A 56-week, Multicenter, Double-blind, Placebo-controlled, Randomized Study to Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Diet and Exercise
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Hanmi Pharmaceutical Company Limited

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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 
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According to template: Version Sanofi dated 12-SEP-2017 based on TransCelerate CPT version 4
Page 1
AMENDED CLINICAL TRIAL PROTOCOL 03
Protocol title:
A 56-week, Multicenter, Double-blind, 
Placebo-controlled, Randomized Study to Evaluate the 
Efficacy and Safety of Efpeglenatide Once Weekly in 
Patients with Type 2 Diabetes Mellitus Inadequately 
Controlled with Diet and Exercise
Protocol number:
EFC14822
Amendment number:
03
Compound number 
(Trademark/INN):
SAR439977/efpeglenatide
Short title:
Efficacy and Safety of Efpeglenatide Versus Placebo in 
Patients with Type 2 Diabetes Mellitus Inadequately 
Controlled with Diet and Exercise (AMPLITUDE-M)
Sponsor name:
Legal registered 
address:
Regulatory agency identifying number(s):
EudraCT number:
2016-001857-42
IND number:
112780
UTN number:
U1111-1182-1806
Approval Date:
7-Jun-2018
Total number of pages:
100
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Sponsor signatory:
Please refer to the last page of this document for electronic signatures including date and time
Monitoring Team Representative’s 
Name and Contact Information:
  
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amended protocol 03
Version number: 1 (electronic 3.0) 
07 June 2018
Amended protocol 02
Version number: 1 (electronic 2.0)
27 March 2018
Amendment 01a
Version number: 1 (electronic 1.0)
16 January 2018
Original Protocol
Version number: 1 (electronic 2.0)
26 September 2017
a
Similar to Amended protocols, Amendment 01 contains the full amended text of the protocol plus description of changes versus the previous 
version of the protocol. The change of the name “amendment” to “amended protocol” is due to process change at the Sponsor company.
AMENDMENT 03 (07 JUNE 2018)
This amendment 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
In response to a BfArM (Germany) request, the protocol was updated to add the rationale for the 
selected efpeglenatide doses and to add an appendix subsection related to acute kidney failure as a 
consequence of severe gastrointestinal (GI) events and dehydration. In response to a request from 
the health authority (HA) in Poland, monthly home urine pregnancy tests have been added. 
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In addition, Sanofi uses this opportunity to edit other sections of the protocol as listed below, to 
update text with new available information (including statistical analysis update in response to an 
FDA request), to align the procedures with those in other studies within the program and/or for 
better clarity.
Inconsistencies, typographical, and spelling errors throughout the document were also corrected.
Section # and 
Name
Description of Change
Brief Rationale
Short title
Section 1.1 
Synopsis
Added study name ‘AMPLITUDE-M’
A name was selected for the program and was added 
to the study title.
Section 1.1 
Synopsis, 
Section 3 Objectives 
and Endpoints
Wording of tertiary objective (immunogenicity) 
and secondary objectives and corresponding 
endpoints of glycemic control, body weight, and 
safety are modified.
Reworded for clarity, and to harmonize with the other 
protocols in the program.
Secondary objective and corresponding 
secondary endpoints which are not part of 
multiplicity analysis are deleted from secondary 
and added under tertiary/exploratory endpoints.
Only key efficacy endpoints included in the hierarchical 
testing and selected safety endpoints will be 
considered Secondary Endpoints; all others will be 
included in Tertiary/exploratory endpoints.
Deletion of safety endpoints: laboratory 
variables, vital signs, and 12-lead ECG.
These are safety parameters assessed during the 
study and will be presented descriptively (detailed in 
SAP). At program level, it was decided not to consider 
them endpoints.
Section 1.1 
Synopsis,
Section 6 Study 
Interventions 
administered
Added placebo to IMP dose schedule table.
Placebo arm dosing was missing by mistake from the 
table.
Section 1.3 
Schedule of 
activities
Minimum duration of screening (V1 to V2 and 
V2 to V3) has been clarified.
To clarify the minimum period needed between 
screening and randomization to allow IMP supply 
(triggered by screening confirmation in IRS).
Added following text for pregnancy test: at on-
site visits and monthly at home in between 
visits.
To add, at Polish HA request, monthly pregnancy tests 
to WOCBP included in the study.
Section 4.3 
Justification for dose
Modified and provided additional information for 
dose justification.
To clarify, at BfArM request, rationale for efpeglenatide
doses to be evaluated in the study.
Section 5.2 
Exclusion criteria
Exclusion criteria E01 modified and added 
history of surgery affecting gastric emptying.
Exclusion criteria E15 modified and added 
‘clinical study involving any other type of 
medical research’.
Exclusion criteria E16 updated to clarify the 
exclusion of participants with previous GLP-1RA 
intolerance.
E01, E15, and E16 were amended to provide more 
details and clarify the patients’ eligibility criteria.
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Section # and 
Name
Description of Change
Brief Rationale
Section 5.2 
Exclusion criteria
Section 10.4 
Appendix 4 
Contraceptive 
guidance and 
collection of 
pregnancy 
information
Exclusion criteria E19 deleted details of male 
contraception.
Deleted details of male contraception from 
Section 10.4 Appendix 4.
Efpeglenatide was not genotoxic, and a fertility and 
early embryonic development study in rats revealed no 
effect on male or female fertility and mating 
performance. 
Furthermore, risk of embryo-fetal toxicity in female 
partners of male subjects taking efpeglenatide (via 
seminal fluid) can be excluded. This is based on an 
exposure assessment performed according to 
methods prosed by Banholzer et al. (1) and an FDA 
guidance of 2015 (2) based on numerous parameters 
such as exposure at no-observed-adverse-effect level
(NOAEL) in embryo-fetal studies in 2 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.
Section 6.3.2 
Randomization code 
breaking during the 
study
Added following text, ‘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 closure. 
Furthermore, when completing forms (eg, AE, 
SAE, adjudication information), the IMP should 
not be disclosed on the forms.’
Protocol updated to reflect the actual instructions 
provided to the sites to ensure blinding preservation at 
Sponsor/CRO team level, to allow an unbiased 
analysis of data.
Section 6.5 
Concomitant therapy
Added note for insulin use and also added 
DPP-4 inhibitors (eg, sitagliptin, saxagliptin, 
vildagliptin, or linagliptin), which are prohibited 
during the study.
This information was omitted in error from previous 
version of the protocol. DPP-4 inhibitors are not 
allowed to be taken during the study as this class is 
not approved for use in combination with a GLP1 RA. 
It was also clarified that short-time administration of 
prandial insulin (for acute illness, surgery etc) is 
allowed.
Recommendation for concomitant use of drugs 
with a narrow therapeutic window was added.
To harmonize with the Investigator’s Brochure for 
efpeglenatide.
Section 8.2.4 
Clinical safety 
laboratory 
assessment
Modified the text pertaining to local laboratory 
results which are used to make study treatment 
decision.
Clarification of the local laboratory results that sites 
need to report in the eCRF to support medical 
evaluation of AEs.
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Section # and 
Name
Description of Change
Brief Rationale
Section 1.1 
Synopsis
Section 9.4.1 
Efficacy analysis
Updated the primary efficacy endpoint analysis 
method.
Following FDA request, the statistical methodology of 
the primary efficacy endpoint has been updated.
Section 9.4.1 
Efficacy analysis
Added subgroups of duration of diabetes 
(<10, ≥10 years) and baseline estimated GFR 
categories (mL/min/1.73 m2): (<30; [30-60]; >60) 
for assessment of treatment effect.
Prioritized order has been changed for 
hierarchical testing procedure of secondary 
endpoints.
Added following endpoint in hierarchical testing 
procedure ‘change from baseline to Week 56 in 
body weight (kg) for efpeglenatide 2 mg versus 
placebo.’
For project harmonization, subgroups for statistical 
analysis have been added. Also the order of the 
secondary endpoints in multiplicity assessment was 
changed, to prioritize:  

At Week 30, testing of body weight for 4mg 
dose before testing of FPG for 6mg dose 
and testing of  HbA1c <7% for 2mg dose 
before testing  of FPG for 4mg dose.

At Week 56, testing of HbA1c < 7% for 6 mg 
dose before testing of body weight for 4mg 
dose.
Section 9.4.1 
Efficacy analysis
Added details of tertiary endpoint analysis under 
separate row.
Updated to follow the change in endpoints explained 
above (moved from secondary to tertiary endpoints).
Section 9.4.2 Safety 
analysis
Added the definition of 30-week on-study 
period.
Specifications for hypoglycemia have been 
added in observation period of safety data.
Following FDA request, the 30 week on study period 
has been added.
Clarification of study period definitions for 
hypoglycemia.
Section 10.5 
Appendix 5 Liver 
and other safety: 
suggested actions 
and follow-up 
assessments
Section 10.6 
Appendix 6 
Monitoring and 
management of 
participants with 
increased lipase 
and/or amylase, or 
calcitonin
All recommended actions regarding selected 
laboratory abnormalities and AEs were 
combined under the same section/appendix 
(Section 10.5 Appendix 5 Liver and other safety: 
suggested actions and follow-up assessments).
A new subsection was added: Section 10.5.4. 
GI events in relation to acute renal failure
Following sections have been also re-
numbered.
Section 10.6 Appendix 6 has been removed. 
Subheadings have been re-numbered 
accordingly.
Section 10.5.4 was added in response to BfArM 
question. Section was reorganized for better clarity 
and easy follow-up by the sites.
Section 10.7 
Appendix 7 Country-
specific 
requirements
A new section was added: Section 10.7 
Country-specific requirements.
To keep the section as per the Sanofi standard format 
and harmonize with the other studies in the program.
Throughout
Minor editorial, typographical error corrections 
and document formatting revisions
Minor, therefore have not been summarized.
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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE..................................................................2
DOCUMENT HISTORY...................................................................................................................................2
AMENDMENT 03 (07 JUNE 2018).................................................................................................................2
OVERALL RATIONALE FOR THE AMENDMENT........................................................................................2
TABLE OF CONTENTS..................................................................................................................................6
LIST OF TABLES .........................................................................................................................................10
LIST OF FIGURES........................................................................................................................................10
1
PROTOCOL SUMMARY ...............................................................................................................11
1.1
SYNOPSIS.....................................................................................................................................11
1.2
SCHEMA........................................................................................................................................16
1.3
SCHEDULE OF ACTIVITIES (SOA)..............................................................................................17
2
INTRODUCTION............................................................................................................................24
2.1
STUDY RATIONALE .....................................................................................................................24
2.2
BACKGROUND .............................................................................................................................24
2.3
BENEFIT/RISK ASSESSMENT.....................................................................................................25
3
OBJECTIVES AND ENDPOINTS .................................................................................................27
3.1
APPROPRIATENESS OF MEASUREMENTS..............................................................................28
4
STUDY DESIGN ............................................................................................................................30
4.1
OVERALL DESIGN........................................................................................................................30
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................30
4.3
JUSTIFICATION FOR DOSE ........................................................................................................31
4.4
END OF STUDY DEFINITION.......................................................................................................31
5
STUDY POPULATION ..................................................................................................................32
5.1
INCLUSION CRITERIA..................................................................................................................32
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5.2
EXCLUSION CRITERIA ...............................................................................................................32
5.3
LIFESTYLE CONSIDERATIONS...................................................................................................34
5.3.1
Meals and dietary restrictions ........................................................................................................34
5.4
SCREEN FAILURES .....................................................................................................................35
6
STUDY INTERVENTION...............................................................................................................36
6.1
STUDY INTERVENTION(S) ADMINISTERED..............................................................................36
6.1.1
Investigational medicinal product(s)...............................................................................................37
6.1.2
Noninvestigational medicinal products ..........................................................................................38
6.1.2.1
Rescue therapy..............................................................................................................................38
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................................................39
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................40
6.3.1
Methods of blinding........................................................................................................................40
6.3.2
Randomization code breaking during the study.............................................................................41
6.4
STUDY INTERVENTION COMPLIANCE ......................................................................................42
6.4.1
Return and/or destruction of treatments ........................................................................................42
6.5
CONCOMITANT THERAPY ..........................................................................................................43
6.6
DOSE MODIFICATION..................................................................................................................43
6.7
INTERVENTION AFTER THE END OF THE STUDY...................................................................43
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..........................................................................................44
7.1
DISCONTINUATION OF STUDY INTERVENTION .....................................................................44
7.1.1
Permanent discontinuation ............................................................................................................44
7.1.2
Temporary discontinuation.............................................................................................................45
7.1.2.1
Rechallenge ...................................................................................................................................46
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................46
7.3
LOST TO FOLLOW UP .................................................................................................................47
8
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................48
8.1
EFFICACY ASSESSMENTS ........................................................................................................48
8.1.1
Hemoglobin A1c.............................................................................................................................48
8.1.2
Fasting plasma glucose .................................................................................................................48
8.1.3
7-point self-monitored plasma glucose profiles .............................................................................48
8.1.4
Body weight....................................................................................................................................49
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8.1.5
Use of rescue therapy....................................................................................................................49
8.1.6
Patient Qualitative Assessment of Treatment................................................................................49
8.2
SAFETY ASSESSMENTS ............................................................................................................50
8.2.1
Physical examinations ...................................................................................................................50
8.2.2
Vital signs.......................................................................................................................................51
8.2.3
Electrocardiograms ........................................................................................................................51
8.2.3.1
12-lead electrocardiogram .............................................................................................................51
8.2.3.2
24-hour Holter electrocardiogram including diary..........................................................................51
8.2.4
Clinical safety laboratory assessments..........................................................................................52
8.2.5
Hypoglycemia.................................................................................................................................53
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................54
8.3.1
Time period and frequency for collecting AE and SAE information...............................................55
8.3.2
Method of detecting AEs and SAEs...............................................................................................56
8.3.3
Follow-up of AEs and SAEs...........................................................................................................56
8.3.4
Regulatory reporting requirements for SAEs .................................................................................56
8.3.5
Pregnancy......................................................................................................................................57
8.3.6
Cardiovascular and death events ..................................................................................................57
8.3.7
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ...........57
8.3.8
Guidelines for reporting product complaints/medical device incidents (including 
malfunctions)..................................................................................................................................57
8.4
TREATMENT OF OVERDOSE......................................................................................................57
8.5
PHARMACOKINETICS..................................................................................................................58
8.6
PHARMACODYNAMICS ...............................................................................................................58
8.7
GENETICS.....................................................................................................................................58
8.8
BIOMARKERS ...............................................................................................................................58
8.8.1
Immunogenicity assessments........................................................................................................59
8.9
HEALTH ECONOMICS..................................................................................................................59
9
STATISTICAL CONSIDERATIONS .............................................................................................60
9.1
STATISTICAL HYPOTHESES.......................................................................................................60
9.2
SAMPLE SIZE DETERMINATION ................................................................................................60
9.3
POPULATIONS FOR ANALYSES.................................................................................................61
9.4
STATISTICAL ANALYSES ............................................................................................................61
9.4.1
Efficacy analyses ...........................................................................................................................62
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9.4.2
Safety analyses..............................................................................................................................66
9.4.3
Other analyses...............................................................................................................................67
9.5
INTERIM ANALYSES ...................................................................................................................68
9.5.1
Data Monitoring Committee ...........................................................................................................68
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................69
10.1
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......69
10.1.1
Regulatory and Ethical Considerations..........................................................................................69
10.1.2
Informed Consent Process ............................................................................................................69
10.1.3
Data Protection ..............................................................................................................................70
10.1.4
Committees Structure ....................................................................................................................71
10.1.4.1 Data Monitoring Committee ...........................................................................................................71
10.1.4.2 Clinical Endpoint Committee..........................................................................................................71
10.1.4.3 Independent Expert........................................................................................................................71
10.1.5
Dissemination of Clinical Study Data.............................................................................................71
10.1.6
Data Quality Assurance .................................................................................................................72
10.1.7
Source documents .........................................................................................................................72
10.1.8
Study and Site Closure ..................................................................................................................73
10.1.9
Publication Policy...........................................................................................................................73
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................73
10.3
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................75
10.4
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................79
10.5
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................82
10.5.1
Laboratory abnormalities ...............................................................................................................82
10.5.2
Monitoring of participants with increased lipase and/or amylase >2 ULN .....................................87
10.5.2.1 Elevation of amylase and/or lipase >2 x ULN without clinical signs and/or symptoms .................87
10.5.2.2 Elevation of amylase and/or lipase >2 × ULN with clinical signs and/or symptoms......................88
10.5.3
Management of participants with increased calcitonin values.......................................................88
10.5.4
Gastrointestinal events in relation to acute renal failure................................................................89
10.6
APPENDIX 6: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................89
10.7
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS..............................................................89
10.8
APPENDIX 8: HYPOGLYCEMIA CLASSIFICATION ....................................................................90
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10.9
APPENDIX 9: PATIENT QUALITATIVE ASSESSMENT OF TREATMENT VERSION 2.............91
10.10
APPENDIX 10: ABBREVIATIONS.................................................................................................93
10.11
APPENDIX 11: PROTOCOL AMENDMENT HISTORY ................................................................95
10.11.1
Amendment 01: 16 January 2018..................................................................................................95
10.11.2
Amendment 02: 27 March 2018.....................................................................................................98
11
REFERENCES.............................................................................................................................100
LIST OF TABLES
Table 1 - Objectives and endpoints...............................................................................................................27
Table 2 - Overview of study interventions administered ...............................................................................36
Table 3 - Rescue criteria ...............................................................................................................................38
Table 4 - Populations for analyses................................................................................................................61
Table 5 - Efficacy analyses ...........................................................................................................................62
Table 6 - Safety analyses..............................................................................................................................66
Table 7 - Other analyses ...............................................................................................................................67
Table 8 - Protocol-required safety laboratory assessments..........................................................................74
Table 9 - Highly effective contraceptive methods .........................................................................................80
LIST OF FIGURES
Figure 1 - Graphical study design .................................................................................................................16
Figure 2 - Hypoglycemia classification..........................................................................................................90
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1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Protocol title: A 56-week, Multicenter, Double-blind, Placebo-controlled, Randomized Study to 
Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly in Patients with 
Type 2 Diabetes Mellitus Inadequately Controlled with Diet and Exercise
Short title:
Efficacy and Safety of Efpeglenatide Versus Placebo in Patients with Type 2 
Diabetes Mellitus Inadequately Controlled with Diet and Exercise 
(AMPLITUDE-M)
Rationale:
This study is designed to demonstrate the efficacy and safety of efpeglenatide when used as 
monotherapy in participants with Type 2 diabetes mellitus (T2DM) who have inadequate 
glycemic control with diet and exercise. Efpeglenatide will be compared to placebo, consistent 
with regulatory guidance.
Objectives and endpoints
Objectives
Endpoints
Primary
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, or 6 mg in comparison to placebo in HbA1c 
change from baseline to Week 30 in participants with T2DM 
inadequately controlled with diet and exercise.

Change from baseline to Week 30 in HbA1c
Secondary
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg in comparison to placebo on 
glycemic control.

Number of participants with HbA1c <7% at
Week 30

Change from baseline to Week 30 in fasting plasma
glucose (FPG)

Change from baseline to Week 56 in HbA1c
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg in comparison to placebo on body 
weight.

Change from baseline to Weeks 30 and 56 in body
weight
To evaluate the safety of once-weekly injection of efpeglenatide 
2, 4, and 6 mg.

Number of participants with at least one
hypoglycemic event during treatment period

Number of hypoglycemic events per
participant-year during treatment period

Number of participants with AEs (see Section 8.3)
AE: adverse event; FPG: fasting plasma glucose; HbA1c: hemoglobin A1c; T2DM: type 2 diabetes mellitus.
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Overall design:
This study is a Phase 3, multicenter, double-blind, placebo-controlled, randomized, 4-arm, parallel 
group study in participants with T2DM who have inadequate glycemic control with diet and 
exercise.
The randomization (1:1:1:1) to efpeglenatide 2 mg, efpeglenatide 4 mg, efpeglenatide 6 mg, or 
placebo will be stratified by Screening hemoglobin A1c (HbA1c; <8%, ≥8%) and Visit 3 
(Baseline, Day 1) body mass index (BMI; <30 kg/m2, ≥30 kg/m2).
An independent Data Monitoring Committee (DMC) will review clinical study safety data and an 
Independent Clinical Endpoint Committee (CEC) will review, assess and/or adjudicate all events 
of death, selected cardiovascular adverse events (AEs), pancreatic events and other selected AEs 
(see Appendix 1 [Section 10.1] for further details of study committees).
Number of participants:
Sufficient participants will be screened to achieve 400 randomized participants assigned to study 
treatment for an estimated total of 100 participants per treatment group. All randomized 
participants will be included in the population analyzed for efficacy endpoints. Section 9.2 gives 
details of the sample size determination.
Intervention groups and duration:
The study will comprise 4 periods:

An up to 3-week Screening Period (with a minimum of 11 days)

A 30-week double-blind, placebo-controlled Core Treatment Period, for efficacy and 
safety assessment

A 26-week double-blind, placebo-controlled Treatment Extension Period; participants will 
remain on the randomized investigational medicinal product (IMP) regimen

A 6-week Follow-up Period to collect post-treatment safety information for all participants 
after last dose of IMP
The maximum study duration per participant will be 65 weeks.
Study interventions
Investigational medicinal product
Efpeglenatide

Formulation: 500 μL of a sterile, non-pyrogenic, clear, colorless solution in a 1 mL 
disposable prefilled syringe (PFS)

Route of administration: subcutaneous (SC)
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
Dose regimen: SC injection once-weekly on the same week day (eg, each Monday) at any 
time of the day
Placebo

Formulation: matching placebo (sterile, non-pyrogenic, clear, colorless solution in a 1 mL 
disposable PFS)

Route of administration: SC

Dose regimen: once-weekly on the same week day (eg, each Monday) at any time of the 
day
The dose will be titrated as shown in the table below. From Week 4 (Visit 5) through the rest of 
the double-blind treatment period, participants will remain on the randomized IMP dose or 
placebo until the end of treatment (EOT) at Week 56 (Visit 14).
Investigational medicinal product dose schedule
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5 onward
Day 1
Visit 3
Week 1
Week 2
Visit 4
Week 3
Week 4
Visit 5
Dosing
on-site
at home
at home
at home
on-site
Efpeglenatide 2 mg
2 mg
2 mg
2 mg
2 mg
2 mg 
Efpeglenatide 4 mg
2 mg
2 mg 
4 mg 
4 mg 
4 mg 
Efpeglenatide 6 mg
2 mg
2 mg
4 mg
4 mg
6 mg 
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
Noninvestigational medicinal products
Rescue therapy
Open-label rescue medication(s) to treat hyperglycemia will be at the discretion of the 
Investigator and in accordance with local standard of care and prescribing practice. Except for 
other glucagon-like peptide 1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase 4 (DPP-4) 
inhibitors, any approved medication(s), including oral antidiabetic drugs or insulin, can be 
prescribed to treat the hyperglycemia. If a participant requires glycemic rescue, the IMP received 
during the randomized, double-blind treatment period should continue and must remain blinded 
until the end of the study (unless the Investigator considers a change necessary for safety reasons).
See Section 6.1.2.1 for full details of rescue therapy. 
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Statistical considerations:

Primary analysis:
The primary efficacy endpoint (change from Baseline to Week 30 in HbA1c) will be analyzed 
using HbA1c values at Baseline and Week 30 (observed or imputed), regardless of treatment 
discontinuation or initiation of rescue therapy. 
The primary analysis method for the primary efficacy endpoint will be an Analysis of Covariance 
(ANCOVA) model with missing values imputed by multiple imputation (MI) analysis methods in 
2 parts as follows:

Missing endpoint data in participants who prematurely discontinue the study treatment 
before the Week 30 visit will be imputed using a model estimated from participants in the 
same treatment arm who prematurely discontinue the study treatment before the Week 30 
visit but have the measurements for the endpoint (retrieved dropouts). Considering that the 
number of participants in each treatment arm who discontinue the study treatment but have
the measurement for the endpoint is expected to be small, a simple imputation model will 
be used, where only the baseline measurements are included as the predictor. Each 
treatment group will have their own imputation model. Missing data will be imputed using 
the regression method. 

Missing endpoint data in all participants, including those in the efpeglenatide arms, who 
stay on the study treatment until the Week 30 visit will be imputed separately, using a 
model estimated from participants in the placebo group who stay on the study treatment 
until the endpoint visit and have the Week 30 data available. The imputation model will 
include the randomization strata and corresponding baseline values but without including 
any intermediate values. Missing data will be imputed using the regression method. 
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data 
sets with complete data. Each of the complete datasets after the imputation will be analyzed by 
the ANCOVA model with the treatment groups (efpeglenatide 2, 4, or 6 mg, or placebo), 
randomization stratum of Screening HbA1c (<8%, ≥8%), randomization stratum of Visit 3 
(Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2), and geographical region as fixed effects, and 
Baseline HbA1c value as a covariate. The Baseline value is defined as the last available value 
prior to the first dose administration of IMP or the last available value on or before the date of 
randomization if not treated with the double-blinded IMP. 
The results from the 10 000 analyses will be combined using Rubin’s formula to provide the 
adjusted mean change in HbA1c from Baseline to Week 30 (regardless of treatment 
discontinuation or initiation of rescue therapy) for each treatment group, as well as the difference 
between each efpeglenatide dose and placebo and the 95% confidence interval (CI) for the 
difference.
The number of retrieved dropouts is expected to be small, and may not have sufficient data to 
support the imputation approach. If there are less than 5 participants in any arm who prematurely 
discontinue the study treatment before the Week 30 visit but have the measurement for the 
endpoint, a back-up imputation method for the primary efficacy analysis will be used. 
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In particular, missing endpoint data in all participants in both efpeglenatide and placebo groups, 
regardless of staying on the study treatment or not, will be imputed using a model estimated from 
participants in the placebo group with endpoint data, where randomization strata and baseline 
HbA1c value are included as the predictors. Missing data will be imputed using the regression 
method.
Hierarchical procedure will be done to adjust for the multiplicity of comparison. First, the highest 
dose of efpeglenatide (6 mg) will be compared to placebo. If the superiority is demonstrated, the 
superiority of 4 mg dose of efpeglenatide versus placebo will be tested. If demonstrated, the 
lowest dose (2 mg) will be tested. When the superiority is not obtained in a step, the sequential 
testing procedure will be stopped.
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group over the whole 
treatment period including the 26-week Safety Extension Period. The summary will include the 
number of observations, mean, standard deviation, standard error (SE), minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from Baseline (±SE) at each of the scheduled visits (using 
observed cases).

Analysis of secondary and other efficacy endpoints:
Continuous secondary efficacy endpoints will be analyzed using the same ANCOVA model with 
missing values imputed by similar MI method as the one used for the primary efficacy endpoint 
analysis. Differences between treatment groups and CIs will be estimated by this method. 
Categorical efficacy endpoints will be analyzed by Cochran-Mantel-Haenszel method stratified 
by the randomization strata. For the HbA1c <7.0% analysis, participants with missing 
HbA1c data at Week 30 or Week 56 will be considered non-responders in the ITT population.
Comparisons of time to event endpoints between treatment groups will be performed using the 
Cox proportional hazards regression model with the treatment groups (efpeglenatide 2, 4, or 6 mg, 
placebo), randomization stratum of Screening HbA1c (<8%, ≥8%), randomization stratum of 
Visit 3 (Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2), and geographical region as the factors.
Data Monitoring Committee: Yes
See Appendix 1 (Section 10.1) for details.
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1.2
SCHEMA
Figure 1 - Graphical study design
1:1:1:1 randomization, stratified by HbA1c (<8%, ≥8%) and Visit 3 (Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2) 
Visit schedule: from Visit 1 (Week -3) to Visit 15 (Week 56/EOT + 6 weeks).
BMI body mass index; EOS end of study; EOT end of treatment; N number of patients; R randomization.
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1.3
SCHEDULE OF ACTIVITIES (SOA)
Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
Injection of weekly 
dose at day of visit
X
X
X
X
X
Participant will self-administer the injection 
only after blood samples have been drawn at 
the respective visit.
Injection of weekly 
dose may be on a 
different day than visit
X
X
X
X
X
X
X
See Table 2 for details of dosing windows
Informed consent
X
Informed consent taken prior to any 
study-related procedures being performed.
Inclusion and exclusion 
criteria
X
X
X
Check eligibility before Visit 2 and before 
Randomization.
Demography, 
medical/surgical history
X
Includes diabetes complications, CV and 
allergy history. Includes alcohol and smoking 
habits.
Physical examination 
X
X
X
X
X
X
X
X
X
X
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Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
Vital signs
X
X
X
X
X
X
X
X
X
X
BP and HR in sitting position after at least 
5 minutes of rest.
Height
X
Body weight
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
The 12-lead ECG recording should be 
obtained in supine position, prior to IMP dose 
administration
Injection training at Visit 2, 
retraining as needed; review 
of injection sites
X
X
X
X
X
X
X
X
X
See Section 6.1
Diary dispensation
X
X
X
X
X
X
X
X
X
Diary review
X
X
X
X
X
X
X
X
X
Glucose meter dispensation 
and training, training for 
hypoglycemia awareness and 
management
X
Diet and lifestyle counseling
X
X
X
X
X
X
X
X
X
As per current practice, to be documented.
IRT contact
X
X
X
X
X
X
X
X
X
X
X
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Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
IMP dispensed
X
X
X
X
X
X
X
X
At Visit 2 placebo training kit(s) will be 
allocated; self-injection will be done at site.
IMP collection and accounting
X
X
X
X
X
X
X
Compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
SMPG, diary, and IMP.
Efficacy
HbA1c
X
X
X
X
X
X
FPG
X
X
X
X
X
X
For these visits, participants need to come in 
fasting condition as described in 
Section 5.3.1.
7-point SMPG profiles
X
X
X
X
X
Performed on at least 1 day in the week prior 
to visits indicated. See Section 8.1.3 for 
complete details.
Fasting (pre-breakfast) 
SMPG
X
X
X
X
X
X
X
X
X
X
X
X
Recommended daily, mandatory at least 
3 days in the week prior to indicated visits with 
the study glucometer before breakfast and 
any intake of antihyperglycemic drug(s).
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Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
Safety
Rescue therapy assessment
X
X
X
X
X
X
X
X
X
X
Assessed by the Investigator after 
Randomization via fasting SMPG performed 
by the participants and/or via the central 
laboratory alerts received on FPG and on 
HbA1c (at Week 12 onward). 
See Section 6.1.2.1.
24-hour ECG (Holter) 
including diary
X
X
X
See Section 8.2.3.2
For 24-hour ECG (Holter) repeat procedure, 
Randomization may be delayed up to 7 days if 
needed.
Hematology
X
X
X
X
X
X
X
See Appendix 2 (Section 10.2).
Clinical chemistry
X
X
X
X
X
X
X
See Appendix 2 (Section 10.2).
Calcitonin
X
X
X
X
X
X
See Appendix 2 (Section 10.2).
Lipid profile
X
X
X
See Appendix 2 (Section 10.2).
Urinalysis
X
X
X
See Appendix 2 (Section 10.2).
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Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
C-peptide (fasting)
X
For this visit, participants need to come in 
fasting condition as described in 
Section 5.3.1. See Appendix 2 (Section 10.2).
Pregnancy test (for WOCBP)
X
X
X
X
X
X
X
X
X
X
Serum pregnancy testing (β-HCG) at 
Screening for WOCBP (Appendix 4
[Section 10.4]), urine pregnancy testing 
subsequently (at on-site visits and monthly at 
home in between visits).
If the urine test is positive, serum β-HCG 
should be tested for confirmation of the 
pregnancy.
Serum FSH and estradiol
X
For women of non-childbearing potential. In 
case the definition of postmenopausal or 
premenopausal cannot be satisfied (see 
Appendix 4, Section 10.4).
Anti-drug antibody sampling
X
X
X
X
X
X
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 
sample for anti-efpeglenatide antibodies 
assessments 4 and 6 months after the end of 
the treatment.
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Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
IMP concentration (PK) 
sampling
X
X
X
X
All participants will have 1 blood sample 
collected just before their weekly injection of 
the IMP (and at least 6 days after last dosing 
of the IMP) at selected clinical visits.
For a subset of participants: 1 additional 
post-dose sample will be taken either 4 days 
(±1 day) after first IMP dose (Week 1), or 
4 days (±1 day) after 4th dose (Week 4), or
4 days (±1 day) after 12th dose (Week 12). 
A separate consent will be signed. See 
Section 8.5.
Participant-reported outcomes
PQATv2
X
X
PQATv2 should be completed by the 
participant as far as possible at home before
on-site visits. See Section 8.1.6
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Procedure
Screening 
Period
Double-blind placebo-controlled Core Treatment 
Period
Double-blind, 
placebo-controlled Safety 
extension Period
Follow-up
Notes
Week
-3
-1
0
BL
2
4
8
12
18
24
30a
36
43
50
56
Last IMP
+6 wks
Visit
1
2
3
R
4

5
6
7
8

9
10
11

12
13

14
EOT
15
EOS
Acceptable range 
(days)
-21
(up 
to)
-7
(±3)
1
14
(3±)
28
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
252
(±5)
301
(±5)
350
(±5)
392
(±5)
434
(±7)
V2 can be done as soon as the Screening 
eligibility is confirmed and at least 7 days after 
screening visit (V1).
V3 can be done 4 to 10 days after V2.
V3 cannot be later than 21 days after V1 
(except in case of Holter re-test when an 
additional 1 week is allowed).
AE/SAE recording
Continuous assessment and recording throughout the study
Concomitant medication 
review
Reporting hypoglycemia 
(symptoms, SMPG)
Hypoglycemia eCRF page must be filled in for 
all SMPG ≤70 mg/dL (3.9 mmol/L) and/or in 
case of symptoms suggesting hypoglycemia
(between V1 and V2, SMPG values measured 
with non-study glucometer can be used)
a
In case of premature permanent IMP discontinuation, participants should have a visit as soon as possible with the assessments normally planned for the EOT visit (Visit 14; except for the 24-hour ECG and the 
7-point SMPG, which will be performed as scheduled). These should be performed as soon as possible after last IMP administration. Afterwards, the participants should continue in the study up to the scheduled 
date of study completion and be followed up according to the study procedures as specified in the protocol (except for PK assessment). Every effort will be made to have participants complete the Visit 10 
(Week 30) and Visit 14 (Week 56) assessments (primary and main secondary endpoints) at the minimum. For safety considerations, participants who wish to terminate all participation in the study should be 
assessed using the procedures normally planned for the post-treatment Follow-up Visit 15 at the minimum. At the time corresponding to their Visit 14 (Week 56), all attempts will be made to contact the participant
to inquire about safety/vital status.
ADA: anti-drug antibody; AE: adverse event; BL: Baseline; β-HCG: beta-human chorionic gonadotropin; BP: blood pressure; CV: cardiovascular; ECG: electrocardiogram; e-CRF: electronic Case Report Form; EOS:
end of study; EOT: end of treatment; FPG: fasting plasma glucose; FSH: follicle stimulating hormone; HbA1c: hemoglobin A1c; HR: heart rate; IMP: investigational medicinal product; IRT: interactive response 
technology; PK: pharmacokinetic; PQATv2: Patient Qualitative Assessment of Treatment version 2; R Randomization; SAE: serious adverse event; SMPG: self-monitored plasma glucose; WOCBP: women of 
childbearing potential.
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2
INTRODUCTION
Efpeglenatide is a GLP-1 RA that is being developed for once-weekly treatment of T2DM.
2.1
STUDY RATIONALE
The primary objective of this study is to assess the effect of the different doses of efpeglenatide on 
glycemic control as measured by the change in HbA1c from Baseline at Week 30, a well-accepted 
benchmark of overall and longer-term glycemic control. Main secondary objectives include 
assessing the effect of efpeglenatide on treatment success factors (proportion of participants who 
achieve HbA1c goals of <7.0%), additional glycemic parameters (FPG, 7-point self-monitored 
plasma glucose [SMPG] profiles [24-hour profile, mean 24-hour SMPG, average pre-breakfast 
SMPG, prandial glucose excursions]), proportion of participants requiring rescue therapy, time to 
initiation of rescue therapy, and on body weight.
2.2
BACKGROUND
Several classes of pharmacological treatments are approved for glucose control in T2DM, but 
good glycemic control remains challenging for many patients and new therapy options are 
necessary.
In recent years, the GLP-1 RA class of pharmacotherapy for T2DM has evolved as an effective 
treatment option from multiple daily over daily to weekly injection. Glucagon-like peptide 1
(GLP-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 their glucose-dependent mechanism of action, GLP-1 RAs are generally 
associated with a low risk of hypoglycemia.
Efpeglenatide (SAR439977), a GLP-1 RA, is a novel long-acting form of CA exendin-4 
(an exendin-4 analogue) that is being developed for the treatment of T2DM by once-weekly 
SC injection with an auto-injector. In clinical Phase 2 studies, it has shown effects on body weight 
and may therefore provide potential for development for use in obesity.
In total, 7 clinical studies (two Phase 1 studies and five Phase 2 studies) in approximately 
1000 participants, with approximately 720 exposed to efpeglenatide, have been completed. The 
Phase 2 studies have been conducted in participants with T2DM and in obese non-diabetic 
individuals. In participants with T2DM, weekly doses between 0.3 to 4 mg or monthly doses 
between 8 to 16 mg were used, whereas in non-diabetic obese subjects, weekly doses of 4 to 6 mg 
and doses of 6 and 8 mg every other week were investigated. Overall, these studies have 
demonstrated that efpeglenatide effect improves glycemic control and reduce body weight, with 
an overall favorable safety and tolerability profile consistent with currently available GLP-1 RAs. 
Three weekly efpeglenatide doses (2, 4, or 6 mg) have been selected based on the Phase 1 and 2 
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study data which suggest that they will demonstrate efficacy in the target population while 
mitigating potential safety concerns and the incidence of AEs.
Details (nonclinical and clinical) about efpeglenatide can be found in the latest edition of the 
Investigator’s Brochure (IB; 3).
2.3
BENEFIT/RISK ASSESSMENT
The non-clinical toxicological data and the safety data from clinical studies with efpeglenatide to
date (with a cut-off date of 22 June 2017) suggest a safety profile consistent with the known AE
profile of currently marketed GLP-1 RAs with the exception of potential liver toxicity. The 
following safety procedures are planned for the clinical study EFC14822:

Potential AEs common to the GLP-1 RA drug class are mainly GI disorders such as 
nausea/vomiting and rarely pancreatitis. Thus far, no case of pancreatitis has been 
identified with efpeglenatide. The trend over time for nausea and vomiting events 
appeared dose-related with an increase after the first injection, and generally decreasing 
thereafter within a period of approximately 2 to 4 weeks. It is anticipated that the planned, 
gradual dose escalation scheme employed in study EFC14822 will reduce intensity and 
frequency of GI events, mainly such as nausea and vomiting. 

Increase in heart rate (HR) is a known side-effect of GLP-1 RAs. In the current study 
EFC14822, both periodic monitoring of vital signs including HR and blood pressure (BP)
and 24-hour electrocardiogram (ECG) recording (Holter) will be performed to monitor for 
any effects on HR. 

The GLP-1 RA class has a box warning related to risk of thyroid C-cell tumors in the US 
label, based on findings in rodents. As the relevance for humans is unclear, GLP-1 RAs 
are contraindicated in participants with a personal or family history of medullary thyroid 
cancer (MTC) or in participants with multiple endocrine neoplasia syndrome Type 2
(MEN-2). In EFC14822, calcitonin will be monitored throughout the study, and 
participants with history of MTC or MEN-2 or with elevated calcitonin levels 
(≥5.9 pmol/L [20 pg/mL]) at Baseline will be excluded from the study. 

Diabetic retinopathy complications have been reported for one of the GLP-1RAs (as of 
05 December 2017). No cases have been reported for efpeglenatide. Participants with a 
recent or planned retinal treatment for retinopathy or maculopathy will be excluded in the 
current study. Diabetic retinopathy complications will be monitored throughout the study.

Additional safety monitoring in study EFC14822 includes the collection of AEs, anti-drug 
antibodies (ADAs; immunogenicity [4, 5]), as well as safety laboratory and 12-lead ECG. 

In the 3 Phase 2 clinical studies with efpeglenatide (HM-EXC-203, HM-EXC-204, and 
HM-EXC-205), overall a total of 
out of 571 participants on efpeglenatide and out of 
183 participants on comparators had post-baseline ALT elevation ≥3 × ULN; most had 
confounding factors (3). In this study, patients with elevated liver enzymes >3 × upper 
limit of the normal (ULN) or total bilirubin >1.5 × ULN (except in cases of 
Gilbert’s syndrome) will be excluded from participation. Liver function tests will be done 
regularly throughout the study.
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Efpeglenatide concentrations will also be sampled in study EFC14822. These sparse 
pharmacokinetic (PK) samples will be used for population PK analyses to determine the 
PK characteristics of efpeglenatide in the target T2DM population.
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 monitor the glucose-lowering effects and to early detect 
eventual adverse reactions.
Placebo injections will not contribute to lower the plasma glucose, but the participation in the 
study may increase participant motivation and result in an improvement of glycemic control. In 
any case the close monitoring will detect early deterioration of glycemic control and allow 
initiation of “rescue therapy” as deemed necessary. The HbA1c and FPG tests will be performed 
approximately every 3 to 4 months. Participants will be provided with a glucose meter and test 
strips to regularly self-measure their plasma glucose. Glycemic control central laboratory alerts on 
FPG and on HbA1c (at Week 12 onwards) will be set up to ensure that glycemic parameters 
remain under predefined rescue thresholds.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of efpeglenatide may be found in the IB (3).
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3
OBJECTIVES AND ENDPOINTS
Table 1 - Objectives and endpoints
Objectives
Endpoints
Primary
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, or 6 mg in comparison to placebo in HbA1c 
change from baseline to Week 30 in participants with T2DM 
inadequately controlled with diet and exercise

Change from baseline to Week 30 in HbA1c
Secondary
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg in comparison to placebo on 
glycemic control

Number of participants with HbA1c <7% at Week 30

Change from baseline to Week 30 in fasting plasma 
glucose (FPG)

Change from Baseline to Week 56 in HbA1c
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg in comparison to placebo on body 
weight

Change from baseline to Weeks 30 and 56 in body 
weight
To evaluate the safety of once-weekly injection of efpeglenatide 
2, 4, and 6 mg

Number of participants with at least one 
hypoglycemic event during treatment period

Number of hypoglycemic events per participant-year 
during treatment period

Number of participants with AEs (see Section 8.3)
Tertiary/exploratory
To characterize the PK of efpeglenatide

Serum Ctrough of efpeglenatide at pre-dose (Weeks 4,
12, 24, and 30)

Serum concentration of efpeglenatide at post-dose 
(either 4 days [±1 day] after first IMP dose [Week 1], 
4 days [±1 day] after 4th dose [Week 4], or 4 days 
[±1 day] after 12th dose [Week 12] in a subset of 
participants, at least 10% of total: [N=12 per group])
To characterize the effect of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg and placebo on participant
perspective on the benefit/risk of treatment

Participant perspective on benefit/risk of the drug 
using PQATv2 at Week 30 and Week 56
To compare the effects of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg with placebo on immunogenicity

Number of participants by ADA status 
(positive/negative) at scheduled visits

Number of participants with treatment-induced ADAs 
(among the participants ADA negative or missing at 
baseline) during the study period

Number of participants with treatment-boosted ADAs 
(among the participants with ADA positive at 
baseline) during the study period

ADA titer at scheduled visits
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Objectives
Endpoints

Number of participants by ADA cross-reactivity to 
endogenous GLP-1 at scheduled visits

Number of participants by ADA cross-reactivity to 
endogenous glucagon at scheduled visits

Number of participants with ADAs directed against 
PEG linker of efpeglenatide at scheduled visits
To compare the effects of once-weekly injection of 
efpeglenatide 2, 4, and 6 mg with placebo on additional 
measures of glycemic control

Number of participants with HbA1c <7% at Week 56

Change from baseline to Week 56 in FPG

Change from baseline to Week 30 and Week 56 in 
mean 24-hour SMPG (7-point profile)

Change from baseline to Week 30 and Week 56 in 
plasma glucose excursions (2-hours PPG minus 
preprandial plasma glucose at breakfast, lunch, and 
dinner) based on 7-point SMPG data

Number of participants with rescue therapy used until 
Week 30 and Week 56

Time to initiation of rescue therapy
ADA anti-drug antibody; AE adverse event; FPG: fasting plasma glucose; GLP-1 glucagon-like peptide 1; HbA1c hemoglobin A1c; 
PEG polyethylene glycol; PK pharmacokinetics; PQATv2 Patient Qualitative Assessment of Treatment version 2; SMPG self-monitored plasma 
glucose; T2DM type 2 diabetes mellitus.
3.1
APPROPRIATENESS OF MEASUREMENTS
Efpeglenatide monotherapy in participants with T2DM who have inadequate glycemic control 
with diet and exercise is expected to lower HbA1c over 30 weeks of treatment (primary efficacy 
analysis).
The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 3 months. 
Hemoglobin A1c has also been shown to correlate with the development of long-term 
complications of diabetes, and reduction of HbA1c is known to reduce the risk of long-term 
microvascular complications. Therefore, HbA1c is considered an appropriate primary endpoint for 
assessing the effect of a treatment on glycemic control. 
The problem of weight gain in T2DM is widely recognized. More than 80% of individuals with 
T2DM are overweight, many at the time of diagnosis. Consequently, iatrogenic weight gain is not 
only unwelcome, but represents an important clinical issue that can become a barrier to the 
successful management of glycemic control. Therefore, in this study, assessing change in body 
weight from Baseline to Week 30 and Week 56 is a secondary endpoint. 
Improvements in pre-prandial and post-prandial plasma glucose (PPG) have been observed with 
efpeglenatide in previous studies. Therefore, assessment of both pre-prandial plasma glucose and 
PPG (by 7-point SMPG profile) is relevant in this study. These 2 parameters are also considered 
by regulatory agencies to be supportive of efficacy of an antidiabetic agent.
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The other efficacy and safety assessments in this study are standard, well-established 
measurements for a Phase 3 study evaluating the treatment of T2DM in adult participants. 
The duration of the study is considered appropriate for enabling an adequate assessment of time 
dependent changes in HbA1c, and to evaluate the safety profile during the Treatment Extension 
Period.
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4
STUDY DESIGN
4.1
OVERALL DESIGN
The current protocol EFC14822, is a multicenter, 30-week, randomized, double-blind, 
placebo-controlled Phase 3 study with an additional 26-week controlled Safety Extension Period 
evaluating the efficacy and safety of efpeglenatide as a monotherapy in participants with 
inadequately controlled with diet and exercise.
Eligible participants will be randomized to 1 of 3 dose levels of efpeglenatide (2, 4, or 6 mg) or to 
placebo, to be administered SC once-weekly. Randomization will be stratified by HbA1c at 
Screening (<8%, ≥8%) and BMI (<30 kg/m2, ≥30 kg/m2) at Visit 3 (Baseline, Day 1). Masked 
weekly dose escalation over the course of 5 weeks will be used to reach the assigned 4 and 6 mg 
efpeglenatide weekly doses. Escalation will start from 2 mg once-weekly to the maximum of 4 or 
6 mg once-weekly, as assigned at Randomization. Participants randomized to the efpeglenatide 
2 mg dose arm will also initiate dosing at 2 mg once-weekly and remain on this dose for the 
treatment duration. In order to blind the treatments, both efpeglenatide and placebo will be 
provided in volume-matched, PFS.
The study will be comprised of 4 periods as follows: 

An up to 3-week Screening Period (with a minimum of 11 days)

A 30-week double-blind, placebo-controlled Core Treatment Period, for efficacy and 
safety assessment

A 26-week double-blind, placebo-controlled Treatment Extension Period; participants will 
remain on the randomized IMP regimen

A 6-week Follow-up Period to collect post-treatment safety information for all participants
after last dose of IMP
The maximum study duration per participant will be 65 weeks. 
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
This study is designed to demonstrate the efficacy and safety of efpeglenatide when used as 
monotherapy in participants with T2DM who have inadequate glycemic control with diet and 
exercise. Efpeglenatide will be compared to placebo, consistent with regulatory guidance. Based 
on the study design, the protocol stipulates that participants can receive antidiabetic rescue 
therapy according to a predefined algorithm. 
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the participants to treatment groups, blinding the 
participants, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating 
the selected AEs in a blinded fashion.
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A parallel-group, randomized placebo-controlled design was selected because trial participants are 
exposed to a single treatment and dose, and assignment to that treatment is based solely on 
chance. This design is free of the limitations of competing designs such as crossover in which 
there may be a carryover of effect from the first to the second treatment. Although this carryover 
effect can be minimized with a washout period, it is possible that some longer-term effects may 
persist. While the sample size of the parallel group design is larger to account for more variability 
when participants cannot serve as their own control, the above-mentioned limitations of the 
crossover design have led the randomized controlled trial design to be the standard for therapeutic 
confirmatory trials for regulatory approval such as this trial.
4.3
JUSTIFICATION FOR DOSE
The selection of efpeglenatide 2, 4, and 6 mg once-weekly doses is based on the results of early 
phase studies. 
Efpeglenatide has shown increasing efficacy up to the highest dose tested. Both once-weekly 
2 mg and 4 mg doses have shown clinically relevant efficacy in study HM-EXC-203. The 
achieved Hb1Ac reduction indicates that the dose-response plateau has not been reached with the 
4 mg dose; this may suggest higher efficacy of the 6 mg dose compared to the 4 mg dose can also 
be expected for glycemic control in diabetic patients. The once-weekly 6 mg dose tested in 
non-diabetic subjects in the Phase 2 study (HM-EXC-205) has shown higher efficacy in the 
decrease of body weight than the once-weekly 4 mg dose in this population.
Nausea and vomiting events appeared to be dose related and the trend over time showed an 
increase in incidence after the first injection with a general decrease thereafter for all tested doses. 
Based on the observed general decrease of GI event incidence after the first week of treatment 
with efpeglenatide, dose increases to achieve the higher doses of 4 and 6 mg (in the corresponding 
arm) will be in 2 mg step intervals every 2 weeks in order to minimize the GI adverse effects. The 
escalation step of 2 mg is small enough to contribute to improvement of GI tolerability at dose 
increase. With this dose escalation schedule, the dose of 4 mg once-weekly will be achieved 
2 weeks and the maximal dose of 6 mg once-weekly will be achieved only 4 weeks after the first 
dose of efpeglenatide.
Please refer to the IB for more details (3).
4.4
END OF STUDY DEFINITION
The end of the study is defined as the date of the last visit of the last participant in the study
(as scheduled per protocol or if trial is stopped prematurely based on the advice of the 
independent DMC or other unforeseen development).
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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 type 2 diabetes mellitus (T2DM), and treated with diet and exercise
I 03.
Hemoglobin A1c (HbA1c) between 7.0% and 10.0% (inclusive) measured by the central 
laboratory at Screening
Informed Consent
I 04.
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 not controlled gastroesophageal 
reflux disease within 6 months prior to Screening or history of surgery affecting gastric 
emptying
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. Retinopathy or maculopathy with one of the following treatments, either recent (within 
3 months prior to Screening) or planned: intravitreal injections or laser or vitrectomy 
surgery 
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E 05. Body weight change of ≥5 kg within the last 3 months prior to Screening
E 06. Systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg at 
Randomization
E 07. End-stage renal disease as defined by estimated glomerular filtration rate (by Modification 
of Diet in Renal Disease [MDRD]) of <15 mL/min/1.73 m2
E 08. Known presence of factors that interfere with the HbA1c measurement (eg, specific 
hemoglobin variants, hemolytic anemia) compromising the reliability of HbA1c 
assessment or medical conditions that affect interpretation of HbA1c results (eg, blood 
transfusion or severe blood loss in the last 3 months prior to Randomization, any condition 
that shortens erythrocyte survival)
E 09. Any clinically significant abnormality identified either in medical history, during physical 
examination, laboratory tests, electrocardiogram (ECG), or vital signs at the time of 
Screening or any adverse event (AE) during the Screening Period which, in the judgment 
of the Investigator, would preclude safe participation in the study and interpretation of the 
study results
E 10. Laboratory findings at the Screening Visit:
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times the 
upper limit of normal (ULN) or 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)
Prior/concomitant therapy
E 11. Participants receiving antidiabetic drug treatment within 3 months prior to Screening 
E 12. Systemic glucocorticoid therapy (excluding topical, intra-articular, or ophthalmic 
application, nasal spray or inhaled forms) for more than 10 consecutive days in the last 
3 months prior to Screening
E 13. Gastric surgery or other gastric procedures intended for weight loss within 2 years prior to 
Screening, or planned during study period
Prior/concurrent clinical study experience
E 14. Exposure to any investigational drugs in the last 4 weeks or 5 half-lives, whichever is 
longer, prior to Screening
E 15. Concomitant enrollment in any other clinical study involving an investigational study 
treatment or any other type of medical research
Other exclusions
E 16. Hypersensitivity to any of the study treatments, or components thereof, or to any GLP-1 
RAs
E 17. History of drug or alcohol abuse within 6 months prior to the time of Screening
E 18. Pregnant (demonstrated by serum pregnancy test at Screening) or breast-feeding women
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E 19. Women of childbearing potential (WOCBP) not willing to use highly effective method(s) 
of birth control (Appendix 4 [Section 10.4]) or who are unwilling to be tested for 
pregnancy during the study period and for at least 5 weeks after the last dose of study 
intervention
E 20. 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 21. Any country-related specific regulation that would prevent the participant from entering 
the study
E 22. Individuals committed to an institution by virtue of an order issued either by the judicial or 
the administrative authorities
Additional criteria at the end of the Screening Period
E 23. No confirmation of complete recording of the 24-hour ECG performed during Screening 
Period
E 24. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol
E 25. Participants who withdraw consent during the Screening Period (starting from signed ICF)
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and dietary restrictions
Diet and exercise 
Lifestyle and diet therapy provided before the time of Screening is to be continued during the 
study. Individualized dietary and lifestyle counseling will be given by a healthcare professional as 
per Schedule of Activities (SoA; Section 1.3) and should be consistent with international or local 
guidelines for participants with T2DM (for example, see 6).
Compliance with the diet and lifestyle counseling will be assessed in case of insufficient glucose 
control (please refer to Section 5.3).
Fasting conditions

For Visits 3 (Day 1), 6 (Week 8), 7 (Week 12), 10 (Week 30), 12 (Week 43), and 
14 (Week 56), participants need to come to the study center in a fasting condition after an 
overnight fast of no less than 8 hours that consisted of no food or liquid intake, other than 
water.

For fasting (pre-breakfast) SMPG, to be performed per the SoA (Section 1.3).
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5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized (randomly assigned to study treatment). A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once in cases where the original screen failure was due to reasons expected to change 
at rescreening (based upon the Investigator’s clinical judgment). A participant should not be 
randomized more than once (ie, entering the randomized period twice).
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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 56 weeks of treatment.
Non-IMP (NIMP) treatment is defined as the rescue medication(s) that will be used to treat 
hyperglycemia if a participant’s glycemic values reach the applicable rescue threshold as defined 
in Section 6.1.2.1. Except for GLP-1 RAs and DPP-4 inhibitors, any approved medication(s),
including oral antidiabetic drugs or insulin, can be prescribed at the Investigator’s discretion to 
treat the hyperglycemia. The regimen of the rescue medications will be in accordance with local 
standard of care and prescribing practice.
6.1
STUDY INTERVENTION(S) ADMINISTERED
Table 2 - Overview of study interventions administered
Study intervention name
Efpeglenatide
Placebo
Dosage formulation
0.5 mL of a 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 mg/500 μL, 4 mg/500 μL, and 6 mg/500 μL
(at 4, 8, and 12 mg/mL concentrations, 
respectively)
NA
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 injection should be changed (rotated) at each time to prevent skin reactions. The site, 
date, and time of administration should be recorded for each injection administration.
For selected visits during the Core Treatment Period up to Week 30 (corresponding to pre-dose 
PK sample collection) the weekly dose will be administered at the site after blood sample 
collection (see SoA, Section 1.3).
For the other weekly administrations, if a dose is missed, participants must be instructed to 
administer the dose as soon as possible if there are at least 3 days (72 hours) until the next 
scheduled dose. If less than 3 days remain before the next scheduled dose, participants should 
skip the missed dose and administer the next dose on the regularly scheduled day. In each 
case, participants should then resume their regular once-weekly dosing schedule. The day of 
weekly administration can be changed if necessary as long as the last dose was administered 
3 or more days before.
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Study intervention name
Efpeglenatide
Placebo
Pre-dose PK samples are expected to be collected at least 6 to 7 days after the last dose of 
IMP. The corresponding study visits (Visit 5, Visit 7, Visit 9 and Visit 10) and the timing of 
previous dose administration should be therefore scheduled to ensure as much as possible this 
duration. 
IMP dose schedule
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Day 1
Visit 3
Week 1
Week 2
Visit 4
Week 3
Week 4
Visit 5
Dosing
on-site
at home
at home
at home
on-site
Efpeglenatide 2 mg
2 mg
2 mg
2 mg
2 mg
2 mg
Efpeglenatide 4 mg
2 mg
2 mg
4 mg
4 mg
4 mg
Efpeglenatide 6 mg
2 mg
2 mg
4 mg
4 mg
6 mg
Placebo
Placebo
Placebo
Placebo
Placebo
Placebo
From Week 4 (Visit 5) through the rest of the double-blind treatment period, participants will 
remain on the randomized IMP dose or placebo until the EOT at Week 56 (Visit 14).
Storage conditions
Store between +2°C and +8°C (36°F and 46°F). Do not freeze, protect from light.
Packaging and labeling
Study treatment will be provided in different types of kit boxes (open-label training kits, 
double-blind titration kits and double-blind treatment kits), in accordance with the administration 
schedule. The content of the labeling is in accordance with the local regulatory specifications 
and requirements.
The details of this table are specific to IMP, information of non-IMP is described in Section 6.1.2
EOT: end-of-treatment, IMP investigational medicinal product; NA not applicable; PFS prefilled syringe; PK: pharmacokinetic; SC subcutaneous; 
SoA: schedule of activities.
6.1.1
Investigational medicinal product(s)
The appropriate number of kits will be dispensed for the period until the next dispensing visit 
(please refer to SoA 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 (Week -1) 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. 
Review of injection technique can be done at any other visit as needed (self-injection with IMP at 
site during selected visits until Week 30). Review of injection sites will be performed at all on-site 
visits.
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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 study 
document.
6.1.2
Noninvestigational medicinal products
6.1.2.1
Rescue therapy
Rescue medication(s) that will be used to treat unacceptable hyperglycemia if a participant’s 
glycemia reaches an applicable rescue threshold is considered NIMP for this study. The threshold 
values are defined as follows in Table 3, dependent on study period.
Table 3 - Rescue criteria
Time in study
Threshold
From Randomization up through the scheduled Week 8 visit (Visit 6)
FPG >15.0 mmol/L (>270 mg/dL)
After the Week 8 visit up through the scheduled Week 12 visit (Visit 7)
FPG >13.3 mmol/L (>240 mg/dL)
After the Week 12 visit (Visit 7) through the end of the 30-week Core 
Treatment Period
FPG >11.1 mmol/L (>200 mg/dL) or HbA1c ≥8.0%
After the Week 30 visit (Visit 10) through the end of the treatment period
(Week 56 [Visit 14])
FPG >8.9 mmol/L (>160 mg/dL) or HbA1c ≥7.0%
FPG fasting plasma glucose; HbA1c hemoglobin A1c
Routine fasting SMPG and central laboratory alerts on FPG (and HbA1c at Week 12 [Visit 7] 
onward) are set up to ensure that glycemic parameter results remain below the predefined 
thresholds.

If 1 fasting SMPG value exceeds the specific glycemic limit on 1 day, the participant
checks it again during the 2 following days. If all the values in 3 consecutive days exceed
the specific limit, the participant should contact the Investigator and a central laboratory
FPG measurement (and HbA1c at Week 12 [Visit 7] onward) be performed as soon as
possible for confirmation

Upon receipt of a central laboratory rescue alert, a central laboratory re-test must be
completed and confirmed as exceeding the threshold for rescue before rescue therapy is
initiated. The re-test confirmation should be performed as soon as possible by unscheduled
visit
In the event that a confirmatory FPG and/or HbA1c exceed the threshold, the Investigator should 
ensure that no reasonable explanation exists for insufficient glucose control and in particular that:

The increased FPG has been tested at a fasted state (ie, no food intake or liquid intake
[except water] for ≥8 hours)

IMP was appropriately injected (as per weekly schedule)

There was no intercurrent disease, which may jeopardize glycemic control (eg, infectious
disease)
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
Compliance to treatment was appropriate

Compliance to diet and lifestyle was appropriate
If any of the above mentioned reasons can reasonably explain the insufficient glycemic control, 
the Investigator should consider not initiating rescue medication and should undertake appropriate 
action, ie:

Assess FPG (ie, after ≥8 hours fast)

Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the electronic Case Report Form [e-CRF] and the 
medical record)

Stress the absolute need to be compliant with treatment

Organize a specific interview with the participant and a Registered Dietician or other 
qualified nutrition professional to reinforce the absolute need to be compliant with diet and 
lifestyle recommendations, and schedule an FPG/HbA1c assessment at the next visit
If none of the above mentioned reasons can be found, or if appropriate action fails to decrease 
FPG/HbA1c under the threshold values, rescue medication may be introduced.
If a participant needs to start rescue therapy, an unscheduled in-person visit will be scheduled to 
perform pre-rescue assessments (as specified for EOT; Week 56/Visit 14], except the 7-point 
SMPG and 24-hour ECG), prior to starting the rescue medication(s).
Prescription of open-label rescue medication(s) to treat hyperglycemia will be at the discretion of 
the Investigator and in accordance with local standard of care and prescribing practice. With the 
exception of other GLP-1 RAs and DPP-4 inhibitors, any approved medication(s), including oral 
antidiabetic drugs or insulin, can be prescribed to treat the hyperglycemia. If a participant requires 
glycemic rescue, the IMP received during the randomized, double-blind treatment period should 
continue and must remain blinded until the end of the study (unless the Investigator considers a 
change necessary for safety reasons).
All rescue medications will be documented in the e-CRF. The cost of rescue therapy not covered 
by health insurance will be reimbursed by the study Sponsor where permitted by local regulations.
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.
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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 IMP received and any discrepancies are reported 
and resolved before use of the study IMP.
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study IMP. All study IMP 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 IMP accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study IMP are 
provided in 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/NIMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure (see 
Section 8.3.8).
A potential defect in the quality of IMP/NIMP/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/NIMP/device and 
eliminate potential hazards.
Under no circumstances will the Investigator supply IMP/NIMP/device to a third party, allow the 
IMP/NIMP/device to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP/device in any other manner.
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING
6.3.1
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 and doses included in the kits. Each titration and treatment kit (and the 
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corresponding 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. 
Members of the CEC will review and adjudicate events in a blinded manner (please refer to 
Appendix 1 [Section 10.1]).
The Investigator will not have access to the data of the primary efficacy endpoint (ie, HbA1c) or
FPG obtained after Baseline/Randomization visit (Visit 3) as those data will be masked. If the
central laboratory detects FPG above the rescue thresholds, the Investigator will receive an alert 
from the central laboratory (see Section 6.1.2.1). The HbA1c alerts will also be sent if a value is 
above threshold at the Week 12 visit (Visit 7) onwards.
6.3.2
Randomization code breaking during the study
The blind may be broken if, in the opinion of the Investigator, it is in the participant’s best interest 
for the Investigator to know the IMP assignment. The Sponsor must be notified before the blind is 
broken unless identification of the IMP is required for a medical emergency in which the 
knowledge of the specific blinded IMP will affect the immediate management of the participant’s 
condition (eg, antidote available). In this case, 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 e-CRF, as applicable.
Code breaking can be performed at any time by using the proper module of the interactive 
response technology (IRT) and/or by calling any other phone number provided by the Sponsor for
that purpose. If the blind is broken, the Investigator should document the date, time of day, and
reason for code breaking. If the code is broken by the Investigator, the participant must withdraw
from IMP administration. 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 closure. Furthermore, when 
completing forms (eg, AE, SAE, adjudication information), the IMP should not be disclosed on 
the forms.
Randomization code breaking will also be performed during the analysis of the PK serum 
concentration samples and ADA samples in order to enable the laboratory to sort the samples 
(verum [dose group], placebo) and start analyzing the samples (verum group only) while the study 
is still ongoing. Only the Project manager and lead scientist at the Bioanalytical laboratory, as
well as the population PK analyst, 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 database lock.
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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 the 
following:

Proper recording of treatment kit number as required on appropriate 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 recorded on the participant diary 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 

For the NIMP not provided by the Sponsor, tracking and reconciliation will be 
documented in participant’s source documents and medication reported in appropriate 
e-CRF pages
6.4.1
Return and/or destruction of treatments
A detailed treatment log of the destroyed IMP will be established with the Investigator (or the
pharmacist) and countersigned by the Investigator and the monitoring team. The Investigator will
not destroy the used and unused IMP unless the Sponsor provides written authorization. For 
NIMP reimbursed by the Sponsor, tracking and reconciliation will be achieved by the Investigator 
(or the pharmacist, if appropriate) as per local requirements.
Sharp containers containing all used PFS will be brought back to the site by the study participant
for the purpose of destruction.
Destruction is strongly encouraged at site level, nevertheless, if the site is not able to destroy or 
destruction is not allowed in the country, all treatments kits will be retrieved by the Sponsor.
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6.5
CONCOMITANT THERAPY
The following treatments are prohibited during the study (including Screening Period and the 
56 weeks of treatment):

Initiation of any antidiabetic agents, including oral or injectable antihyperglycemic agents 
other than the IMP before pre-rescue assessments and initiation of rescue therapy
Note: (short-term use [<10 consecutive days] of short-acting insulin for treatment of acute 
illness or surgery is allowed)

Initiation of any GLP-1 RAs (eg, exenatide, liraglutide, dulaglutide, or semaglutide) and 
DPP-4 inhibitors (eg, sitagliptin, saxagliptin, vildagliptin, or linagliptin)

Initiation of any prescription weight loss drugs (eg, phentermine, lorcaserin, or orlistat)

Gastric surgery or other gastric procedures for weight loss

Systemic use of glucocorticoids for more than 10 consecutive days (topical, nasal spray, 
and inhaled or intra-articular applications are allowed)

Any investigational drug other than IMP for this study
Glucagon-like petide-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. 
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:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
6.6
DOSE MODIFICATION
Up-titration of IMP from Randomization to Week 5 is described in Table 2. From Week 5 
throughout the rest of the entire double-blind treatment period, participants will remain on the 
randomized IMP (efpeglenatide assigned dose or placebo) until the EOT at Week 56.
6.7
INTERVENTION AFTER THE END OF THE STUDY
The IMPs will not be provided after the EOT period.
When a participant’s participation in the trial ends, the participant 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 should be distinguished from (additional) withdrawal of 
consent for follow-up visits and from withdrawal of consent for non-participant contact 
(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. 
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 e-CRF. In any case, the participant should remain in the study as long as 
possible to collect endpoint data at Week 30 and Week 56 and vital safety status at the scheduled 
end of study time.
7.1.1
Permanent discontinuation
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. Participants 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: eg, laboratory abnormalities 
(see decision tree and general guidance for the follow-up of laboratory abnormalities in 
Appendix 5 [Section 10.5.1]), 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 5 [Section 10.5.2]), or calcitonin value ≥50 pg/mL 
(see Appendix 5 [Section 10.5.3])

If, in the Investigator's opinion, continuation with the administration of IMP would be 
detrimental to the participant’s well-being

Pregnancy (in female participants)

Confirmed intolerance to the allocated dose of IMP
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
Any code breaking requested by the Investigator

At the specific request of the Sponsor
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 56 weeks of the 
study. A high rate of missing data could jeopardize efficacy results of the study. See the SoA
(Section 3.1) 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 participants 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, the participants will be assessed using the procedure normally planned for the EOT
Visit including a PK sample when the permanent discontinuation occurred during the core 
treatment period and visit can be scheduled 7 days after the permanent discontinuation of 
intervention. For participants who discontinue IMP but remain in the study, the remaining visits 
should occur as scheduled where possible. The Investigators should discuss with them key visits 
to attend. All efforts should be made to continue to follow the participants for primary and 
secondary endpoints, after the discontinuation of treatment.
The value of all their study data collected during their continued involvement will be emphasized 
as important to the public health value of 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.
7.1.2
Temporary discontinuation 
Temporary intervention discontinuation corresponds to at least 1 dose not administered to the 
participants.
All IMP discontinuation should initially be considered as temporary unless permanent
discontinuation is mandated by the protocol (see Section 7.1), 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.
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Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs (including intolerance to IMP planned dose). For all temporary intervention
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
e-CRF. 
7.1.2.1
Rechallenge
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. In case of IMP intolerance, a one-time re-challenge is recommended following 
temporary discontinuation before deciding to permanently discontinue the IMP. If a maximum of 
2 consecutive doses are missed, the IMP can be restarted with the last dose given. In cases of 3 or 
more consecutive doses are missed, the titration is highly recommended to be re-initiated to 
minimize the risk of GI events (especially if the temporary discontinuation was related to a 
GI event).
Participants who temporarily discontinue IMP should be reassessed at every visit to determine 
whether it is possible to safely resume IMP. If a decision has been made that the discontinuation is 
permanent, then the participant should be considered as permanently discontinued and the 
corresponding e-CRF page should be completed. Please note that permanent discontinuation 
should be a last resort.
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.
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented.
Participants who have withdrawn from the study cannot be re-randomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused.
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7.3
LOST TO FOLLOW UP
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
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 in 
the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from 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 before confirming Visit 2 in 
IRT, to confirm that potential participants meet all eligibility criteria. Eligibility criteria 
will be evaluated again before randomization, including additional criteria at the end of 
Screening Period (see Section 5.2). The Investigator will maintain a Screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
Screening failure, as applicable. 
8.1
EFFICACY ASSESSMENTS
8.1.1
Hemoglobin A1c
The primary efficacy endpoint and 2 secondary efficacy endpoints are assessed by measurement 
of HbA1c. For the eligibility and efficacy assessments of the study, HbA1c is measured at 
different time points during study, by a certified level I “National Glycohemoglobin 
Standardization Program” central laboratory. 
If a participant needs to receive rescue antidiabetic medication (see Section 6.1.2.1), assessment 
of HbA1c should be performed before the introduction of the rescue medication(s).
8.1.2
Fasting plasma glucose
Plasma glucose will be assessed in the fasting state (as defined in Section 5.3.1) according to the 
schedule detailed in the SoA (Section 1.3). If participant is not fasting at the time of the visit a 
re-test should be scheduled in fasting status for the next day (or as soon as possible). For the 
efficacy assessments of the study, FPG is measured at a central laboratory.
8.1.3
7-point self-monitored plasma glucose profiles
The 7-point SMPG will be performed over a single 24-hour period, on at least 1 day within the 
weeks prior to selected study visits (see SoA, Section 1.3), and must be recorded in the participant 
diary. Participant should repeat the 7-point SMPG profile if any time point is missed.
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The 7-point SMPG profile should be measured at the following 7 points: pre-breakfast and 
2 hours post-breakfast, pre-lunch, 2-hour post-lunch, pre-dinner, 2-hour post-dinner, and at 
bedtime. Two hours post-prandial (breakfast, lunch, and dinner) is defined as 2 hours after the 
start of the meal.
On days when 7-point profiles are done, fasting pre-breakfast SMPG will be considered as the 
first point of measurement, ie, “pre-breakfast” time point. 
8.1.4
Body weight
Body weight will be measured to allow the estimation of change from Baseline to Weeks 30 
and 56 in body weight.
Body weight is measured according to the schedule detailed in the SoA (Section 1.3) with the 
participant wearing only undergarments or very light clothing and no shoes, and with an empty 
bladder.
The same scale should be used throughout the study, and calibrated on a regular basis as 
recommended by the manufacturer. Calibration should be documented in source documents. 
The use of balance scales is recommended; if digital scales are used, testing with standard weights 
is of particular importance. The floor surface on which the scale rests must be hard and should not 
be carpeted or covered with other soft material. The scale should be balanced with both weights at 
zero and the balance bar aligned. The participant should stand in the center of the platform as 
standing off-center may affect measurement. The weights are moved until the beam balances 
(the arrows are aligned). The weight is read and recorded in the e-CRF and source documents. 
Self-reported weights are not acceptable; participants must not read the scales themselves.
8.1.5
Use of rescue therapy
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
treatment period to allow determination of the start of rescue treatment and the percentage of 
participants using rescue therapy at Weeks 30 and 56. Routine fasting SMPGs will be measured 
by the participants, and alerts on FPG and/or HbA1c will be sent to the Investigator from the 
central laboratory to ensure that glycemic parameter results remain within predefined thresholds. 
For details and further actions should FPG and/or HbA1c values rise above thresholds, refer to
Section 6.1.2.1.
8.1.6
Patient Qualitative Assessment of Treatment 
The Patient Qualitative Assessment of Treatment version 2 (PQATv2; see Appendix 9; 
Section 10.9) is intended for the collection of participant-perceived benefit-risk of 
glucose-lowering treatment with IMP.
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This participant qualitative assessment should take between 10 and 20 minutes to complete. 
The participants will be asked to complete it from home just before the on-site visits planned at 
Weeks 30 and 56. They will be asked to do it by themselves without any help from friends or 
relatives. Use of this questionnaire will be limited to participants in countries where PQATv2 is 
available in the local language.
At the beginning of the Weeks 30 (Visit 10) and 56 (Visit 14) patient visits, Investigators will 
have to review participant’s answers in order to identify any potential AEs reported by 
participants within the open-ended questions. Investigators will discuss with the participant’s
potential AEs identified; Investigators will not discuss any other aspects of the answers with the 
participant, and will not ask participants to change their answers. If AEs that were previously not 
captured are identified during this process, they should be reported as described in
Appendix 3 (Section 10.3).
If a participant discontinues treatment with IMP during the Treatment Period, the participant will 
be asked to complete the PQATv2 at the time of discontinuation. Even if he/she remains in the 
study, the participant will not need to complete it again at the following scheduled visits: Week 30 
and/or Week 56.
8.2
SAFETY ASSESSMENTS 
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
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.

At the following on-site visits, a limited physical examination focused on any affected 
body area or organ system and other symptomatic or related organ system(s) will be 
performed.

Height will be measured at Screening only. If for any reason it was not measured at this 
visit, it can be measured at any other visit in the study.

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 AE.
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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 5-minute rest period, and then again after 1 minute in both arms while the participant is 
in a 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
8.2.3.1
12-lead electrocardiogram
A 12-lead ECG recording will be performed locally as scheduled in SoA (see Section 1.3).
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). The Investigator 
should review the ECG trace and document the interpretation, sign and date the ECG print out and 
record it in the e-CRF. Each ECG trace must be compared with the Screening ECG results. 
All original ECG traces must be 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.
8.2.3.2
24-hour Holter electrocardiogram including diary
Holter ECG will be collected over approximately 24 hours starting on selected visits as presented 
in the SoA (see Section 1.3). Twenty–four hour average and night time average HR will be 
derived based on the Holter monitoring. 
Instruction and diary for participants’ notes while they are wearing the ECG device will be 
provided by the Investigator.
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Holter recordings will be sent to an ECG reading center for further analysis. If the Holter memory 
cards are to be downloaded to compact discs (CDs)/digital versatile discs (DVDs) at the study site 
and the CDs/DVDs are then shipped to the reading center, the study site will keep a copy of the 
CDs/DVDs and will not erase the memory cards until being notified by the reading center to do so 
(when Holter recordings will be correctly downloaded into the reading center system). 
Paper copies of all notifications will be kept as source documents on the study site. The digital 
recording, data storage, and transmission need to comply with all applicable regulatory 
requirements (eg, Food and Drug Administration 21 Code of Federal Regulation [CFR] Part 11).
A complete recording is to be confirmed prior to Randomization.
If the Holter ECG needs to be repeated to get a complete evaluation, Randomization may be 
delayed by up to 7 days.
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 (Section 1.3) for the timing and frequency of sample collection. 

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 e-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 or 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 (Section 1.3).

If local laboratory results are used to make study treatment decision, for response 
evaluation, or to diagnose/follow-up and AEs, then the results must be recorded in the 
e-CRF.

Recommended decision trees for the management of certain laboratory abnormalities are 
provided in Appendix 5 (Section 10.5.1).
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8.2.5
Hypoglycemia
During the study, participants must be instructed to document any hypoglycemic episodes in their 
study diary. Hypoglycemia will be reported in the specific hypoglycemia event information form 
in e-CRF with onset date and time, symptoms and/or signs, the SMPG value if available, and the 
treatment. Hypoglycemia fulfilling the seriousness criteria will be documented in addition on the 
SAE form in the e-CRF.
Hypoglycemic events will be categorized (7, 8, 9) as follows (also see Appendix 8 
[Section 10.8]):

Severe hypoglycemia: Severe hypoglycemia is an event that requires the 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 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 SAEs.

Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia is an 
event during which typical symptoms of hypoglycemia are accompanied by a measured 
plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). Clinical symptoms that are 
considered to result from a hypoglycemic episode are, eg, increased sweating, 
nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma

Asymptomatic hypoglycemia: Asymptomatic hypoglycemia is an event not accompanied 
by typical symptoms of hypoglycemia but with a measured plasma glucose concentration 
≤3.9 mmol/L (≤70 mg/dL)

Probable symptomatic hypoglycemia: Probable symptomatic hypoglycemia is an event 
during which symptoms of hypoglycemia are not accompanied by a plasma glucose 
determination, but was presumably caused by a plasma glucose concentration 
≤3.9 mmol/L (≤70 mg/dL); symptoms treated with oral carbohydrate

Relative hypoglycemia: (recently termed “pseudo-hypoglycemia”) is an event during 
which the person with diabetes reports any of the typical symptoms of hypoglycemia, and 
interprets the symptoms as indicative of hypoglycemia, but with a measured plasma 
glucose concentration >3.9 mmol/L (>70 mg/dL)
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In addition to the threshold of plasma glucose of ≤3.9 mmol/L (≤70 mg/dL), documented 
hypoglycemia with a measured plasma glucose concentration < 3.0 mmol/L (<54 mg/dL) will also 
be analyzed (9).
Hypoglycemic events will be evaluated regardless of the time of onset during the study and time 
of the day.
In addition, hypoglycemia events will be evaluated at the following time periods defined by time 
of the day:

Nocturnal hypoglycemia defined by time of the day: any hypoglycemia of the above 
categories that occurs between 00:00 and 05:59, regardless of whether the participant was 
awake or woke up because of the event

Daytime hypoglycemia: any hypoglycemia of the above categories that occurs between 
06:00 and 23:59
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
Adverse event of special interest
An adverse event of special interest (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. The classification of AESI may 
be changed during the study by protocol amendment (eg, further AE classified as AESI, or AE 
losing their AESI status).

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/NIMP (see Section 8.3.5); 
-
In the event of pregnancy in a female participant, IMP should be discontinued. 

Symptomatic overdose (serious or nonserious) with IMP/NIMP;
-
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 (eg, two or more injections) if given within 3 days (72 hours)
-
An overdose (accidental or intentional) with the NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the recommended dose during the planned interval(s)
-
Of note, asymptomatic overdose has to be reported as a standard AE

Increase in ALT >3 × ULN (see Appendix 5 [Section 10.5])
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3).
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
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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 and/or study (see Section 7). 
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 AEs 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 5, Section 10.5.2] pancreatitis, and pancreatic neoplasm ) – will be 
adjudicated by CEC

Major adverse cardiovascular events (MACE; cardiovascular (CV) death, myocardial 
infarction (MI), or stroke) and other specific CV events (eg, heart failure leading to 
hospitalization) – will be adjudicated by CEC

Calcitonin increase >5.9 pmol/L (20 pg/mL) and thyroid C-cell neoplasm 
(see Appendix 5, [Section 10.5.3])

Acute renal failure (see Appendix 5 [Section 10.5.4] for definition)

Diabetic retinopathy complications (will be reviewed by an independent ophthalmologist 
expert; see Appendix 1 [Section 10.1.4.3]); a written report from professional eye care 
provider will be required

Severe injection site reaction

Severe allergic reactions

Severe immune complex disease
8.3.1
Time period and frequency for collecting AE and SAE information 
All AEs, SAEs, AESIs, and AEs requiring specific monitoring will be collected from the date of 
signing the ICF until the end of the study as defined by the protocol for that participant, at the 
time points specified in the SoA (Section 1.3).
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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 AEs and SAEs 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. All SAEs, non-serious AESIs, and AEs requiring specific 
monitoring (as defined in Appendix 3 [Section 10.3]), 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). Further information on follow-up procedures is given in Appendix 3 (Section 10.3).
8.3.4
Regulatory reporting requirements for SAEs
The following are requirements for reporting of SAEs:

Prompt notification by the Investigator to the Sponsor of an 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 an 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.
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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 
(Visit 15).

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).

In the event of pregnancy in a female participant, IMP should be discontinued.

A pregnancy will be qualified as an SAE only if it fulfills 1 of the seriousness criteria (see 
Appendix 3 [Section 10.3]).

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.6
Cardiovascular and death events
For cardiovascular events, see Section 8.3.
8.3.7
Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs
Not applicable.
8.3.8
Guidelines for reporting product complaints/medical device incidents (including 
malfunctions)
Any defect in the IMP/NIMP/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.
8.4
TREATMENT OF OVERDOSE
The Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the Investigator should:
1. Contact the Medical Monitor immediately.
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities.
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF.
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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

Blood samples will be collected for measurement of serum concentrations of efpeglenatide 
as specified in the SoA (see Section 1.3). Instructions for the collection and handling of 
biological samples will be provided by the Sponsor. The actual date and time (24-hour 
clock time) of each sample will be recorded along with the date, time, and site (abdomen)
of drug administration. Samples not collected, missed or lost, for any reason should be 
recorded

For a subset of participants, 10% of total (N=12 per group): 1 additional post-dose sample 
will be taken either 4 days (±1 day) after 1st IMP dose (Week 1), or 4 days (±1 day) after 
4th dose (Week 4), or 4 days (±1 day) after 12th dose (Week 12). To reach this number and 
due to the blind design of the study, PK post-dose sample will be collected in the first 
80 randomized participants who will accept this additional sampling, sign the separate 
section of the main consent form and provide a valid post-dose sample

The collected blood samples will be used to determine concentration of efpeglenatide in 
serum and these concentration data will be summarized and reported in the CSR

The concentrations data will be used to perform a population PK analysis by non-linear
mixed effects modeling and the results will be reported in a separate population PK report

Samples collected for analyses of efpeglenatide serum concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study if 
warranted upon agreement with the Sponsor
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel.
8.6
PHARMACODYNAMICS
Pharmacodynamic parameters are not evaluated as a part of this study.
8.7
GENETICS
Genetics are not evaluated in this study.
8.8
BIOMARKERS
Biomarkers are not evaluated in this study.
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8.8.1
Immunogenicity assessments
Blood samples are taken to assess the ADA status (positive/negative) and level (titer). 
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 at 
the time points specified in the SoA (Section 1.3).
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 sample for 
anti-efpeglenatide antibodies assessments 4 and 6 months after the end of the treatment.
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
For the primary efficacy variable of change from Baseline to Week 30 in HbA1c, the following 
statistical null hypothesis and alternative will be tested for each efpeglenatide dose:

H0: No treatment difference

H1: efpeglenatide has a higher reduction in HbA1c from Baseline than placebo
Based on data from previous Phase 1 and 2 studies and modeling, a minimum treatment effect 
difference of -0.6% in HbA1c change from Baseline to Week 30 was considered as reasonable for 
this study.
9.2
SAMPLE SIZE DETERMINATION 
The sample size calculations are performed based on the primary endpoint, change in HbA1c (%) 
from Baseline to Week 30.
A sample size of approximately 100 participants per arm (ie, 100 participants for each of the 
efpeglenatide doses and 100 for the placebo group) has 89% (96%) power to detect a treatment 
difference of -0.5% (-0.6%) between each dose of efpeglenatide and placebo in HbA1c change 
from Baseline to Week 30, assuming a common standard deviation of 1.1% (2-sided, α=0.05) for 
each comparison. 
Hence, there are 4 parallel dosing arms:

Efpeglenatide 2 mg, N=100

Efpeglenatide 4 mg, N=100

Efpeglenatide 6 mg, N=100

Efpeglenatide placebo, N=100
Hierarchical procedure will be done to adjust the multiplicity of comparison.
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9.3
POPULATIONS FOR ANALYSES
For purposes of analysis, the following populations are defined (Table 4):
Table 4 - 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 
in IRT database, regardless of whether the treatment kit was used or not.
ITT
All randomized participants irrespective of rescue therapy use and compliance with
the study protocol and procedures. Participants will be analyzed in the treatment 
group to which they are randomized.
Safety
All participants randomly assigned to IMP and who take at least 1 dose of IMP. 
Participants will be analyzed according to the treatment they actually received.
ADA
All participants from the safety population with at least 1 post-Baseline valid 
ADA sample after drug administration 
PK
All participants from the safety population with at least 1 valid PK sample available for 
analysis.
ADA anti-drug antibody; ICF informed consent form; IRT interactive response technology; ITT intent to treat; PK pharmacokinetic.
9.4
STATISTICAL ANALYSES
The statistical analysis plan will be developed and finalized before database 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.
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9.4.1
Efficacy analyses
Table 5 - Efficacy analyses
Endpoint
Statistical Analysis Methods
Primary
Change in HbA1c from 
Baseline to Week 30
Primary analysis:
The primary efficacy endpoint will be analyzed using all HbA1c values at Baseline and Week 30 
(observed or imputed), regardless of treatment discontinuation or initiation of rescue therapy 
(ITT estimand).
The primary analysis method for the primary efficacy endpoint will be an ANCOVA model with 
missing values imputed by MI analysis method in two parts as follows:

Missing endpoint data in participants who prematurely discontinue the study treatment 
before the Week 30 visit will be imputed using a model estimated from participants in the 
same treatment arm who prematurely discontinue the study treatment before the Week 
30 visit but have the measurement for the endpoint (retrieved dropouts). Considering that 
the number of participants in each treatment arm who discontinue the study treatment 
but have the measurement for the endpoint is expected to be small, a simple imputation 
model will be used, where only the baseline measurements are included as the predictor. 
Each treatment group will have their own imputation model. Missing data will be imputed 
using the regression method. 

Missing endpoint data in all participants, including those in the efpeglenatide arms, who 
stay on the study treatment until the Week 30 visit will be imputed separately, using a 
model estimated from participants in the placebo group who stay on the study treatment 
until the Week 30 visit and have the endpoint data available. The imputation model will 
include the randomization strata and corresponding baseline values without including 
any intermediate. Missing data will be imputed using the regression method. 
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data sets 
with complete data. The completed data sets will be analyzed using an ANCOVA model with 
treatment groups, randomization strata, and geographical regions as fixed effects and the 
corresponding baseline values as a covariate.  
The Baseline value is defined as the last available value prior to the first dose administration of 
IMP or the last available value on or before the date of Randomization if not treated with the 
double-blinded IMP. 
The results from the 10 000 analyses will be combined using Rubin’s formula and provide the 
adjusted mean change in HbA1c from Baseline to Week 30 (regardless of treatment 
discontinuation or initiation of rescue therapy) for each treatment group, as well as the difference 
between each efpeglenatide dose and placebo and the 95% CI for the difference. 
A hierarchical procedure will be applied to adjust for the multiplicity of comparison on the primary 
endpoint:

First, the highest dose of efpeglenatide (6 mg) will be compared to placebo to 
demonstrate superiority of this dose versus placebo 

If superiority is demonstrated for efpeglenatide 6 mg, the superiority of 4 mg dose of 
efpeglenatide versus placebo will be tested 

If superiority is also demonstrated for 4 mg dose, the lowest dose (2 mg) will be tested 
for superiority over placebo
When the superiority is not obtained in a step, the sequential testing procedure will be stopped.
As noted, the number of retrieved dropouts is expected to be small, and may not have sufficient 
data to support the imputation approach in item 1 described above. If there are less than 
5 participants in any arms who prematurely discontinue the study treatment before the Week 30 
visit but have the measurement for the endpoint, a back-up imputation method for the primary 
efficacy analysis will be used. In particular, missing endpoint data in all participants in both 
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Endpoint
Statistical Analysis Methods
efpeglenatide and placebo groups, regardless of staying on the study treatment or not, will be 
imputed using a model estimated from participants in the placebo group with endpoint data, where 
randomization strata and corresponding baseline values are included as the predictors. Missing 
data will be imputed using the regression method. 
Sensitivity analysis:
Tipping point analysis based on the same MI method as described above will be performed to 
examine the robustness of the results from the primary analysis. A penalty δ will be added to 
participants in efpeglenatide groups (2, 4, or 6 mg) who have no HbA1c data at Week 30. The 
penalty will be gradually increased to evaluate at which level the conclusion of the analyses in 
terms of statistical significance is changed for each efpeglenatide dose group. The tipping point is 
the penalty level, at which the magnitude of efficacy reduction in participants without HbA1c data at 
Week 30 creates a shift in the treatment effect of efpeglenatide from being statistically significantly 
better than placebo to a non-statistically significant effect. The penalty δ will start at 0 and increase 
by 0.01 at each imputation until non-statistically significance is found. Least square mean 
difference between each efpeglenatide dose and placebo and its associated p-value will be 
provided for each penalty level. 
The primary endpoint will be assessed too by an ANCOVA model with missing values imputed by 
Control-based MI method (copy to reference) under the MNAR framework in the ITT population. 
Data will be imputed 10 000 times.

For placebo participants, missing data will be imputed based on the placebo group data 

For participants in the efpeglenatide groups, missing data will be imputed as if the 
participants were on placebo throughout the study 
In particular, a 2-step approach will be used:

Step 1: Use the Markov Chain Monte Carlo method conjunction with the 
IMPUTE=MONOTONE option in PROC MI to create an imputed data set with a 
monotone missing pattern

Step 2: Based on the MONOTONE data sets obtained from Step 1, build the imputation 
model using the regression method on data from the placebo group, and use the built 
model conditional on the participant’s previous observed data to impute the missing data 
in both placebo and efpeglenatide groups. The imputation model will include the 
randomization stratum of HbA1c value at Screening (<8%, ≥ 8%), and the randomization 
stratum of Visit 3 (Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2). This will be 
implemented using MNAR statement in PROC MI
Each of the complete datasets after the imputation will be analyzed using the same ANCOVA
model as used for the primary analysis. Results from each complete dataset will be combined 
using Rubin’s formula.
Descriptive analyses will be conducted to explore missing data patterns for HbA1c in the primary 
efficacy analysis, with number and percentage of participants in each of the following categories 
presented by treatment group.

Pattern 1: participants without Baseline if any

Pattern 2: participants with Baseline but without post-Baseline value during the 30-week 
Core Treatment Period

Pattern 3: participants with Baseline and at least 1 post-Baseline value during the 
30-week Core Treatment Period but not at Week 30

Pattern 4: participants with Baseline and Week 30 value during the 30-week Core 
Treatment Period
HbA1c values by visit will be presented by missing data pattern for each treatment group, using 
descriptive statistics and/or graphs
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Assessment of treatment effect by subgroup:
Primary efficacy endpoint will be further analyzed to examine the consistency of the treatment 
effect across the subgroups defined by the following Baseline covariates:

Race (White, Black or African American, Asian, Other) (any race groups with fewer than 
5 participants may be combined with “Other” category as appropriate) 

Ethnicity (Hispanic, Not Hispanic)

Age group (<50, ≥50 to <65, ≥65 years) (any category with fewer than 5 participants 
may be combined with another category as appropriate)

Gender (Male, Female)

Duration of diabetes (<10, ≥10 years)

Baseline HbA1c (<8.0%, ≥8.0%)

Baseline BMI (<30 kg/m2, ≥30 kg/m²)

Country

United States/non-United States

Baseline estimated GFR categories (mL/min/1.73m²): (<30; [30-60]; ≥60)
The treatment effects (efpeglenatide 2, 4, or 6 mg, versus placebo) across the subgroups defined 
for each of these factors will be estimated for the change from Baseline to Week 30 in HbA1c in 
the ITT population, and using a similar approach as applied to the analysis for the primary efficacy 
endpoint. The ANCOVA model will include treatment groups (efpeglenatide 2, 4, or 6 mg, placebo) 
and randomization stratum of Screening HbA1c (<8%, ≥8%), randomization stratum of Visit 3 
(Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2), subgroup factor, treatment-by-subgroup factor, and 
region as fixed factors and using Baseline HbA1c value as a covariate. The adjusted estimates of 
treatment mean differences (each efpeglenatide dose versus placebo) with SE and 95% CIs will be 
provided as appropriate across the subgroups. A graphical presentation of the results (ie, forest 
plot) will also be provided.
In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, Baseline HbA1c, Baseline BMI), only the subgroup factor (as a single factor or an interaction 
term) will be included in the model in order to avoid the issue of collinearity in the analysis. The 
corresponding strata factor will not be included in the model. In case that the subgroup factor is 
country, the region will not be included in the model.
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided by treatment group for HbA1c value over the 
whole treatment period including the 26-week Safety Extension Period. The summary will include 
the number of observations, mean, SD, SE, minimum, median, and maximum. Graphical 
presentations will also be used to examine trends over time using mean values (±SE) and mean 
changes from Baseline (±SE) at each of the scheduled visits (using OC).
Secondary
-
Change from baseline 
to Week 56 in HbA1c
-
Change from baseline 
to Week 30 in FPG 
-
Number of 
participants with 
HbA1c <7.0% at 
Week 30
-
Change from baseline 
to Weeks 30 and 56 in 
Continuous secondary efficacy endpoints will be analyzed using the same ANCOVA model with 
missing values imputed as the one used for the primary efficacy endpoint analysis. Differences 
between treatment groups and CIs will be estimated by this method. 
Categorical efficacy endpoints will be analyzed by Cochran Mantel Haenszel method stratified by 
the randomization stratum of Screening HbA1c (<8%, ≥8%) and randomization stratum of Visit 3 
(Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2). For the HbA1c <7.0% analysis, participants with 
missing HbA1c data at Week 30 or Week 56 will be considered non-responders in the ITT 
population.
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for continuous efficacy endpoints for each 
treatment group over the whole treatment period including the 26-week Safety Extension Period. 
The summary will include the number of observations, mean, SD, SE, minimum, median, and 
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body weight
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits (using OC).
Multiplicity considerations
To control the family-wise type I error, a step-down testing procedure will be applied. For the 
primary efficacy endpoint (change from Baseline to Week 30 in HbA1c), the 3 efpeglenatide doses 
will be tested in the order of 6 mg, 4 mg, and 2 mg. once the primary endpoint is statistically 
significant at α=0.05 (2-sided) for all 3 efpeglenatide doses, a hierarchical testing procedure will be 
performed to test the following study secondary efficacy endpoints by the following prioritized 
order:
1.
HbA1c <7% at Week 30 for efpeglenatide 6 mg versus placebo (yes/no)
2.
HbA1c <7% at Week 30 for efpeglenatide 4 mg versus placebo (yes/no)
3.
Change from Baseline to Week 30 in body weight (kg) for efpeglenatide 6 mg versus 
placebo
4.
Change from Baseline to Week 30 in body weight (kg) for efpeglenatide 4 mg versus 
placebo
5.
HbA1c <7% at Week 30 for efpeglenatide 2 mg versus placebo (yes/no)
6.
Change from Baseline to Week 30 in FPG (mmol/L, mg/dL) for efpeglenatide 6 mg 
versus placebo
7.
Change from Baseline to Week 30 in FPG (mmol/L, mg/dL) for efpeglenatide 4 mg 
versus placebo
8.
Change from Baseline to Week 56 in body weight (kg) for efpeglenatide 6 mg versus 
placebo
9.
Change from Baseline to Week 56 in HbA1c (%) for efpeglenatide 6 mg versus placebo
10. Change from Baseline to Week 56 in body weight (kg) for efpeglenatide 4 mg versus 
placebo
11. Change from Baseline to Week 56 in HbA1c (%) for efpeglenatide 4 mg versus placebo
12. Change from Baseline to Week 56 in HbA1c (%) for efpeglenatide 2 mg versus placebo
13. Change from Baseline to Week 56 in body weight (kg) for efpeglenatide 2 mg versus 
placebo
The testing will stop as soon as an endpoint for an efpeglenatide dose is found to be not 
statistically significant at α=0.05 (2-sided) for 1 efpeglenatide dose. No multiplicity adjustment will 
be made on other secondary efficacy variables or the comparison of other efpeglenatide dose 
versus placebo than mentioned above.
Tertiary 
-
7 point SMPG profile
-
HbA1c <7.0% at 
Week 30 and 
Week 56 
-
Rescue therapy used 
during the treatment 
period until Weeks 30 
and 56 (yes/no)
-
Time to initiation of 
rescue therapy 
(weeks)
Comparisons of time to event endpoints between treatment groups will be performed using the 
Cox proportional hazards regression model with the treatment groups (efpeglenatide 2, 4, or 6 mg, 
placebo), randomization stratum of Screening HbA1c (<8%, ≥8%), randomization stratum of Visit 3 
(Baseline, Day 1) BMI (<30 kg/m2, ≥30 kg/m2), and region as the factors. The curve of the 
cumulative incidence of participants with rescue initiation will be estimated using Kaplan-Meier 
method by study treatment group.
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for continuous efficacy endpoints for each 
treatment group over the whole treatment period including the 26-week Safety Extension Period. 
The summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from Baseline (±SE) at each of the scheduled visits (using OC).
ANCOVA Analysis of Covariance; BMI body mass index; CI confidence interval; FPG fasting plasma glucose; HbA1c hemoglobin A1c; ITT intent 
to treat; MI multiple imputation; MNAR missing not at random; OC observed cases; SD standard deviation; SE standard error; 
SMPG self-monitoring plasma glucose. 
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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 whole on-treatment period is defined as the time from the first injection of IMP up to 
30 days (7 days for hypoglycemia) after the last injection of IMP;
-
The 30-week core on-treatment period is defined as the time from the first injection of 
IMP up to Visit 10 (Week 30) (or Day 210 if Visit 10 [Week 30] visit is missing) or up 
to 30 days (7 days for hypoglycemia) after the last injection of IMP, whichever comes 
earlier

The 30-week on-study period is defined from the first injection of IMP up to Week 30,
irrespectively if IMP was still used or already discontinued at Week 30.

The post-treatment period is defined as the time starting 31 days (8 days for 
hypoglycemia) after the last injection of IMP (after the whole 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 (TEAEs) 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.
Table 6 - Safety analyses
Endpoint
Statistical Analysis Methods
AEs
All AEs will be coded to a "LLT", “PT”, "HLT", and “HLGT” and associated “SOC” using the version of 
MedDRA currently in use by the Sponsor at the time of database 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.
The primary focus of AE reporting will be on TEAEs. Pretreatment and posttreatment AEs will be 
described separately.
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 and all 
TEAEs leading to death.
Tables will be presented on the “30-week main on-treatment period” and on the “whole on-treatment 
period including the 26-week controlled Treatment Extension Period”.
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Adverse events, SAEs and AEs leading to death tables also will be presented on the 30-week 
on-study period too.
Hypoglycemia
The number (%) of participants with at least 1 hypoglycemia event during the whole on-treatment 
period will be assessed per type of hypoglycemic event (see Section 8.2.5) and according to time of 
occurrence (nocturnal [ie, 00:00 to 05:59 am], any time of the day). Documented hypoglycemia 
(symptomatic or asymptomatic) will be also evaluated for the more stringent SMPG threshold of 
<54 mg/dL (3.0 mmol/L).
Summaries will be presented overall and by type of event for each treatment group.
The total number of events (per 100 participant-years) will be computed and summarized overall and 
by type of event for each treatment group.
Similar summaries will also be provided for the 30-week core on-treatment period.
Vital signs and laboratory 
data
ECG & Holter data
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 
considered medically important by the Sponsor according to predefined criteria/thresholds based on 
literature review, will be summarized at any time during the 30-week core on-treatment period and 
during the whole 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 on-treatment period will be 
summarized by treatment group whatever the Baseline level and according to Baseline status.
Tables will be presented on the “30-week main on-treatment period” and on the “whole on-treatment 
period including the 26-week controlled Treatment Extension Period”
Exploratory
Will be described in the statistical analysis plan finalized before database lock
AE adverse event; ECG electrocardiogram; HLGT higher-level grouped term; HLT higher-level term; LLT lower-level term; MedDRA Medical 
Dictionary for Regulatory Activities; PCSA potentially clinically significant abnormalities; PT preferred term; SAE serious adverse event; SOC 
system organ class; TEAE treatment-emergent adverse event.
9.4.3
Other analyses 
Pharmacokinetic exploratory analyses will be described in the statistical analysis plan finalized 
before database lock. Analyses of other endpoints are detailed in Table 7.
Table 7 - Other analyses
Endpoint
Statistical Analysis Methods
Efpeglenatide ADA
Summaries of ADA data will be 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: 

Number and percentage of participants by ADA status (positive/negative) at scheduled visits

Number and percentage of participants with treatment-induced ADAs (among the participants 
with ADA negative or missing at baseline) during the study period

Number and percentage of participants with treatment-boosted ADAs (among the participants 
with ADA positive at baseline) during he study period

ADA titer at schedule timepoint will be summarized by visit using descriptive statistics by number 
(n), median, quartiles, minimum, and maximum. 

Number and percentage of participants by ADA cross-reactivity to endogenous GLP-1 (positive or 
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negative) at scheduled visits

Number and percentage of participants by ADA cross-reactivity to endogenous glucagon 
(positive or negative) at scheduled visits

Number and percentage of participants with ADAs directed against the PEG linker of 
efpeglenatide at scheduled visits.
Correlation, scatterplots and/or subgroup analyses will be conducted as appropriate to assess the 
relationship between immunogenicity endpoints and efficacy/safety assessments.
PK endpoints: 
serum 
concentration of 
efpeglenatide at 
pre-dose and 
post-dose
Efpeglenatide pre-dose and post-dose serum concentrations of participants in the efpeglenatide groups will 
be listed and summarized by visit in the PK population, using descriptive statistics by N, geometric mean, 
coefficient of variation, median, minimum and maximum.
PRO:
The analysis of PRO endpoints will be descriptive with no formal testing. Summary statistics at scheduled 
visits will be provided by treatment group. Graphical presentations will also be used to illustrate trends over 
time.
Participants’ answers to the open-ended questions of PQATv2 will be analyzed qualitatively and 
quantitatively, as relevant, using appropriate data analysis software. 
The analysis method for this exploratory analysis will be provided in a separate SAP and the analyses 
results will be documented in a separate report.
ADA anti-drug antibodies; GLP-1 glucagon-like peptide 1; PEG polyethylene glycol, PK pharmacokinetic; PQATv2 Patient Qualitative 
Assessment of Treatment version 2; PRO participant-reported outcome ; SAP statistical analysis plan. 
9.5
INTERIM ANALYSES 
Not applicable.
9.5.1
Data Monitoring Committee
See Appendix 1 (Section 10.1) 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 Council for 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 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 Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 
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
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. 

Participants who are rescreened are required to sign a new ICF.

The ICF will contain a separate section that addresses the participation in the post-dose PK 
assessment sub-study. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are 
free to refuse to participate and may withdraw their consent at any time and for any reason 
during the storage period. A separate signature will be required to document a participant's 
agreement to allow any remaining specimens to be used for exploratory research. 
Participants who decline to participate in this optional research will not provide this 
separate signature.
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 of 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.
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10.1.4 Committees Structure
10.1.4.1 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.
10.1.4.2 Clinical Endpoint Committee
Independent CEC(s) 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, the CRO and the Investigators, and will be implemented to review, 
assess and/or adjudicate all events of death, selected cardiovascular events (non-fatal myocardial 
infarction, 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.
10.1.4.3 Independent Expert
An independent ophthalmologist expert will review in a treatment-blinded manner all reported 
AEs suspected to be diabetic retinopathy-related to assess the presence of retinopathy and 
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 ICO guidelines
(10) 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.
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In addition, results from clinical trials in participants 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 
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 e-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 e-CRF 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 or 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 8 will be performed by the central laboratory, except urine 
pregnancy tests and urinalysis by dipstick, which will be performed locally.

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.

Additional tests may be performed at a local laboratory at any time during the study as 
determined necessary by the Investigator or required by local regulations. If they are used 
to evaluate an AE (diagnostic, follow-up, outcome), the results must be entered into the 
e-CRF.
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Table 8 - Protocol-required safety laboratory assessments
Laboratory 
assessmentsa
Parameters
Hematology
Platelet count
Red blood cell count
Hemoglobin
Hematocrit
WBC count with differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical chemistry
Creatinine
Potassium
Aspartate 
aminotransferase
Total bilirubin (in case of values above 
the normal range, differentiation in 
conjugated and non-conjugated 
bilirubin)
Sodium
Alkaline 
phosphatase
Alanine 
aminotransferase
Estimated glomerular filtration rate 
(MDRD formula)
Amylase
Lipase
Routine urinalysis
pH, glucose, protein, blood/hemoglobin, ketones, leucocyte, by dipstick
Lipid profile
Triglyceride
Cholesterol:
Total cholesterol
Low-density lipoprotein cholesterol
High-density lipoprotein cholesterol
Anti-drug antibodies
Serum anti-drug antibody sample
Calcitonin
Calcitonin
Other Screening tests

Follicle-stimulating hormone and estradiol (as needed in unconfirmed postmenopausal 
women)

NOTE: For women of non-childbearing potential (Appendix 4, Section 10.4), 
follicle-stimulating hormone and estradiol levels should be tested in case the definition of 
postmenopausal or premenopausal cannot be satisfied; eg, no medical document of 
hysterectomy or cessation of menses <12 months without an alternative medical cause.

Serum human β-HCG pregnancy test (as needed for women of childbearing potential)b

C-peptide
NOTES :
a
All study-required laboratory assessments will be performed by a central laboratory except urine pregnancy tests and urinalysis by dipstick, 
which will be performed locally; the results of each test must be entered into the e-CRF.
b
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.
β-HCG human beta-chorionic gonadotropin; MDRD Modification of Diet in Renal Disease; WBC white blood cell; WOCBP women of childbearing 
potential.
Investigators must document their review of each laboratory safety report.
Hemoglobin A1c and FPG values that could unblind the study will not be reported to study sites 
or other blinded personnel after Visit 3 (Day 1), until the study has been unblinded. Details of the 
conditions in which unblinding can occur, and the procedure, are detailed in Section 6.3.2.
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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 participant 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. Such instances will be captured in the efficacy assessments.
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they 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.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
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
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).
An 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 
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.
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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/AESI 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 e-CRF.

It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to Sponsor representative in lieu of completion of the SAE/AESI e-CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor 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 Sponsor 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.

The Investigator will submit any initial SAE/AESI data to the Sponsor representative
within 24 hours of its acknowledgement.
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 a Sponsor 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 Sponsor 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 Sponsor 
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.

If a participant dies during participation in the study or during a recognized Follow-up 
Period, the Investigator will provide the Sponsor representative with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed e-CRF.

The Investigator will submit any updated SAE/AESI data to the Sponsor representative
within 24 hours of receipt of the information.
REPORTING OF SAEs/AESIs
SAE reporting to Sponsor representative via an electronic data collection tool

The primary mechanism for reporting an SAE/AESI to Sponsor 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/AESI data collection tool.
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
The site will enter the SAE/AESI data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE/AESI from a study participant or receives updated 
data on a previously reported SAE/AESI after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE/AESI form or to 
the Sponsor representative by telephone.

Contacts for SAE/AESI 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. Post-menopausal female:
-
A post-menopausal 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 9.
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 9 - 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 other highly effective method of contraception, with 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.
PREGNANCY TESTING:

WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test
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
Additional pregnancy testing should be performed at each on-site visit during the 
treatment period, at the last study visit (6 weeks ±7days after the last dose of study 
treatment), 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 no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure
Female participants who become pregnant 

The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure

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
10.5.1 Laboratory abnormalities
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met.
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
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)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
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.
•For individuals of African descent, the relevant value of concern is <1000/mm3
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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 AEs 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 laboratory 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 Appendix 3 (Section 10.3) for guidance on safety reporting.

Normalization is defined as ≤ ULN or baseline value, if baseline value is > ULN.
INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
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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 AEs in Appendix 3 (Section 10.3) is met.
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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Increase in creatine phosphokinase (CPK) is to be recorded as an AE only if at least 1 of the 
criteria in the general guidelines for reporting AEs 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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10.5.2 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.
10.5.2.1 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 × ULN, a retest (centrally assessed as far as 
possible) must be performed as follows:

If value(s) is/are >2 to 3 × ULN: retest within 7 days,

If value(s) is/are >3 × ULN: retest within 48 hours,

If the value(s) remain(s) >2 × ULN upon retesting: amylase and/or lipase levels should be 
retested weekly until values are <2 × ULN.
In case a retest is >2 × ULN a gastroenterological evaluation and imaging (ultrasound and/or 
computed tomography [CT] or magnetic resonance imaging [MRI] with contrast, as appropriate) 
is highly recommended. The absence of clinical signs and/or symptoms should be documented in 
the source documents (if clinical signs and/or symptoms develop, please see Appendix 5 
Section 10.5.2.2 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.
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10.5.2.2 Elevation of amylase and/or lipase >2 × ULN with clinical signs and/or symptoms.
In the presence of clinical signs and/or symptoms evocative of pancreatitis (as previously 
described) 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 × ULN, then 
amylase and/or lipase levels should be retested as described in Appendix 5 Section 10.5.2.1 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 (Section 10.5.2.1 and Section 10.5.2.2) as previously described, 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 specific 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.
10.5.3 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 (as final diagnostic if available 
or as “increased calcitonin”); all appropriate clinical and laboratory documentations should 
also be reported in the corresponding eCRF pages
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
An ultrasound scan of the thyroid is highly recommended to be performed and the 
participant may be referred to a Specialist if judged necessary (per clinical practice and 
local guidelines)

The participant should continue to be followed according to protocol schedule (including 
planned calcitonin measurements). The AE form and all other related eCRF pages 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 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 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.
10.5.4 Gastrointestinal events in relation to acute renal failure
Acute renal impairment caused by dehydration is a potential risk described for other GLP-1 RA. 
Acute renal impairment is not thought to be caused directly by GLP-1 RA (including 
efpeglenatide) without dehydration.
In case of prolonged or severe nausea and vomiting, if clinically indicated, serum creatinine 
measurement should be performed at the central laboratory. If there is an acute increase of serum 
creatinine, metformin must be discontinued (if concomitantly taken) until resolution of renal 
dysfunction. Please also refer to Appendix 5 (Section 10.5.1), increase in serum creatinine 
flowchart for further recommendations.
10.6
APPENDIX 6: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING
Not applicable.
10.7
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS
Not applicable.
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10.8
APPENDIX 8: HYPOGLYCEMIA CLASSIFICATION
Figure 2 - Hypoglycemia classification 
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10.9
APPENDIX 9: PATIENT QUALITATIVE ASSESSMENT OF TREATMENT VERSION 2
The following questions ask for your opinion on the drug you received during this clinical study.
There are no right or wrong answers; we would like to better understand your own experience of 
the drug.
1.
During this trial, what were the main benefits you experienced with the drug you received? 
Free-text
2.
On a scale of 0 to 10, how beneficial was the drug you received during this trial?
3.
During this trial, what were the main disadvantages you experienced with the drug you received? 
Free-text
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4.
On a scale of 0 to 10, how disadvantageous was the drug you received during this trial?
5.
After this trial, would you be willing to continue using the drug you received during this trial? 
Yes 
No 
Please explain why?
Free-text
6.
Based on your own experience in this trial, please select a response on the scale below

- 3

- 2

- 1

0

1

2

3
The disadvantages 
of the drug I 
received 
significantly 
outweigh the 
benefits
There were 
equal benefits 
and 
disadvantages 
of the drug I 
received
The benefits of 
the drug I 
received 
significantly 
outweigh the 
disadvantages
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10.10 APPENDIX 10: ABBREVIATIONS
ADA:
anti-drug antibody
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase
ANCOVA:
Analysis of Covariance
AST:
aspartate aminotransferase
BMI:
body mass index
BP:
blood pressure
CDs:
compact discs
CEC:
clinical endpoint committee
CFR:
Code of Federal Regulation
CI:
confidence interval
CIOMS:
Council for International Organizations of Medical Sciences
CT:
computed tomography
DMC:
data monitoring committee
DPP-4:
dipeptidyl peptidase 4
DVDs:
digital versatile disc
ECG:
electrocardiogram
e-CRF:
electronic Case Report Form
EOT:
end of treatment
FPG:
fasting plasma glucose
GCP:
Good Clinical Practice
GI:
gastrointestinal
GLP-1:
glucagon-like peptide 1
GLP-1 RA:
glucagon-like peptide 1 receptor agonist
HA:
health authority
HbA1c:
hemoglobin A1c
HR:
heart rate
HRT:
hormonal replacement therapy
IB:
Investigator's Brochure
ICF:
informed consent form
ICH:
International Council for Harmonisation
IEC:
Independent Ethics Committees
IMP:
investigational medicinal product
IRB:
Institutional Review Board
IRT:
interactive response technology
MDRD:
modification of diet in renal disease
MEN-2:
multiple endocrine neoplasia syndrome type 2
MI:
multiple imputation
MRI:
magnetic resonance imagine
MTC:
medullary thyroid cancer
NIMP:
noninvestigational medicinal product
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NOAEL:
no-observed-adverse-effect level
PEG:
polyethylene glycol
PFS:
prefilled syringe
PK:
pharmacokinetic
PPG:
post-prandial plasma glucose
PQATv2:
patient qualitative assessment of treatment version 2
SAE:
serious adverse event
SC:
subcutaneous
SE:
standard error
SMPG:
self-monitored plasma glucose
SoA:
schedule of assessments
T2DM:
type 2 diabetes mellitus
TEAE:
treatment-emergent adverse event
ULN:
upper limit of the normal
WOCBP:
women of childbearing potential
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10.11 APPENDIX 11: PROTOCOL AMENDMENT HISTORY
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC).
10.11.1 Amendment 01: 16 January 2018
This amendment 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
Following US IRB Protocol review, it was requested to update sections related to male 
contraception and legally authorized representative. Updates to the following sections were also 
made, based on US FDA advice: statistical analysis and methods of unblinding. 
In addition, Sanofi uses this opportunity to edit other sections of the protocol as listed below, to 
update text with new available information, to align the procedures with those in other studies 
within the program and/or for better clarity: 

Schedule of activities, exploratory endpoints and dosing instructions (for PK pre-dose),

Benefit/Risk assessment, 

Exclusion criteria, 

Anti-drug antibody measurements, 

Committee Structure. 
Inconsistencies, typographical, and spelling checks were also run throughout the document and 
corrected.
Section # and 
Name
Description of Change
Brief Rationale
Section 1.1 
Synopsis, 9.4.1 
Efficacy analyses 
Control-based MI method for analysis of 
primary/secondary efficacy endpoints for 
missing data changed to retrieve drop-out 
method 
Control-based imputation method moved to 
sensitivity analysis
To update analysis of primary/secondary efficacy 
endpoints with retrieve drop-out method to handle 
missing values following US FDA recommendation
To update sensitivity analysis
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Section # and 
Name
Description of Change
Brief Rationale
Section 5.2 
Exclusion criteria, 
Section 10.4 
Appendix 4 
Contraceptive 
guidance and 
collection of 
pregnancy 
information
Exclusion criteria E19 modified to add required 
contraception duration to study period and at 
least 5 weeks after last dose of study treatment 
for women and required contraception duration 
for male for at least 5 weeks after the last dose 
of study intervention and sperm donation 
restriction during this period is added
To add male exclusion criteria related to required 
contraception during the study 
Section 6.3.1 
Methods of blinding, 
6.3.2 Randomization 
code breaking 
during the study
The text for bioanalyst unblinding deleted from 
Section 6.3.1 and additional text pertaining to 
PK analyst unblinding is added
To clarify, at US FDA request, the samples to be 
analyzed for PK and ADA during the study
Section 9.4.2 Safety 
analyses
Text included to add 30-week core treatment 
period for safety analysis
Clarification of treatment periods for which safety 
tables will be provided as per US FDA 
recommendation
Appendix 1 
Section 10.1.2. 
Informed consent 
process
Involvement of legally authorized representative 
in informed consent process deleted
The age of majority is not >18 in any participating 
country. Protocol procedures require participants to be 
able to self-manage different activities so a legally 
authorized representative is not accepted. Legally 
authorized representative has been removed following 
US IRB request
Section 1.1 
Synopsis, Section 3 
Objectives and 
endpoints, 
Section 9.4.3 Other 
analyses  
Text for ADA measurement schedule modified
ADA endpoints wording was changed following 
additional team discussion and recommendation
Section 1.3 
Schedule of 
activities
Permitted window of up to -21 days added to 
Screening period Visit 1 and ±3 days deleted for 
Visit 3. Notes for permitted window for Visits 2 
and 3 added
To clarify the permitted window for visits during 
Screening period (Visit 1 and Visit 2) and remove 
window from Visit 3 (Randomization, Day 1)
Section 1.3 
Schedule of 
activities
Diary dispensation schedule added on Visits 3, 
5, 6, 7, 9, 10, 12, and 14 (EOT)
To clarify in Scope of Activities the requirement for 
dispensation of paper diary at all visits
Section 1.3 
Schedule of 
activities
Table 1 
Objectives and 
Endpoints
PK pre-dose was removed from Baseline and 
was added at Week 24 visit. PK endpoint has 
been updated accordingly
Participants in this study should not have been treated 
with any antidiabetic medication within 3 months prior 
to the study. For this reason the baseline PK pre-dose 
sampling was considered non-informative and was 
replaced with a sample at Week 24 to better 
characterize the PK profile of the patients.  
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Section # and 
Name
Description of Change
Brief Rationale
Table 2
Overview of study 
interventions 
administered
Additional instructions have been provided for 
the timing of IMP administration prior to PK 
pre-dose (expected to be 6 to 7 days)
We need PK samples which are far enough removed 
from the period between time of injection and Cmax
(Tmax) such that the large, random fluctuations in 
concentration which typically occur during that period 
will not confound our estimates. Because for 
efpeglenatide Cmax typically occurs around 4 days after 
injection, PK samples taken during the first 5 to 6 days 
after dosing will still be heavily influenced by random 
fluctuations in Cmax and Tmax, and essentially 
uninformative with regard to clearance. 
Section 2.3 
Benefit/Risk 
assessment
Cut-off date of 22 June 2017 for safety 
information was included 
To clarify this information and to be able to make a 
correct time reference for safety data presented in this 
section.
Section 2.3 
Benefit/Risk 
assessment
Following text:

The GLP-1 RA class has a box
warning related to risk of thyroid C-cell
tumors in the label, based on findings
in rodents.
Replaced with:

The GLP-1 RA class has a box
warning related to risk of thyroid C-cell
tumors in the US label, based on
findings in rodents.
To clarify that only US label for GLP-1 RA has a box 
warning for thyroid C-cell tumors
Section 2.3 
Benefit/Risk 
assessment
Following text added about diabetic retinopathy 
complication:
Diabetic retinopathy complications have been 
reported for one of GLP-1 RAs (as of 
05 December 2017). No case has been 
reported for efpeglenatide. Participants with a 
planned retinal treatment for retinopathy or 
maculopathy will be excluded in the current 
study. Diabetic retinopathy complications will be 
monitored throughout the study.
To add new available data on retinopathy and methods 
to mitigate the participant’s risk during the study
Section 2.3 
Benefit/Risk 
assessment
Text for ALT increase in overall a total of 12 out 
of 571 subjects on efpeglenatide and 3 out of 
183 subjects on comparators for Phase 2 
clinical studies added
To clarify prior ALT increase events in Phase 2 studies
Section 5.2 
Exclusion criteria
Exclusion criteria 04 modified to detail 
description for exclusion of retinopathic
participants
To clarify the retinopathy exclusion criteria
Section 5.2 
Exclusion criteria
Hematological laboratory results deleted from 
Exclusion Criteria 10
To remove hematology laboratory results from 
exclusion criteria as there is no related safety signal to 
efpeglenatide so far
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Section # and 
Name
Description of Change
Brief Rationale
Section 7.1.2.1 
Rechallenge
”Consecutive” was added to the text:
If a maximum of 2 (two) consecutive doses are 
missed, the IMP can be restarted with the last 
dose given. In cases of 3 (three) or more 
consecutive doses are missed, the titration 
should be re-initiated.
To clarify the conditions when the re-titration with IMP 
is needed following temporary discontinuation.
Section 8.3 Adverse 
events and serious 
adverse events
Text to define symptomatic overdose with the 
IMP as at least twice the planned dose given 
within 3 days (72 hours) is added
To separately define the overdose of IMP considering 
longer half-life of efpeglenatide
Sections 8.3.8.1
Appendix 6
These sections have been removed
Appendix 6 has been made “Not applicable”
It was clarified that the study intervention is not a 
medical device per regulatory definition so no related 
information and reporting rules are applicable. It is a 
combined product. Sponsor’s procedures for product 
technical complaints will be followed.
Section 10.1.3 Data 
protection
Text for collection of participants race and 
ethnicity added
Race is collected in this trial as it is requested by 
regulatory authorities and the information was missing 
from the Protocol
Section 10.1.4 
Committees 
Structure
Addition of pancreatic events (and need for 
gastroenterologist) to events adjudicated by 
CEC
Addition of Independent Expert for review of all 
reported AEs suspected to be diabetic 
retinopathy-related
Both pancreatic events and diabetic retinopathy 
complications are included in the Adverse Events 
requiring specific monitoring. Pancreatic events were 
planned be adjudicated by the CEC, but by mistake 
they were omitted from description of the Committee. 
Based on the recent reporting of diabetic retinopathy 
complication for another drug in same class, it was 
decided to add an independent expert to review all 
reported events for confirmation and causality 
assessment. 
Section 6.1 Study 
intervention(s) 
administered
Table 2
Content of formulation buffer for IMP corrected 
from  “sodium citrate, polysorbate 20, mannitol, 
and methionine” to “citric acid monohydrate, 
L-methionine, polysorbate 20, D-mannitol, 
sodium hydroxide and water for injection”
Initial formulation was incorrectly entered in the initial 
protocol
Throughout
Minor editorial, typo error corrections and 
document formatting revisions
Minor, therefore have not been summarized
10.11.2
Amendment 02: 27 March 2018
This amendment 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
Following Medicines and Healthcare products Regulatory Agency (MHRA) request, the protocol
was updated to clarify the contraception requirements for women of childbearing potential 
(WOCBP).
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Section # and Name
Description of Change
Brief Rationale
Section 10.4 
Appendix 4 Contraceptive 
guidance and collection of 
pregnancy information
Appendix modified to add ova donating 
restriction for female participants for the duration 
of the study and at least 5 weeks after last dose 
of study treatment. Change of wording in Table 9 
related to drug-interaction potential of oral 
hormonal contraception and recommended 
measures.
To clarify, at UK MHRA request, the 
recommendations for methods of 
contraception and ova donating restriction 
for WOCBP.
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11
REFERENCES
1. Banholzer ML, Wandel C, Barrow P,   Mannino M,  Schmitt G, et al. Clinical trial 
considerations on male contraception and collection of pregnancy information from female 
partner: update. Clin Transl Med. 2016;5(1):23.
2. US Department of Health and Human Services Food and Drug Administration Center for 
Drug Evaluation and Research (CDER) (2015) Assessment of male-mediated developmental 
risk for pharmaceuticals guidance for industry: guidance for industry (draft guidance).
3. Investigator's Brochure, SAR439977, latest edition.
4. FDA draft Guidance for Industry: Assay Development and Validation for Immunogenicity 
Testing of Therapeutic Protein Products, April 2016.
5. Committee for Medicinal Products for Human Use (CHMP): Guideline on Immunogenicity 
Assessment of Biotechnology-derived Therapeutic Proteins, 
EMEA/CHMP/BMWP/14327/2006.
6. Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the 
Management of adults with diabetes. Diabetes Care. 2014;37(Suppl. 1):S120–S143
7. 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;28(5):1245-9.
8. 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.
9. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L 
(54 mg/dL) should be reported in clinical trials: a joint position statement of the American 
Diabetes Association and the European Association for the study of diabetes. Diabetes Care. 
2017;40(1):155-7.
10. International Council of Ophthalmology. ICO Guidelines for Diabetic Eye Care [cited 2018 
Jan 10]. Available from: 
http://www.icoph.org/downloads/ICOGuidelinesforDiabeticEyeCare.pdf.
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ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
EFC14822 16.1.1 Amended protocol 03
Clinical Approval
Clinical Approval
Regulatory Approval