
  by armn; 
      *** Note: Simulate time to event. As a sensitivity analysis, 
multiply hazard (lambda) for treated subjects by the delta1 ***;  
 
 
  if armn=1 then 
 
 
  _lbdcur=Lambda1*1; 
 
   else 
_lbdcur=Lambda1*&delta1; 
 
      Scens=1*exp(-1*(adt-trtedt)*_lbdcur);  ** compute 1- 
survival at censored time; 
 
      Fcens=1-Scens; 
 
      u=Fcens+ranuni(14828)*(1-Fcens);  ** simulate uniform r.v 
from Fcens to 1; 
 
      imp_censor_date =trtedt - (log(1-u))/_lbdcur; 
 
      format imp_censor_date YYMMDD10.; 


Statistical Analysis Plan  
12-Aug-2020 
SAR439977-EFC14828 - efpeglenatide 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 59 
 
  if imp_censor_date > scv then 
 
 
  do; imp_censor_date  = scv; 
 
 
 
  imp_censor=0;   /*imp-censor: 1 event, 0 further 
censored*/ 
 
 
 end; 
 
 else 
 
 
 do; imp_censor=1;   end; 
     run; 
/*observed data no missing data first: sce2 and sce3*/ 
   data complete; 
   
 set sce1 sce2 sce3; 
 
  imp_censor=cnsrn; 
 
  imp_censor_date=adt; 
 
  _imput_=0; 
 
 do i = 1 to 100; 
 
 
 _imput_=_imput_+1; 
 
 
 output; 
 
  end; 
    run; 
 
   /*combine observed data with imputed data (sce4 with missing data) 
*/ 
   data imputed; 
 
  set complete tempdata; 
 
  imp_time=imp_censor_date- rfstdt; 
 
  if armn=1 then armpool=1; else armpool=2; /*armpool combine 
treatment group 4mg and 6mg in one group*/ 
 
  drop loglike logpost u iteration;  
    run; 
  
   /*proc print data=imputed (obs=1000); 
   var armn armpool; 
    run; */ 
 
   proc sort data=imputed; 
 
  by _imput_ armpool; 
   run; 
 
  proc phreg data = imputed; 
 
 by _imput_; 
 
 class armpool (ref=first) region1 STRATUM; 
 
 model imp_time*imp_censor(0)=armpool region1 STRATUM/risklimits 
rl; 
 
 ods output ParameterEstimates=_es; 
   run; 
/********************************************************/ 
    proc sort data=_es; 
        by parameter ClassVal0; 
     run;  
    proc mianalyze data=_es alpha=0.05; 


Statistical Analysis Plan  
12-Aug-2020 
SAR439977-EFC14828 - efpeglenatide 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 60 
 
    by Parameter ClassVal0; 
 
     modeleffects Estimate; 
 
     STDERR StdErr; 
 
    ods output ParameterEstimates = _es_mianal;     
    run; 
 
   data mihr; 
   
  set _es_mianal; 
 
  where parameter='armpool';  /*only keep hazard ratio of 
treatment*/ 
 
  LogHR_mi=Estimate; 
 
  HR_mi=exp(Estimate); 
 
  HR_LCL_mi=exp(LCLMean); 
 
  HR_UCL_mi=exp(UCLMean); 
 
  Delta=&delta1;  
 
  keep Parameter ClassVal0 LogHR_mi HR_mi HR_LCL_mi HR_UCL_mi 
Probt delta; 
 
  rename Probt=Probt_mi; 
   run; 


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