A 30-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 Metformin Alone or in Combination With Sulfonylurea
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Sanofi

Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity
According to template: Version Sanofi dated 12-SEP-2017 based on TransCelerate CPT version 4
Page 1
CLINICAL TRIAL PROTOCOL
Protocol title:
A 30-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 Metformin Alone or in Combination with 
Sulfonylurea
Protocol number:
EFC15337
Amendment number:
Original protocol
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 Metformin Alone or in Combination with 
Sulfonylurea (AMPLITUDE-S)
Sponsor name:
Legal registered 
address:
Regulatory agency identifying number(s):
EudraCT number:
Not applicable
IND number:
112780
UTN number:
U1111-1205-1291
Approval Date:
20 June 2018
Total number of pages:
90
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Sponsor signatory:
Please refer to the last page of this document for electronic signatures including date and time.
Monitoring Team’s Representative
Name and Contact Information:
  
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TABLE OF CONTENTS
TABLE OF CONTENTS..................................................................................................................................3
LIST OF TABLES ...........................................................................................................................................7
LIST OF FIGURES..........................................................................................................................................7
1
PROTOCOL SUMMARY .................................................................................................................8
1.1
SYNOPSIS.......................................................................................................................................8
1.2
SCHEMA........................................................................................................................................13
1.3
SCHEDULE OF ACTIVITIES (SOA)..............................................................................................14
2
INTRODUCTION............................................................................................................................19
2.1
STUDY RATIONALE .....................................................................................................................19
2.2
BACKGROUND .............................................................................................................................19
2.3
BENEFIT/RISK ASSESSMENT.....................................................................................................20
3
OBJECTIVES AND ENDPOINTS .................................................................................................22
3.1
APPROPRIATENESS OF MEASUREMENTS..............................................................................23
4
STUDY DESIGN ............................................................................................................................25
4.1
OVERALL DESIGN........................................................................................................................25
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN.........................................................................25
4.3
JUSTIFICATION FOR DOSE ........................................................................................................26
4.4
END OF STUDY DEFINITION.......................................................................................................26
5
STUDY POPULATION ..................................................................................................................27
5.1
INCLUSION CRITERIA..................................................................................................................27
5.2
EXCLUSION CRITERIA ...............................................................................................................28
5.3
LIFESTYLE CONSIDERATIONS...................................................................................................30
5.3.1
Meals and dietary restrictions ........................................................................................................30
5.4
SCREEN FAILURES .....................................................................................................................31
6
STUDY INTERVENTION...............................................................................................................32
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6.1
STUDY INTERVENTION(S) ADMINISTERED..............................................................................32
6.1.1
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................33
6.1.2
NONINVESTIGATIONAL MEDICINAL PRODUCT .......................................................................34
6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ......................................................37
6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING .......................................38
6.3.1
Methods of blinding........................................................................................................................38
6.3.2
Randomization code breaking during the study.............................................................................39
6.4
STUDY INTERVENTION COMPLIANCE ......................................................................................39
6.4.1
Return and/or destruction of treatments ........................................................................................40
6.5
CONCOMITANT THERAPY ..........................................................................................................40
6.6
DOSE MODIFICATION..................................................................................................................41
6.7
INTERVENTION AFTER THE END OF THE STUDY...................................................................41
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ...........................................................................................42
7.1
DISCONTINUATION OF STUDY INTERVENTION .....................................................................42
7.1.1
Permanent discontinuation ............................................................................................................42
7.1.2
Temporary discontinuation.............................................................................................................43
7.1.3
Rechallenge ...................................................................................................................................44
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY..................................44
7.3
LOST TO FOLLOW UP .................................................................................................................45
8
STUDY ASSESSMENTS AND PROCEDURES ...........................................................................46
8.1
EFFICACY ASSESSMENTS ........................................................................................................46
8.1.1
Hemoglobin A1c.............................................................................................................................46
8.1.2
Fasting plasma glucose .................................................................................................................46
8.1.3
Body weight....................................................................................................................................46
8.1.4
7-point self-monitored plasma glucose profiles .............................................................................47
8.1.5
Use of rescue therapy....................................................................................................................47
8.2
SAFETY ASSESSMENTS ............................................................................................................48
8.2.1
Physical examinations ...................................................................................................................48
8.2.2
Vital signs.......................................................................................................................................48
8.2.3
Electrocardiograms ........................................................................................................................49
8.2.4
Clinical safety laboratory assessments..........................................................................................49
8.2.5
Hypoglycemia.................................................................................................................................50
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8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...........................................................51
8.3.1
Time period and frequency for collecting AE and SAE information...............................................52
8.3.2
Method of detecting AEs and SAEs...............................................................................................53
8.3.3
Follow-up of AEs and SAEs...........................................................................................................53
8.3.4
Regulatory reporting requirements for SAEs .................................................................................53
8.3.5
Pregnancy......................................................................................................................................53
8.3.6
Cardiovascular and death events ..................................................................................................54
8.3.7
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ...........54
8.3.8
Guidelines for reporting product complaints/medical device incidents (including 
malfunctions)..................................................................................................................................54
8.4
TREATMENT OF OVERDOSE......................................................................................................54
8.5
PHARMACOKINETICS..................................................................................................................55
8.6
PHARMACODYNAMICS ...............................................................................................................55
8.7
GENETICS.....................................................................................................................................55
8.8
BIOMARKERS ...............................................................................................................................55
8.8.1
Immunogenicity assessments........................................................................................................56
8.9
HEALTH ECONOMICS..................................................................................................................56
9
STATISTICAL CONSIDERATIONS .............................................................................................57
9.1
STATISTICAL HYPOTHESES.......................................................................................................57
9.2
SAMPLE SIZE DETERMINATION ................................................................................................57
9.3
POPULATIONS FOR ANALYSES.................................................................................................58
9.4
STATISTICAL ANALYSES ............................................................................................................58
9.4.1
Efficacy analyses ...........................................................................................................................58
9.4.2
Safety analyses..............................................................................................................................62
9.4.3
Other analyses...............................................................................................................................63
9.5
INTERIM ANALYSES ....................................................................................................................64
9.5.1
Data Monitoring Committee (DMC)................................................................................................64
10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................65
10.1
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS.......65
10.1.1
Regulatory and Ethical Considerations..........................................................................................65
10.1.2
Informed Consent Process ............................................................................................................65
10.1.3
Data Protection ..............................................................................................................................66
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10.1.4
Committees Structure ....................................................................................................................67
10.1.5
Dissemination of Clinical Study Data.............................................................................................67
10.1.6
Data Quality Assurance .................................................................................................................68
10.1.7
Source documents .........................................................................................................................68
10.1.8
Study and Site Closure ..................................................................................................................69
10.1.9
Publication Policy...........................................................................................................................69
10.2
APPENDIX 2: CLINICAL LABORATORY TESTS .........................................................................69
10.3
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................71
10.4
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................75
10.5
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................79
10.5.1
Laboratory abnormalities ...............................................................................................................79
10.5.2
Monitoring of participants with increased lipase and/or amylase >2 ULN .....................................84
10.5.3
Management of participants with increased calcitonin values.......................................................85
10.5.4
Gastrointestinal events in relation to acute renal failure................................................................86
10.6
APPENDIX 6: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................86
10.7
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS..............................................................86
10.8
APPENDIX 8: HYPOGLYCEMIA CLASSIFICATION ....................................................................87
10.9
APPENDIX 9: ABBREVIATIONS...................................................................................................88
11
REFERENCES...............................................................................................................................90
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LIST OF TABLES
Table 1 - Objectives and endpoints...............................................................................................................22
Table 2 - Overview of study interventions administered ...............................................................................32
Table 3 - Rescue criteria ...............................................................................................................................35
Table 4 - Populations for analyses................................................................................................................58
Table 5 - Efficacy analyses ...........................................................................................................................58
Table 6 - Safety analyses..............................................................................................................................63
Table 7 - Other analyses ...............................................................................................................................64
Table 8 - Protocol-required safety laboratory assessments..........................................................................70
Table 9 - Highly effective contraceptive methods .........................................................................................77
LIST OF FIGURES
Figure 1 - Graphical study design .................................................................................................................13
Figure 2 - Hypoglycemia classification..........................................................................................................87
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1
PROTOCOL SUMMARY
1.1
SYNOPSIS
Protocol title: A 30-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 Metformin Alone or in 
Combination with Sulfonylurea
Short title:
Efficacy and Safety of Efpeglenatide Versus Placebo in Patients with Type 2 
Diabetes Mellitus Inadequately Controlled with Metformin Alone or in 
Combination with Sulfonylurea (AMPLITUDE-S)
Rationale:
This study is designed to demonstrate the efficacy and safety of efpeglenatide in participants with 
Type 2 diabetes mellitus (T2DM) who have inadequate glycemic control with metformin alone or 
in combination with sulfonylurea (SU). Efpeglenatide will be compared to placebo.
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 metformin alone or in combination 
with SU

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 <7.0% at 
Week 30

Change from baseline to Week 30 FPG
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 Week 30 in body weight
To evaluate the safety of once weekly injection of efpeglenatide 
2, 4, and 6 mg

Number of participants with at least 1 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; SU: sulfonylurea; T2DM: type 2 diabetes mellitus.
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Overall design:
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 4-arm, parallel 
group study in participants with T2DM inadequately controlled with metformin alone or in 
combination with SU.
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 SU use at 
screening (Yes/No).
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 640 participants randomized to study treatment 
(160 participants per treatment group). It is expected that approximately 400 participants to be 
enrolled from China and approximately 240 participants from the US, with approximately 50% of 
participants being on metformin alone and approximately 50% on metformin + SU. 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 comprises 3 periods as follows:

An up to 3-week screening period (with a minimum of 10 days)

A 30-week double-blind, placebo-controlled treatment period for efficacy and safety 
assessments

A 6-week posttreatment follow-up period to collect safety information after last dose of 
IMP
The maximum study duration per participant will be 39 weeks.
Study interventions
Investigational medicinal product
Efpeglenatide/Matching placebo

Formulation: 500 µL of a sterile, non-pyrogenic, clear, colorless solution in a 1 mL 
disposable prefilled syringe (PFS)

Route of administration: subcutaneous (SC)

Dose regimen: SC injection once weekly on the same week day (eg, each Monday) at any 
time of the day
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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 investigational 
medicinal product (IMP) until the end of treatment (EOT) at Week 30 (Visit 11).
Investigational medicinal product dose schedule
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5 onward
Day 1
Week 1
Week 2
Week 3
Week 4
Visit 3
Visit 4
Visit 5
Dosing
On-site
At home
On-site
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
Metformin and sulfonylurea

Route(s) of administration: Oral

Dose regimen: Administered as per Investigator and in accordance with local labeling. 
Metformin, if taken as the only oral antidiabetic (OAD), should be at a dose of 
≥1500 mg/day (or maximum tolerated dose, or as per country regulation if less). 
Sulfonylurea, if taken, should be at least half of maximum recommended dose according 
to national label. Dose(s) should be kept stable throughout the study unless dose reduction 
is needed for safety reasons.
Rescue therapy 

Route(s) of administration: Oral, injectable

Dose regimen: Open-label rescue medication(s) to treat hyperglycemia will be prescribed 
at the discretion of the Investigator and in accordance with local standard of care and 
prescribing practice. With the exception of other glucagon-like peptide-1 receptor agonists 
(GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, any approved medication(s) 
can be prescribed to treat the hyperglycemia. If a participant requires glycemic rescue, the 
IMP received during the randomized, double-blind treatment period should be continued
(unless the Investigator considers a change necessary for safety reasons) and must remain 
blinded until the end of the study. Refer to Section 6.1.2.2 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 measured 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:
1. Missing endpoint data for participants who prematurely discontinue the IMP before the 
endpoint visit will be imputed using a model estimated from participants in the same 
treatment arm who prematurely discontinue the IMP before the endpoint visit but have the 
measurements for the endpoint (retrieved dropouts). Considering that the number of 
participants in each treatment arm who discontinue the IMP but have the measurement for 
the endpoint is expected to be small, we propose to use a simple imputation model, where 
only the baseline measurements are included as the predictors. Each treatment group will 
have their own imputation model. Missing data will be imputed using the regression 
method.
2. Missing endpoint data in all participants, including those in the efpeglenatide groups, who 
stay on the IMP until the endpoint visit, will be imputed separately, using a model 
estimated from participants in the placebo group who stay on the IMP until the endpoint 
visit and have the endpoint data available. The imputation model will include the 
randomization strata (screening HbA1c [<8%, ≥8%], SU use at screening [Yes/No]), and 
baseline HbA1c value. 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 completed datasets after the imputation will be analyzed by the 
ANCOVA model with the treatment groups (efpeglenatide 2, 4, or 6 mg, placebo), randomization 
stratum of screening HbA1c (<8%, ≥8%), randomization stratum of screening SU (Yes/No) and 
country (US; China) 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-blind 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 IMP 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.
As noted, the number of retrieved dropouts is expected to be small, and there may not be 
sufficient data to support the imputation approach in item 1 described above. If there are fewer 
than 5 participants, in any treatment arm, who prematurely discontinue the IMP before the 
Week 30 visit but have the HbA1c measurements for the endpoint, a back-up imputation method 
for the primary efficacy analysis will be used. In particular, missing endpoint data for all 
participants in both efpeglenatide and placebo groups, regardless of staying on the IMP or not, 
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will be imputed using a model estimated from participants in the placebo group with endpoint 
data, where randomization strata and baseline HbA1c values are included as the predictors. 
Missing data will be imputed using the regression method.
A hierarchical procedure will be performed to adjust for the multiplicity of comparison. First, the 
highest dose of efpeglenatide (6 mg) will be compared to placebo. If superiority is demonstrated
for the 6 mg dose of efpeglenatide, the superiority of the 4 mg dose of efpeglenatide versus 
placebo will be tested. If superiority is also demonstrated for the 4 mg dose of efpeglenatide, the 
lowest dose (2 mg) will be tested for superiority over placebo. When 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 double-blind 
treatment period. The summary will include the number of observations, mean, standard deviation
(SD), 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[OC]).

Analysis of secondary and other efficacy endpoints:
Continuous secondary efficacy endpoints will be analyzed using the same ANCOVA model with 
missing values imputed by MI method as the method 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 the Cochran-Mantel-Haenszel method 
stratified by the randomization strata. For the HbA1c <7.0% analysis, participants with missing 
HbA1c data at Week 30 will be considered non-responders in the intent-to-treat (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 
screening SU use (Yes/No), and country (US, China) as the factors.
1.
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 (<8.0% and ≥8.0%) and SU use (Yes/No) at screening.
Visit schedule: From Visit 1 (Week -3) to Visit 12 (Week 30/EOT + 6 weeks)
EOS: end of study; EOT: end of treatment; R: Randomization.
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1.3
SCHEDULE OF ACTIVITIES (SOA)
Screening
Double-blind placebo-controlled Treatment period
Post-
treatment 
Follow-up
Notes
Visit
1
2
3
4
5
6
7
8
9
10
11
12
R


EOT
EOS
Week
-3
-1
0
Baseline
2
4
6
8
12
18
24
30a
Last IMP
+ 6 weeks
Acceptable range (days)
-10 to 
- 21
-7
(±3)
1
14
(±3)
28
(±3)
42
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
259
(±7)
V2 can be done as soon as the screening eligibility is confirmed
V3 can be done 4 to 10 days after V2
V3 should be done at least 10 days after V1 (to allow IMP to be sent to 
the site) and no later than 21 days after V1
Injection of weekly dose on 
the day of visit
X
X
X
X
X
X
Participant will self-administer the injection only after blood samples 
(if any) have been drawn at the respective visit.
Injection of weekly dose 
may be on a different day 
than visit
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, cardiovascular (CV) and allergy 
history, alcohol and smoking habits
Physical examination
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Blood pressure (BP) and heart rate (HR) in sitting position after at least 
5 minutes of rest
Height 
X
Body weight 
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
The 12-lead ECG recording should be obtained in supine position, prior 
to IMP dose administration
IMP injection training at 
V2/retraining as needed
X
X
X
X
X
X
X
See Section 6.1.1
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Screening
Double-blind placebo-controlled Treatment period
Post-
treatment 
Follow-up
Notes
Visit
1
2
3
4
5
6
7
8
9
10
11
12
R


EOT
EOS
Week
-3
-1
0
Baseline
2
4
6
8
12
18
24
30a
Last IMP
+ 6 weeks
Acceptable range (days)
-10 to 
- 21
-7
(±3)
1
14
(±3)
28
(±3)
42
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
259
(±7)
V2 can be done as soon as the screening eligibility is confirmed
V3 can be done 4 to 10 days after V2
V3 should be done at least 10 days after V1 (to allow IMP to be sent to 
the site) and no later than 21 days after V1
Review of injection sites
X
X
X
X
X
X
X
X
Diary dispensation
X
X
X
X
X
X
X
X
Diary review and collection
X
X
X
X
X
X
X
X
Review of SMPG and 
metformin and sulfonylurea 
doses
X
X
X
X
X
X
X
X
X
X
X
Glucose meter dispensation 
and training
X
Will include training for hypoglycemia awareness and management
Diet and life style 
counselling
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
IMP dispensation
X
X
X
X
X
X
X
At V2, placebo training kit(s) will be allocated; self-injection will be done 
at site (see Section 6.1.1)
IMP collection and 
accounting
X
X
X
X
X
X
X
Training kit will be collected and accounted at V2 (see Section 6.1.1)
Compliance
X
X
X
X
X
X
X
X
X
X
SMPG, IMP, diary
Efficacy:
HbA1c
X
X
X
X
FPG
X
X
X
X
For these visits, participants need to come in fasting conditions as 
described in Section 5.3.1 and Section 8.1.2
C-peptide (fasting)
X
For this visit, participants need to come in fasting conditions as 
described in Section 5.3.1
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Screening
Double-blind placebo-controlled Treatment period
Post-
treatment 
Follow-up
Notes
Visit
1
2
3
4
5
6
7
8
9
10
11
12
R


EOT
EOS
Week
-3
-1
0
Baseline
2
4
6
8
12
18
24
30a
Last IMP
+ 6 weeks
Acceptable range (days)
-10 to 
- 21
-7
(±3)
1
14
(±3)
28
(±3)
42
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
259
(±7)
V2 can be done as soon as the screening eligibility is confirmed
V3 can be done 4 to 10 days after V2
V3 should be done at least 10 days after V1 (to allow IMP to be sent to 
the site) and no later than 21 days after V1
7-point SMPG profiles 
X
X
X
Performed on at least 1 day in the week prior to visits indicated. See
Section 8.1.4 for details
Fasting (before breakfast) 
SMPG
X
X
X
X
X
X
X
X
X
X
Daily within the first 8 weeks after randomization and at least 3 days in 
the other weeks, prior to visits indicated. See Section 8.1.2 for details
Safety:
Hematology
X
X
X
X
X
See Appendix 2 (Section 10.2)
Clinical chemistry
X
X
X
X
X
See Appendix 2 (Section 10.2)
Calcitonin
X
X
X
X
X
See Appendix 2 (Section 10.2)
Lipid profile 
X
X
See Appendix 2 (Section 10.2)
Urinalysis
X
X
See Appendix 2 (Section 10.2)
Pregnancy test (for women 
of childbearing potential)
X
X
X
X
X
X
X
X
Serum pregnancy testing (β-HCG) at screening for women of 
childbearing potential (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)
ADA sampling
X
X
X
X
X
Participants positive for ADAs at the end of study, and who experienced 
severe injection site or hypersensitivity reaction at any time during the 
study, will be asked to provide sample for anti-efpeglenatide antibodies 
assessments 4 and 6 months after the EOT
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Screening
Double-blind placebo-controlled Treatment period
Post-
treatment 
Follow-up
Notes
Visit
1
2
3
4
5
6
7
8
9
10
11
12
R


EOT
EOS
Week
-3
-1
0
Baseline
2
4
6
8
12
18
24
30a
Last IMP
+ 6 weeks
Acceptable range (days)
-10 to 
- 21
-7
(±3)
1
14
(±3)
28
(±3)
42
(±3)
56
(±3)
84
(±3)
126
(±3)
168
(±3)
210
(±3)
259
(±7)
V2 can be done as soon as the screening eligibility is confirmed
V3 can be done 4 to 10 days after V2
V3 should be done at least 10 days after V1 (to allow IMP to be sent to 
the site) and no later than 21 days after V1
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) for the predose IMP serum concentration (Ctrough) at selected 
clinical visits.
For a subset of participants, 1 additional postdose sample will be taken 
either 4 days (±1 day) after first IMP dose or 4 days (±1 day) after 4th 
dose or 4 days (±1 day) after 12th dose. A separate consent will be 
signed. See Section 8.5
Rescue therapy assessment
Continuous assessment and recording during treatment period
After randomization, the need of rescue treatment should be assessed 
by the Investigators via fasting SMPG performed by the participants 
and/or via the central laboratory alerts received on FPG and on HbA1c 
(from Week 12 onwards). See Section 6.1.2.2
Concomitant medication 
review
Continuous assessment and recording throughout the study
AE/SAE recording
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 SMPGs measured with nonstudy glucometer can 
be used)
a
In case of premature permanent IMP discontinuation, the participant should have a visit as soon as possible after the last IMP administration with the assessments normally planned for EOT visit. Afterwards, 
the participants should continue in the study up to the scheduled date of study completion and be followed according to the study procedures as specified in the protocol. Every effort should be made to have the
participant complete the Week 30 Visit´s assessments (primary and main secondary endpoints) as the minimum. For safety reasons, participants who wish to terminate participation in the study, should be 
assessed 6 weeks (±1 week) from the last IMP dose (at the minimum) using the procedure normally planned for the posttreatment follow-up visit at EOS. At the time corresponding to their Week 30 Visit, all 
attempts will be made to contact the participant to inquire about safety and/or vital status.
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Abbreviations: ADA: antidrug antibody, AE: adverse event, AESI: adverse event of special interest, β-HCG: beta-human chorionic gonadotropin, ECG: electrocardiogram, EOS: end of study, EOT: end of treatment, 
FPG: fasting plasma glucose, FSH: follicle-stimulating hormone, HbA1c: glycosylated hemoglobin, IMP: investigational medicinal product, IRT: interactive response technology, PK: pharmacokinetics, R:
randomization; SAE: serious adverse event, SMPG: self-monitored plasma glucose.
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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 aim for the present trial is to compare efpeglenatide once-weekly versus placebo as addition 
to metformin alone or with SU, in a population of subjects with T2DM, in terms of glycaemic 
control, weight control, and other efficacy and safety parameters.
2.2
BACKGROUND
Although lifestyle changes, including diet, and exercise, are valuable components of diabetes 
treatment, the vast majority of people with T2DM require pharmacological therapy to control the 
disease. Metformin is recommended as the standard first-line therapy in the absence of any 
contraindications or tolerability issues, as per current guidance. In case of metformin failure or 
intolerance, a combination of metformin with 1 of the 6 available treatment options 
(SU, thiazolidinedione, DPP-4 inhibitor, sodium/glucose cotransporter 2 (SGLT2) inhibitor, 
GLP-1 RA, or basal insulin) can be considered as second-line choices (1).
In recent years, the GLP-1 RA class of pharmacotherapy for T2DM has evolved as an effective 
treatment option, from multiple daily through daily-to-weekly injection. GLP-1 is an endogenous 
enteroendocrine hormone secreted by L-cells of the distal intestine in response to oral nutrient 
ingestion. It has multiple physiologic effects that contribute to controlling hyperglycemia, such as 
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 exendin-4 (exenatide) analogue 
that is being developed for the treatment of T2DM by once-weekly SC injection. 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) including approximately 
1000 participants (~720 exposed to efpeglenatide) have been completed. The Phase 2 studies have 
been conducted in participants with T2DM and in obese nondiabetic 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 nondiabetic obese participants, weekly doses of 4 to 6 mg and doses of 6 mg and 8 mg 
every other week were investigated. Overall, these studies have demonstrated that efpeglenatide 
improves glycemic control and reduces body weight, with an overall favorable safety and 
tolerability profile consistent with currently available GLP-1 RAs. Based on Phase 1 and 2 study 
data, 3 weekly efpeglenatide doses (2, 4, or 6 mg) have been selected for use in Phase 3 studies.
These doses are expected to demonstrate efficacy in the target population while mitigating 
potential safety concerns and the incidence of AEs.
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Details (nonclinical and clinical) about efpeglenatide can be found in the latest edition of the 
Investigator’s Brochure (IB, [2]).
2.3
BENEFIT/RISK ASSESSMENT
The nonclinical 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 EFC15337:

Gastrointestinal (GI) disorders such as nausea/vomiting and rarely pancreatitis are the 
most common AEs to the GLP-1 RAs class. 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 EFC15337 will reduce intensity and 
frequency of GI events, mainly nausea and vomiting.

Increase in heart rate is a known side effect of GLP-1 RA. In study EFC15337, periodic 
monitoring of vital signs including heart rate and blood pressure (BP) will be regularly 
performed.

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 patients with a personal or family history of medullary 
thyroid cancer (MTC) or in patients with multiple endocrine neoplasia syndrome Type 2 
(MEN-2). In study EFC15337, patients with history of MTC or MEN-2 or with elevated 
calcitonin levels (≥5.9 pmol/L [20 pg/mL]) at screening will not be randomized. 
Calcitonin will be monitored throughout the study and guidelines for follow-up are 
provided if this threshold will be reached after randomization.

Diabetic retinopathy complications have been reported for one of GLP-1 RAs (as of 
05 December 2017). No cases have been reported for efpeglenatide. Patients 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 EFC15337 includes the collection of AEs, antidrug 
antibodies (ADAs, immunogenicity, [3, 4]), as well as safety laboratory and 12-lead 
electrocardiogram (ECG).

In 3 large Phase 2 clinical studies with efpeglenatide (HM EXC-203, HM-EXC-204, and 
HM-EXC-205), overall, a total of 12 out of 571 participants on efpeglenatide and 3 out of 
183 participants on comparators had post-baseline alanine aminotransferase (ALT) 
elevation ≥3 × ULN; most had confounding factors (2). In this study, patients with 
elevated liver enzymes >3 × upper limit of 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 EFC15337. These sparse 
pharmacokinetic (PK) samples will be used for population PK (popPK) 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. Suggested actions and follow-up measurements for laboratory 
abnormalities and other safety findings are provided in Appendix 5 (Section 10.5) of the protocol.
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 fasting plasma glucose (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. Central laboratory 
alerts on FPG and HbA1c (from Week 12 and 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 adverse events of efpeglenatide may be found in the IB (2).
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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 metformin alone or in combination 
with SU

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 <7.0% at 
Week 30

Change from baseline to Week 30 FPG
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 Week 30 in body weight
To evaluate the safety of once weekly injection of efpeglenatide 
2, 4, and 6 mg

Number of participants with at least 1 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 compare the effects of once weekly injection of 
efpeglenatide 2, 4, and 6 mg with placebo on glycemic control

7-point SMPG profile at baseline and Week 30

Change from baseline to Week 30 in mean 
24-hour SMPG (7-point profile)

Change from baseline to Week 30 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

Time to initiation of rescue therapy
To characterize the pharmacokinetics (PK) of efpeglenatide

Serum concentration (Ctrough) of efpeglenatide at 
predose (Weeks 4, 12, 24, 30)

Serum concentration of efpeglenatide at postdose 
(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] in a subset of 
participants, at least 10% of total: [N= approximately 
16 per group])
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Objectives
Endpoints
To evaluate the immunogenicity of once weekly injection of 
efpeglenatide 2, 4, and 6 mg

Number of participants by ADA status 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 ADA positive at Baseline) 
during the study period

ADA titer at scheduled visits

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 
the polyethylene glycol (PEG) linker of efpeglenatide 
at scheduled visits
AE: adverse event, ADA: antidrug antibody, ECG: electrocardiogram, FPG: fasting plasma glucose, HbA1c: hemoglobin A1c, GLP-1: 
glucagon-like peptide-1, IMP: investigational medicinal product, PK: pharmacokinetic, PPG: postprandial glucose, SMPG: self-monitored plasma 
glucose, SU: sulfonylurea, T2DM: type 2 diabetes mellitus.
3.1
APPROPRIATENESS OF MEASUREMENTS
Efpeglenatide, added to metformin alone or to metformin and SU in participants with T2DM who 
have inadequate glycemic control on their previous antidiabetic therapy, 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 measure for 
assessing the efficacy of a novel treatment for Type 2 diabetes.
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 is a secondary endpoint. 
Improvements in preprandial and postprandial plasma glucose (PPG) have been observed with 
efpeglenatide in previous studies. Therefore, assessment of both preprandial plasma glucose and 
PPG (by 7-point self-monitored plasma glucose [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 study is considered to be sufficient for achieving stable conditions with IMP after 
reaching the targeted dose, for enabling an adequate assessment of time dependent changes in 
HbA1c, and to evaluate the safety profile during the treatment period.
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4
STUDY DESIGN
4.1
OVERALL DESIGN
The current protocol EFC15337, is a multicenter, randomized, double-blind, placebo-controlled 
Phase 3 study evaluating the efficacy and safety of efpeglenatide addition in participants 
inadequately controlled with metformin alone or in combination with SU.
Eligible participants will be randomly assigned 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 SU use at screening (Yes/No). Masked weekly dose 
escalation over the course of 4 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 randomly assigned 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 PFSs.
The study will be comprised of 3 periods as follows: 

An up to 3-week screening period (with a minimum of 10 days)

A 30-week double-blind, placebo-controlled treatment period, for efficacy and safety 
assessments

A 6-week posttreatment follow-up period to collect safety information after last dose of 
IMP (treatment completed or permanent IMP discontinuation)
The maximum study duration per participant will be 39 weeks.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
This study is designed to demonstrate the efficacy and safety of efpeglenatide when used as added 
antidiabetic treatment in participants with T2DM who have inadequate glycemic control with 
metformin alone or in combination with SU. Efpeglenatide will be compared to placebo. 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 HbA1c reduction indicates that the dose-response plateau has not been reached with the 
4 mg dose so most likely, 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 events 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 after the first dose of efpeglenatide 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 (2).
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 T2DM
I 03.
Diabetes diagnosed at least 1 year before screening
I 04.
Participants on a background antidiabetic treatment for which all of the below apply:
a) Participants on metformin alone or in combination with SU, for at least 3 months prior to 
screening
b) Participants on stable dose of at least 1500 mg/day of metformin (if this is the only OAD), 
or individually tolerated maximum dose, or as per country regulation if less, for at least 
3 months prior to screening
c) Participants on at least half of maximum approved dose of SU (if taken) according to 
national label and at a stable dose for at least 3 months prior to screening
I 05.
HbA1c between 7.0% and 10.0% (inclusive) measured by the central laboratory at 
screening
  
Informed Consent
I 06.
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
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5.2
EXCLUSION CRITERIA 
Participants are excluded from the study if any of the following criteria apply:
Medical conditions
E 01. History of severe hypoglycemia requiring emergency room admission or hospitalization 
within 3 months prior to screening
E 02. 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
E 03. 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 requiring medical treatment within 6 months prior to screening or history of 
surgery affecting gastric emptying
E 04. History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy 
has been performed), pancreatitis during previous treatment with incretin therapies, 
chronic pancreatitis, pancreatectomy
E 05. Personal or family history of MTC or genetic conditions that predisposes to MTC 
(eg, multiple endocrine neoplasia syndromes)
E 06. Body weight change of ≥5 kg within the last 3 months prior to screening
E 07. Systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg at 
randomization
E 08. Severe renal disease as defined by estimated glomerular filtration rate (eGFR, by 
Modification of Diet in Renal Disease [MDRD]) of <30 mL/min/1.73 m2
E 09. Laboratory findings at the Screening Visit:

ALT or aspartate aminotransferase (AST) >3 × ULN or total bilirubin >1.5 × ULN (except 
in case of documented Gilbert’s syndrome)

Amylase and/or lipase: >3 × ULN

Calcitonin ≥5.9 pmol/L (20 pg/mL)
E 10. 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 conditions
that shortens erythrocyte survival)
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E 11. Any clinically significant abnormality identified either in medical history or during 
screening evaluation (eg, physical examination, laboratory tests, ECG, vital signs) or any 
AE during screening period, which, in the judgment of the Investigator, would preclude 
safe participation in the study or constrains efficacy assessment
Prior/concomitant therapy
E 12. Participants having received any antidiabetic drug other than metformin and SU within 
3 months prior to screening
E 13. Participants having received any type of insulin for more than 30 consecutive days at any 
time (except for treatment of gestational diabetes)
E 14. 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 15. 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 16. Participation in any previous clinical trial of efpeglenatide/HM11260C
E 17. Exposure to any investigational drugs in the last 4 weeks or 5 half-lives, whichever is 
longer, prior to screening
E 18. Concomitant enrollment in any other clinical study involving an investigational study 
treatment or any other type of medical research
  
Other exclusions
E 19. Any contraindication to use metformin and SU (if taken) as defined in the national product 
label(s)
E 20. Hypersensitivity to any of the study treatments, or components thereof, or to any GLP-1 
RAs
E 21. History of drug or alcohol abuse within 6 months prior to the time of screening
E 22. Pregnant (confirmed by serum pregnancy test at screening) or breastfeeding women
E 23. 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 IMP
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E 24. 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 25. Any country-related specific regulation that would prevent the participant from entering 
the study
E 26. 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 27. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol
E 28. 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 5).
Fasting conditions

For Visits 3 (Day 1), 7 (Week 8), 8 (Week 12), and 11 (Week 30), 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.

Fasting (prebreakfast) SMPG must 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 IMP). 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 events (SAEs).
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 
randomly assigned 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 30 weeks of treatment.
Non-IMP (NIMP) treatment is defined as previous background antidiabetic treatment (metformin, 
SU) and 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 6.1.2.2. Except for 
GLP-1 RAs and DPP-4 inhibitors, any approved medication(s) can be prescribed at the 
Investigator’s discretion to treat the hyperglycemia. The regimen of the rescue medication(s) 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
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)
2/500 µL, 4/500 µL, and 6 mg/500 µL (for 4, 8, and 
12 mg/mL concentrations, respectively)
NA
Route of administration
SC injection
SC injection
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Study intervention 
name
Efpeglenatide
Placebo
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, thigh or upper arm. 
For each injection, the date, time, and region of administration should be recorded. Within any
selected region, the site of injection should be changed (rotated) at each administration to 
prevent skin reactions.
For selected visits during the treatment period up to Week 30 (corresponding to predose 
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 it 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.
Predose 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 8, Visit 10, and Visit 11) and the timing of dose 
administration before each of these visits should be scheduled to ensure, as much as possible,
the duration of 6 to 7 days between them is maintained.
IMP dose schedule
Dose 1
Dose 2
Dose 3
Dose 4
Dose 5
Day 1
Week 1
Week 2
Week 3
Week 4
Visit 3
Visit 4
Visit 5
Dosing
(on-site)
(at home)
(on-site)
(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 30.
Storage conditions
Store between +2°C and +8°C (36°F and 46°F). Do not freeze, protect from light.
Packaging and labeling
IMP will be provided in boxes 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 separately in this section.
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 PRODUCTS
The appropriate number of kits will be dispensed for the period until the next dispensing visit 
(please refer to the SoA, Section 1.3). Storage conditions and use-by-end date (when required by 
country regulations) are part of the label text.
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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.
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 PRODUCT
6.1.2.1
Background medication 
Metformin/Sulfonylurea
Participants are enrolled with a background therapy consisting of metformin alone or in 
combination with SU. Background metformin and SU are considered as NIMPs. Metformin and 
SU (commercial formulations) will be administered orally according to the locally approved label.
The dose of metformin, if taken as the only OAD, must be of ≥1500 mg/day (or as per country 
regulation if less) or maximum tolerated dose (maximum tolerated dose needs to be documented).
The dose of SU, if taken, must be at least half of maximum recommended dose according to 
national label. Participants are enrolled with their antidiabetic background therapy taken at a 
stable dose for at least 3 months prior to the Screening visit. Doses of metformin and, if 
applicable, SU should be kept stable throughout the study unless dose reduction is needed for 
safety reasons.
In participants with HbA1c <8% at screening, the dose of SU is allowed to be decreased by at 
least 25% at randomization (according to investigator’s clinical judgment) in order to decrease the 
risk of hypoglycemia. For these patients, in case of uncontrolled SMPG values between Week 6 
(Visit 6) and Week 12 (Visit 8), the SU dose can be progressively increased up to the Screening 
dose unless occurrence of hypoglycemia prevents this. Increasing the SU dose up to the screening 
dose level is not considered as rescue therapy. 
In participants with HbA1c ≥8 % at screening, no SU dose adjustment is required at 
randomization.
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Study participants, especially those on SU, must be educated to recognize and manage 
hypoglycemia. They also must be informed about the importance of adherence to dietary 
instructions (avoid deficient caloric intake). After randomization, once the double-blind study 
medication is added and increasingly contributing to the glucose-lowering activity, the risk of 
hypoglycemia may increase. In order to prevent hypoglycemia, a reduction of the SU dose might 
be considered in, for example in the following situations:

Fasting (prebreakfast) SMPG below 100 mg/dL as a result of a consistently falling trend 
observed in the preceding 7 days

Fasting (prebreakfast) SMPG below 80 mg/dL

In case of 2 or more symptomatic or 1 severe hypoglycemic episode
6.1.2.2
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 in Table 3, and are dependent on study period.
Table 3 - Rescue criteria
Time in study
Threshold
From randomization up through the scheduled Week 8 visit (Visit 7)
FPG >15.0 mmol/L (>270 mg/dL)
After the Week 8 visit up through the scheduled Week 12 visit (Visit 8)
FPG >13.3 mmol/L (>240 mg/dL)
After the Week 12 visit through the end of the 30-week treatment period
FPG >11.1 mmol/L (>200 mg/dL) or HbA1c ≥8.5%
FPG fasting plasma glucose; HbA1c hemoglobin A1c
Routine fasting SMPG and central laboratory alerts on FPG (and HbA1c from Week 12 [Visit 8] 
onwards) will be set up to ensure that glycemic parameter results remain below the predefined 
thresholds.
If a fasting SMPG value exceeds the specific glycemic limit on 1 day, the participant must check 
it again during the following 2 days. If all the SMPG values in 3 consecutive days exceed the 
specific limit, the participant should contact the Investigator and a central laboratory FPG 
measurement (and HbA1c from Week 12 onwards) be performed as soon as possible for 
confirmation.
Upon receipt of a central laboratory alert for either FPG or HbA1c, a central laboratory retest 
must be completed and confirmed as exceeding the threshold for rescue before rescue therapy is 
initiated. The retest confirmation should be performed as soon as possible during an unscheduled 
visit.
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In the event that a confirmatory FPG and/or HbA1c value exceeds 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 fasting status (ie, no food or liquid intake [except 
water] for ≥8 hours)

IMP was given at the planned dose and was appropriately injected (as per weekly 
schedule)

There was no intercurrent disease, which may jeopardize glycemic control (eg, infectious 
disease)

Compliance to treatment was appropriate

Compliance to diet and lifestyle was appropriate
If any of the above-mentioned explanations can reasonably explain the insufficient glycemic 
control, the Investigator should consider not initiating rescue medication(s) and should undertake 
appropriate action as follows, ie:

Assess FPG (ie, after the participant has fasted for ≥8 hours)

Initiate an evaluation and treatment of intercurrent disease (to be reported in the 
AE/concomitant medication parts of the electronic Case Report Form (eCRF) and the 
medical record)

Stress the absolute need for the participant 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 an appropriate action fails to decrease 
FPG/HbA1c below the threshold values, rescue medication(s) may be introduced.
If a participant needs to start rescue therapy, an unscheduled in-person visit will be scheduled to 
perform prerescue assessments (which are the same as those specified for EOT, Week 30,
Visit 12) 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 medications (including 
increase of prior metformin or SU dose) can be prescribed to treat the hyperglycemia. Increasing 
the SU dose up to the Screening dose level is not considered as rescue therapy in participants 
whose SU dose was temporarily decreased for HbA1c <8.0% at Week -1 or for hypoglycemia.
If a participant requires glycemic rescue, the IMP received during the randomized, double-blind 
treatment period should be continued and must remain blinded until the end of the study (unless 
the Investigator considers a change necessary for safety reasons).
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All concomitant antidiabetic medications (background OAD[s] and/or rescue therapy) will be 
documented in the eCRF.
The cost of NIMPs 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.
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.
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 intervention.
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.
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).
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 
conditions, 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).
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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
All participants will be centrally assigned to randomized study IMP using interactive response 
technology (IRT) as summarized in the SoA (Section 1.3). Before the study is initiated, 
instructions on how to access IRT will be provided to each site.
A randomized participant is a participant who has been randomly allocated to a study IMP,
regardless whether the IMP kit was used or not. A participant cannot be randomly assigned more 
than once in the study.
Returned study IMP should not be redispensed to the participants.
6.3.1
Methods of blinding
During the entire double-blind treatment period, 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. Each titration and treatment kit (and the 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 IMP 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 also 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 the baseline/randomization visit (Visit 3) as those data will be masked. If the 
central laboratory detects FPG greater than the rescue thresholds, the Investigator will receive an 
alert from the central laboratory (see Section 6.1.2.2). The HbA1c alerts will also be sent if a 
value is greater than the threshold from the Week 12 visit (Visit 8) onwards.
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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 study treatment will affect the immediate management of the 
participant’s conditions (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 eCRF, as applicable.
Code breaking can be performed at any time by using the proper module of the 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 details to the Sponsor’s representative 
or to any staff members until database closure. Furthermore, when completing forms (eg, AE, 
SAE, adjudication information), the study treatment 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 popPK 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.
The DMC will receive 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 reaction (SUSAR) unblinding by 
the Sponsor.
6.4
STUDY INTERVENTION COMPLIANCE
Measures taken to ensure and document treatment compliance and IMP/NIMP accountability 
include the following:

Proper recording of treatment kit number as required on appropriate eCRF page for 
accounting purposes

All medication treatment kits (whether empty or unused) will be returned by the 
participant at each visit when treatment dispensing is planned
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
The Investigator or his/her delegate will track treatment accountability/compliance by
comparing the treatment kit number recorded on the patient diary with the treatment kit 
number of returned treatment kits (whether empty or unused) and completes the 
participant treatment log

The monitor in charge of the study will then check the data entered on the IMPs 
administration page of the eCRF by comparing them with the IMPs that have 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 
eCRF 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 PFSs 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.
6.5
CONCOMITANT THERAPY
The following treatments are prohibited during the study (including during screening period and 
the 30 weeks of the treatment period):

Initiation of any antidiabetic agents, other than the IMP, or increase in dose of preexisting 
OAD(s), before pre-rescue assessments and initiation of rescue therapy (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, 
inhaled, or intra-articular applications are allowed)

Any investigational drug other than IMP for this study
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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 4 is described in Table 2. From Week 4 (Visit 5)
through the rest of the double-blind treatment period, participants will remain on the randomized 
IMP (efpeglenatide assigned dose or placebo) until the EOT at Week 30 (Visit 12).
6.7
INTERVENTION AFTER THE END OF THE STUDY
The IMPs will not be provided after the end of the treatment period.
When a participant’s participation in the trial ends, the 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 follow-up 
(eg, medical record checks). 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 eCRF. In any case, the participant should remain in the study as long as 
possible to collect endpoint data at Week 30 vital safety status at the scheduled end of study.
7.1.1
Permanent discontinuation
Permanent IMP discontinuation is any IMP 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 the IMP 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 eCRF.
A participant should withdraw from treatment with IMP in case of the following:

Intercurrent conditions that require discontinuation of IMP: eg, laboratory abnormalities 
(see decision tree and general guidance for the follow-up of laboratory abnormalities in 
Appendix 6 [Section 10.5]), diagnosis of acute pancreatitis confirmed by gastroenterologic 
evaluation and imaging, unless a clear cause unrelated to IMP is confirmed and the 
participant has recovered from pancreatitis (see Appendix 7 [Section 10.5.2]), or calcitonin 
value ≥50 pg/mL (see Appendix 7 [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

Any code breaking requested by the Investigator

At the specific request of the Sponsor
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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 30 weeks of the 
study. A high rate of missing data could jeopardize efficacy results of the study. Refer to the SoA
(Section 1.3) for data to be collected at the time of IMP 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 
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 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 if this visit can be scheduled 6 to 7 days after the permanent 
discontinuation of IMP. For participants who discontinue IMP but remain in the study, the 
remaining visits should occur as scheduled where possible. The Investigators should discuss with 
the key visits to attend. All efforts should be made to continue to follow the participants for 
primary and secondary endpoints, after the discontinuation of IMP.
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 
IMP 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 study IMP discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed.
7.1.2
Temporary discontinuation
Temporary IMP discontinuation corresponds to at least 1 (one) 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.
Temporary IMP discontinuation may be considered by the Investigator because of suspected AEs 
(including intolerance to IMP planned dose). For all temporary IMP discontinuations, duration 
should be recorded by the Investigator in the appropriate pages of the eCRF.
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7.1.3
Rechallenge
Reinitiation of treatment 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 it is safe for the participant to restart the IMP. In case of IMP intolerance, a 
one-time rechallenge 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 where 3 or more consecutive doses are missed, the 
titration should be reinitiated.
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 eCRF 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.
Refer to the 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 
eCRF 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 rerandomized (treated) in the study. 
Their inclusion and randomization 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/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 as 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 IMP.

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 the 
screening period (see Section 5.1 and 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 1 secondary efficacy endpoint are assessed by the 
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 therapy (see Section 6.1.2.2), then the HbA1c assessment 
should be performed before the introduction of rescue medication(s).
8.1.2
Fasting plasma glucose
Plasma glucose will be assessed in a fasted 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 
retest should be scheduled in a fasting state 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
Body weight
Body weight will be measured to allow the estimation of change from baseline to Week 30 in 
body weight.
Body weight is measured at every on-site study visit, with the participant wearing only 
undergarments or very light clothing and no shoes, and with an empty bladder.
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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 must be moved until the beam balances 
(the arrows are aligned). The weight must be read and recorded in the eCRF and source 
documents. Self- reported weights are not acceptable; participants must not read the scales 
themselves.
8.1.4
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 patient
diary. Participants should repeat the 7-point SMPG profile if any time point is missed.
The 7-point SMPG profile should be measured at the following 7 points: prebreakfast and 2 hours 
postbreakfast, prelunch and 2-hour postlunch, predinner and 2-hour postdinner, and at bedtime. 
Two hours postprandial (breakfast, lunch, and dinner) is defined as 2 hours after the start of the 
meal.
On days when 7-point SMPG profiles are measured, the fasting prebreakfast SMPG profile will 
be considered as the first point of measurement, ie, “prebreakfast” time point.
8.1.5
Use of rescue therapy
The use of rescue medication(s) for hyperglycemia will be assessed and reported throughout the 
treatment period to allow determination of the start of rescue therapy and the percentage of 
participants using rescue therapy at Week 30. Routine fasting SMPGs will be measured by the 
participants, and alerts on FPG and/or HbA1c will be sent from the central laboratory to the 
Investigator to ensure that glycemic parameter results remain within predefined thresholds. For 
details and further actions should FPG and/or HbA1c values rise to values greater than the 
predefined thresholds, refer to Section 6.1.2.2.
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8.2
SAFETY ASSESSMENTS 
The 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 other selected 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
8.2.2
Vital signs

Blood pressure and pulse measurements will be assessed while the participant is in a 
seated position using the same device (automated BP monitor or a manual 
sphygmomanometer) for each participant

At the Screening Visit (Visit 1), BP will be measured on both arms to identify and select 
the appropriate arm for future measurements. Seated BP should be measured in both arms 
after at least a 5-minute rest period, and then again after 1 minute in both arms 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 eCRF

At subsequent visits, BP and pulse measurements are to be performed using the
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
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8.2.3
Electrocardiograms
8.2.3.1
12-lead electrocardiogram
A 12-lead ECG recording will be performed locally as scheduled in the SoA (see Section 1.3).
The 12-lead ECG should be performed after the participant has been in the supine position for at 
least 10 minutes 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 eCRF. 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.
8.2.4
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 eCRF. 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 conditions.

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 an AE, then the results must be recorded in the eCRF.

Recommended decision trees for the management of certain laboratory abnormalities are 
provided in Appendix 5 (Section 10.5).
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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 
of the eCRF page with onset date and time, symptoms and/or signs, the SMPG value if available, 
and the treatment. Hypoglycemia fulfilling the seriousness criteria must be documented in 
addition on the SAE form in the eCRF.
Hypoglycemic events will be categorized (6, 7, 8) as follows (also see Appendix 8 
[Section 10.8]):

Severe hypoglycemia: Severe hypoglycemia is an event requiring 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 reported 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 less than or equal to 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 
less than or equal to 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 less than or 
equal to 3.9 mmol/L (70 mg/dL); symptoms are treated with oral carbohydrate. 

Relative hypoglycemia: (recently termed “pseudohypoglycemia”) 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 greater than 3.9 mmol/L (70 mg/dL).
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In addition to the threshold of plasma glucose of less than or equal to 3.9 mmol/L (70 mg/dL), 
documented hypoglycemia with a measured plasma glucose concentration less than 3.0 mmol/L 
(54 mg/dL) will also be analyzed (8).
Hypoglycemic events will be evaluated regardless of the time of onset during the study and time 
of the day.
In addition, hypoglycemic 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 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 non-serious) 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 IMP or study procedures, or that caused 
the participant to discontinue the study IMP and/or study (see Section 7).
Adverse events requiring specific monitoring
An AE requiring specific monitoring is a serious or nonserious 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 the 
specific eCRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria).
The AEs requiring specific monitoring for this study are as follows: 

Severe GI events

Severe hypoglycemia (see Section 8.2.5)

Pancreatic events (including abnormal values of pancreatic enzymes [see Appendix 7,
Section 10.5.2]) – will be adjudicated by CEC

Major adverse cardiovascular events (MACE; CV death, myocardial infarction, 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 7, 
[Section 10.5.3])

Acute renal failure (see Appendix 5 [Section 10.5] 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).
Investigators are not obligated to actively seek AEs or SAEs 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 IMP or study participation, the Investigator must promptly notify the Sponsor.
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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 
nonleading 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, nonserious 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 Board 
(IRB)/Independent Ethics Committees (IECs), and Investigators.

Investigator safety reports must be prepared for SUSARs 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 the report along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.5
Pregnancy

Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study IMP and until the Follow-up Visit (Visit 12).

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.
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
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 CV events, see details of the AEs requiring specific monitoring above.
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 the 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 do the following:
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 
eCRF.
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.
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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 region 
(abdomen, thigh, or arm) of drug administration. Samples not collected, missed or lost, for 
any reason should be recorded.

For a subset of participants, 10% of total (N=16 per group): 1 additional postdose sample 
will be taken either 4 days (±1 day) after 1st IMP dose, or 4 days (±1 day) after 4th dose, 
or 4 days (±1 day) after 12th dose. To reach this number and due to the blind design of the 
study, PK postdose sample will be collected in the first 130 randomized participants who 
will accept this additional sampling, sign the separate consent form and provide a valid 
postdose 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 will be used to perform a popPK analysis by nonlinear mixed effects 
modeling and results will be reported in separate popPK 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 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 or negative) and level (titer). Cross 
reactivity of confirmed positive samples to endogenous GLP-1 (positive or negative), endogenous 
glucagon (positive or negative), neutralizing capacity of ADAs, and presence of antibodies against 
polyethylene glycol (PEG) (positive or negative) will also be evaluated in serum at the time points 
specified in the SoA (Section 1.3).
Participants positive for ADAs at the end of study, and who experienced severe injection site or 
hypersensitivity reaction at any time during the study, will be asked to provide sample for 
anti-efpeglenatide antibodies assessments 4 and 6 months after the EOT.
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 were performed based on the primary endpoint, change in HbA1c 
(%) from baseline to Week 30.
A sample size of 160 per arm (ie, 160 participants for each of the efpeglenatide dose and 160 for 
the placebo group) has >99% power to detect a treatment difference of -0.6% between each dose 
of efpeglenatide and placebo in HbA1c change from baseline to Week 30, assuming a common 
SD of 1.1% (2-sided, α=0.05) for each comparison. Furthermore, with approximately 50% of 
participants being on metformin alone (ie, 80 per arm) and approximately 50% on 
metformin + SU (ie., 80 per arm), there will be 92% (81%) power to detect a treatment difference 
of -0.6% (-0.5%) between each efpeglenatide dose and placebo within the subgroup of 
participants on metformin alone or subgroup of participants on metformin + SU.
Hence, there are 4 parallel dosing arms as follows:

Efpeglenatide 2 mg, N=160

Efpeglenatide 4 mg, N=160

Efpeglenatide 6 mg, N=160

Efpeglenatide placebo, N=160
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 
the IRT database, regardless of whether the treatment kit was used or not.
ITT
All participants randomized 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 randomly assigned.
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 postbaseline 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.
9.4.1
Efficacy analyses
Table 5 - Efficacy analyses
Endpoint
Statistical Analysis Methods
Primary
Change from baseline to 
Week 30 in HbA1c
Primary analysis:
The primary efficacy endpoint will be analyzed using all HbA1c values measured 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 ANCOVA model with 
missing values imputed by MI analysis methods in 2 parts as follows:
1.
Missing endpoint data for participants who prematurely discontinue the IMP before 
the endpoint visit will be imputed using a model estimated from the participants in 
the same treatment arm who prematurely discontinue the IMP before the endpoint 
visit but have the measurement for the endpoint (retrieved dropouts). Considering 
that the number of participants in each treatment arm who discontinue the IMP but 
have the measurement for the endpoint is expected to be small, we propose to use a
simple imputation model, 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.
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2.
Missing endpoint data in all participants, including those in the efpeglenatide groups, 
who stay on the IMP until the endpoint visit will be imputed separately, using a 
model estimated from participant in the placebo group who stay on the IMP until the 
endpoint visit and have the endpoint data available. The imputation model will 
include the randomization strata (screening HbA1c [<8%, ≥8%], SU use at 
screening [Yes/No]), and baseline HbA1c value. 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 completed datasets after the imputation will be analyzed 
by the ANCOVA model with the treatment groups (efpeglenatide 2, 4, or 6 mg, placebo),
randomization stratum of screening HbA1c (<8%, ≥8%), randomization stratum of screening 
SU (Yes/No) and country (US; China) 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 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.
There may not be enough number of retrieved dropouts to support the imputation approach for 
the group with missing data that prematurely discontinue treatment, described above. If the 
number of participants who prematurely discontinue the IMP before the endpoint visit but have 
the measurement for the endpoint is <5 in any treatment arms, a back-up imputation method 
for the primary efficacy analysis will be used. In particular, missing endpoint data for all 
participants in both efpeglenatide and placebo groups, regardless of staying on the IMP or not, 
will be imputed using a model estimated from participants in the placebo group with endpoint 
data, where randomization strata and baseline HbA1c values are included as the predictors. 
Missing data will be imputed using the regression method.
A hierarchical procedure will be performed to adjust for the multiplicity of comparison on the 
primary endpoint as follows:

First, the highest dose of efpeglenatide (6 mg) will be compared to placebo

If superiority is demonstrated for the 6 mg dose of efpeglenatide, the superiority of 
the 4 mg dose of efpeglenatide versus placebo will be tested

If superiority is also demonstrated for the 4 mg dose of efpeglenatide, the lowest 
dose (2 mg) will be tested for superiority over placebo
When superiority is not obtained in a step, the sequential testing procedure will be stopped.
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. Least 
squares mean difference between each efpeglenatide dose and placebo and its associated 
p-value will be provided for each penalty level.
Another sensitivity analysis method for the primary efficacy endpoint (change from baseline to 
Week 30 in HbA1c) will be an ANCOVA model with missing values imputed by control-based 
MI method (copy to reference) under the missing not at random framework in the ITT
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population.

For participants in the placebo group, missing data will be imputed based on the 
placebo group data

For participants in the efpeglenatide group, missing data will be imputed as if the 
participants were on placebo throughout the study
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, placebo), randomization stratum of 
screening HbA1c (<8%, ≥8%), randomization stratum of Screening SU (Yes/No) and country
as fixed effects, and baseline HbA1c value as a covariate. Same results as the primary
analysis will be provided.
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 values, if any

Pattern 2: participants with baseline values but without postbaseline values during 
the 30-week treatment period

Pattern 3: participants with baseline values and at least 1 postbaseline value during 
the 30-week treatment period but not at Week 30

Pattern 4: participants with baseline values and a Week 30 value during the 30-week 
treatment period
HbA1c values by visit will be presented by missing data pattern for each treatment group, 
using descriptive statistics and/or graphs.
Assessment of treatment effect by subgroup:
The 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 to <75, ≥75 years) (any category with fewer than 
5 participants may be combined with another category as appropriate)

Gender (Male, Female)

Diabetes duration (<10, ≥10 years)

Baseline HbA1c (<8.0%, ≥8.0%)

SU use at screening (Yes/No)

Baseline BMI level (<25, ≥25 to <30, ≥30 kg/mg2)

Country (US, China)
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 mg, 4 mg, or 6 mg, placebo) and randomization stratum of screening HbA1c (<8%, ≥8%), 
randomization stratum of screening SU (Yes/No) and geographical region (US; China), 
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 across the 
subgroups, as appropriate. A graphical presentation of the results (ie, forest plot) will also be 
provided.
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In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, baseline HbA1c), 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. 
Secondary
Number of participants with 
HbA1c <7.0% at Week 30
Change from baseline to 
Week 30 in body weight and 
FPG
Continuous secondary efficacy endpoints will be analyzed using the same ANCOVA model 
with missing values imputed by MI method as the method 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 the Cochran-Mantel-Haenszel method 
stratified by the randomization strata. For the HbA1c <7.0% analysis, participants with missing 
HbA1c data at Week 30 will be considered nonresponders 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 each treatment group over the 
whole treatment 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 OCs).
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 30 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). No multiplicity adjustment will be made on other 
secondary efficacy variables or the comparison of other efpeglenatide dose versus placebo 
than mentioned above.
Exploratory endpoints
7-point SMPG
Rescue therapy used during the 
treatment period until Week 30
Time to initiation of rescue 
therapy
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 SU use (Yes/No), and country (US, China) as the factors. The curve of the 
cumulative incidence of participants with rescue therapy initiation will be estimated using 
Kaplan-Meier method by treatment group.
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. The summary will include the number of observations, mean, SD, SE, 
minimum, median, and maximum. Graphical presentations will also be used to examine trends 
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over time using mean values (±SE) and mean changes from baseline (±SE) at each of the 
scheduled visits (using OCs).
ANCOVA: analysis of covariance; CI: confidence interval; FPG: fasting plasma glucose; HbA1c: hemoglobin A1c; ITT: intent-to-treat; SE:
standard error; OC: observed case; SMPG: self-monitored plasma glucose; SU: sulfonylurea
9.4.2
Safety analyses
All safety analyses will be performed on the safety population, as defined in Section 9.3. 
The observation period of safety data is divided into 3 main segments as follows:

The pretreatment period is defined as the time from informed consent up to the time of the 
first injection of IMP

The on-treatment period is defined as the time from the first injection of IMP up to 
30 days (7 days for hypoglycemia) after the last injection of IMP

The posttreatment period is defined as the time starting 31 days (8 days for hypoglycemia)
after the last injection of IMP (after the on-treatment period)
The AE observations will be classified per the observation periods of safety data as defined above 
into the following:

Pretreatment AEs are AEs that developed or worsened or became serious during the 
pretreatment period

Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious 
during the on-treatment period

Posttreatment AEs are AEs that developed or worsened or became serious during the 
posttreatment period.
In addition, the on-study period is defined from the first injection of IMP up to the last study visit 
of the participants or the date of last available information if participants discontinue the study 
prematurely.
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Table 6 - Safety analyses
Endpoints
Statistical Analysis Methods
AEs
All AEs will be coded to an “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 who experienced 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, 
all TEAEs leading to death, AESI, AE requiring specific monitoring.
Tables will be presented on the “on-treatment period” and for the “on-study period” (for AEs, 
SAEs, and AEs leading to death).
Hypoglycemia
The number (%) of participants with at least 1 hypoglycemic event during the 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], daytime [ie, 06:00 am to 23:59]). Documented 
hypoglycemia (symptomatic or asymptomatic) will be also evaluated for the more stringent SMPG 
threshold of 3.0 mmol/L (<54 mg/dL).
Summaries will be presented overall and by type of event for each treatment group.
The total number of events (per participant-years) will be computed and summarized overall and 
by type of event for each treatment group.
Vital signs, laboratory, and 
ECG 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 on-treatment period.
Results will be presented both in standard international and conventional US units.
The incidence of normal and abnormal ECG status at any time during the on-treatment period will 
be summarized by treatment group whatever the baseline level and according to baseline status.
Exploratory
Will be described in the statistical analysis plan finalized before database lock.
AE: adverse event; AESI: adverse event of special interest; 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; SMPG, self-monitored plasma glucose, SOC: system organ class; TEAE: treatment-emergent adverse event
9.4.3
Other analyses
Analyses of other endpoints are detailed in Table 7.
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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 ADA negative at baseline) during the study period

Number and percentage of participants with treatment-boosted ADAs (among the 
participants ADA positive at baseline) during the study period

ADA titer at scheduled visits

Number and percentage of participants by ADA cross-reactivity to endogenous GLP-1 
(positive/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 predose and 
post dose
Efpeglenatide predose and postdose 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.
ADA: antidrug antibodies; GLP-1: glucagon-like peptide-1; PK: pharmacokinetic; PEG: polyethylene glycol; SAP: Statistical Analysis Plan.
9.5
INTERIM ANALYSES
Not applicable.
9.5.1
Data Monitoring Committee (DMC)
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 ICH Good Clinical Practice (GCP) Guidelines
-
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 

The Investigator will be responsible for the following:
-
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC
-
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures
-
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
10.1.2 Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.
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
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 (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant.

Participants who are rescreened are required to sign a new ICF.

The ICF will contain a separate section that addresses the participation in the postdose 
PK assessment substudy. 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: white, black or African American, Asian, 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 Food and Drug Administration (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 the following:

Review of accumulating clinical study safety data, and

Making a recommendation to the Sponsor regarding the study following each meeting
The DMC will review and analyze, 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 CV 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 participants should have eye examinations based on their 
retinopathy status, performed by a professional eye care provider according to International 
Council of Ophthalmology (ICO) guidelines (9) or local standards. This should occur quarterly at 
minimum, especially for participants at high risk.
10.1.5 Dissemination of Clinical Study Data
Sanofi shares information about clinical trials and results on publicly 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 clinical trial register (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, the Sponsor will 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 eCRF 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 eCRF.

The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

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 eCRF 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 eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available

Definition of what constitutes source data can be found in a separate study document
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10.1.8 Study and Site Closure
The Sponsor 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 (at the study 
site).

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 the local 
laboratory test results are used to evaluate an AE (diagnostic, follow-up, outcome), the
results must be entered into the eCRF.
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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
AST
Total bilirubin (in case of values 
above the normal range, 
differentiation in conjugated and 
non-conjugated bilirubin)
Sodium
Alkaline 
phosphatase
ALT
eGFR (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 ADA
Calcitonin
Calcitonin
Other Screening tests

Follicle-stimulating hormone and estradiol (as needed in unconfirmed postmenopausal 
women)
NOTE: For women not of 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 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 eCRF.
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.
ADE: antidrug antibody; ALT: alanine aminotransferase; AST: aspartate transaminase; β-HCG: beta-human chorionic gonadotropin; eGFR: 
Epidermal growth factor receptor; 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.
The HbA1c 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 conditions including either an 
increase in frequency and/or intensity of the conditions

New conditions detected or diagnosed after study IMP 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 IMP 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 conditions

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 
conditions

Medical or surgical procedure (eg, endoscopy, appendectomy): the conditions 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 conditions 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
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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.
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 eCRF.

It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor representative in lieu of completion of the SAE/AESI eCRF page.

There may be instances when copies of medical records for certain cases are requested by
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.
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
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe.
Assessment of causality

The Investigator is obligated to assess the relationship between study IMP and each 
occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.

The Investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study IMP administration will 
be considered and investigated.

The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor 
representative.

The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs

The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 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 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed eCRF.
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
The Investigator will submit any updated SAE/AESI data to the Sponsor representative 
within 24 hours of receipt of the information.
REPORTING OF SAEs/AESI
SAE/AESI reporting to Sponsor representative via an electronic data collection tool

The primary mechanism for reporting an SAE/AESI to the 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.

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 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 postmenopausal 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.
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3. Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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 IMP.
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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 (ie, until 
Follow-up Visit 15) after the last dose of IMP.
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PREGNANCY TESTING:

WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test.

Additional pregnancy testing should be performed at each on-site visit during the 
treatment period, at the last study visit (6 weeks ±7days after the last dose of IMP), 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 poststudy 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/she 
may learn of an SAE through spontaneous reporting.

Any female participant who becomes pregnant while participating in the study will 
discontinue study IMP.
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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 lab results to decide on further reporting/monitoring/discontinuation. 
Note:

“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening.

See Section 10.3 for guidance on safety reporting.

Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN.
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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 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 documentation.
10.5.2.1 Elevation of amylase and/or lipase >2 × 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 Section 10.5.2.2).
Best clinical judgment is to be used when interpreting elevated serum amylase and lipase levels in 
asymptomatic participants. Temporary discontinuation of the IMP may be considered in these 
cases if deemed necessary by the Investigator.
10.5.2.2 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 Section 10.5.2.1, or more often if 
clinically indicated.
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A gastroenterologic evaluation and imaging (ultrasound and/or CT or MRI with contrast, as 
appropriate) must be performed as clinically indicated and as per clinical practice and local 
guidelines. If a diagnosis of pancreatitis is confirmed, IMP should not be restarted and should be 
permanently discontinued.
In both cases as previously described (Section 10.5.2.1 and Section 10.5.2.2), all laboratory or 
clinical documentations must be collected. If the retest confirms lipase and/or amylase values are 
>2 ULN, the event must be reported in the eCRF 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 are 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 eCRF 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. 

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.
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
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 RAs. 
Acute renal impairment is not thought to be caused directly by GLP-1 RAs (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), 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: ABBREVIATIONS
AE:
adverse event
AESI:
adverse event of special interest
ALT:
alanine aminotransferase
ANCOVA:
analysis of covariance
AST:
aspartate aminotransferase
BP:
blood pressure
CEC:
Clinical Endpoint Committee
CFR:
Code of Federal Regulations
CI:
confidence interval
CT:
computed tomography
CV:
cardiovascular
DMC:
data monitoring committee
DPP-4:
dipeptidyl peptidase 4
ECG:
electrocardiogram
eCRF:
electronic Case Report Form
eGFR:
estimated glomerular filtration rate
EOT:
end of treatment
FDA:
Food and Drug Administration
FPG:
fasting plasma glucose
FSH:
follicle-stimulating hormone
GCP:
Good Clinical Practice
GI:
gastrointestinal
GLP-1:
glucagon-like peptide-1
GLP-1 RA:
glucagon-like peptide 1 receptor agonist 
HbA1c:
hemoglobin A1c
HRT:
hormonal replacement therapy
IB:
Investigator's Brochure
ICF:
informed consent form
ICO:
International Council of Ophthalmology
IEC:
Independent Ethics Committees
IMP:
investigational medicinal product
IRB:
Institutional Review Boards
IRT:
interactive response technology
ITT:
intent-to-treat
MDRD:
modification of diet in renal disease
MEN 2:
multiple endocrine neoplasia syndrome type 2
MI:
multiple imputation
MRI:
magnetic resonance imaging
MTC:
medullary thyroid cancer
NIMP:
noninvestigational medicinal product
OAD:
oral antidiabetic
OC:
observed cases
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PEG:
polyethylene glycol
PFS:
prefilled syringe
PK:
pharmacokinetic
popPK:
population PK
PPG:
postprandial plasma glucose
SAE:
serious adverse event
SC:
subcutaneous
SD:
standard deviation
SE:
standard error
SGLT2:
sodium/glucose cotransporter 2
SMPG:
self-monitored plasma glucose
SoA:
schedule of activities
SU:
sulfonylurea
SUSAR:
suspected unexpected serious adverse reaction
T2DM:
type-2 diabetes mellitus
TEAEs:
treatment-emergent adverse events
ULN:
upper limit of normal
WOCBP:
women of childbearing potential
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11
REFERENCES
1. American Diabetes Association. Standards of Medical Care in Diabetes – 2017. Diabetes 
Care. 2017 Jan;40(Suppl 1):S132-S5.
2. Investigator's Brochure, SAR439977, latest edition.
3. FDA draft Guidance for Industry: Assay Development and Validation for Immunogenicity 
Testing of Therapeutic Protein Products [Online]. 2016 Apr [cited 2016 Apr 22]; Available 
from: 
URL:https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidan
ces/ucm192750.pdf
4. Committee For Medicinal Products For Human Use (CHMP): Guideline on Immunogenicity 
Assessment of Biotechnology-derived Therapeutic Proteins, 
EMEA/CHMP/BMWP/14327/2006 [Online]. 2007 Dec 13; Available from: 
URL:http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500003946.pdf
5. Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer-Davis EJ, et al. Nutrition 
therapy recommendations for the Management of adults with diabetes. Diabetes Care. 
2014;37(Suppl. 1):S120–43.
6. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2005 May;28(5):1245-9.
7. 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.
8. 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 Jan;40(1):155-7.
9. 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) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFC15337 16.1.1 Protocol
Clinical Approval
Regulatory Approval
Clinical Approval