Clinical trial NCT03684642
Conditions: Type 2 Diabetes Mellitus
Sponsor: Sanofi
Start date: 2018-09-26; Completion date: 2020-11-17
Enrollment: 908 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the non-inferiority of once weekly injection of efpeglenatide in comparison to once weekly injection of dulaglutide on glycated hemoglobin (HbA1c) change in participants with Type 2 diabetes mellitus (T2DM) inadequately controlled with metformin.

Secondary Objectives:

* To demonstrate the superiority of once weekly injection of efpeglenatide with once weekly injection of dulaglutide on glycemic control.
* To demonstrate the superiority of once weekly injection of efpeglenatide with once weekly injection of dulaglutide on body weight.
* To evaluate the safety of once weekly injection of efpeglenatide and once weekly injection of dulaglutide.

Detailed description:
Study duration per participant was approximately 65 weeks including an up to 3-week Screening Period, a 56-week Treatment Period and a 6-week safety Follow-up Period.

Arms: arm 1: Participants received Efpeglenatide subcutaneous (SC) injection once weekly up to Week 56 on top of metformin. Participants initiated dosing at 2 mg once weekly and increased every 2 weeks to the maximum of 4 mg once weekly for the treatment duration. arm 2: Participants received Efpeglenatide SC injection once weekly up to Week 56 on top of metformin. Participants initiated dosing at 2 mg once weekly and increased every 2 weeks to the maximum of 6 mg once weekly for the treatment duration. arm 3: Participants received Dulaglutide SC injection once weekly up to Week 56 on top of metformin. Participants initiated dosing at 0.75 mg once weekly and increased after 2 weeks to 1.5 mg once weekly for the treatment duration.
Interventions: intervention 1: Efpeglenatide intervention 2: Dulaglutide intervention 3: Background therapy Metformin
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection; Route of administration: SC intervention 2: Pharmaceutical form: solution for injection; Route of administration: SC intervention 3: Pharmaceutical form: tablet; Route of administration: oral; Dose to be kept stable throughout the study.

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: Version Sanofi dated 12-SEP-2017 based on TransCelerate CPT version 4 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 
Protocol title: 
A 56-week, Multicenter, Open-label, Active-controlled, 
Randomized Study to Evaluate the Efficacy and Safety 
of Efpeglenatide Once Weekly Compared to Dulaglutide 
Once Weekly in Patients with Type 2 Diabetes Mellitus 
Inadequately Controlled with Metformin 
Protocol number: 
EFC14829 
Amendment number: 
01 
Compound number 
(Trademark/INN): 
SAR439977/efpeglenatide 
Short title: 
Efficacy and Safety of Efpeglenatide Versus Dulaglutide 
in Patients with Type 2 Diabetes Mellitus Inadequately 
Controlled with Metformin (AMPLITUDE-D) 
Sponsor name: 
Legal registered 
address: 
Regulatory agency identifying number(s): 
EudraCT number: 
2017-002956-10 
IND number: 
112780 
UTN number: 
U1111-1205-3150 
Approval Date: 
31-Jul-2019
Total number of pages: 106 
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: 
 
NCT03684642


Amended Clinical Trial Protocol 01 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01  
All 
31 July 2019, version 1 (electronic 1.0) 
Original Protocol 
 
20 June 2018, version 1 (electronic 2.0) 
Amended protocol 01 (31 July 2019) 
This amended protocol is considered to be nonsubstantial because it does not significantly impact 
the safety or physical/mental integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT 
The protocol was updated to make the pharmacokinetic (PK) dataset more robust by timing the 
collections to coincide with the absorption phase of efpeglenatide and by collecting additional PK 
samples postdose.  
In addition, Sanofi took this opportunity to clarify other sections of the protocol as listed below. 


Amended Clinical Trial Protocol 01 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
activities - IMP concentration 
(PK) sampling 
Modified postdose PK sampling time from “4 days 
(±1 day)” to “3 days (±1 day)” and specified the sample 
collection window as “preferably between Week 8 and 
Week 12” 
Description of PK note has been changed from:  
“All participants will have one blood sample collected just 
before their weekly injection of the IMP (and at least 
6 days after last dosing of IMP) for the predose IMP 
serum concentration (Ctrough) at selected clinical visits. 
See Section 8.5.  
For a subset of participants, at least 1 additional post 
dose 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.” 
To:  
“All participants assigned to efpeglenatide will have 1 
blood sample collected just before their weekly injection 
(and at least 6 days after last dose administration) for the 
predose serum concentration (Ctrough) of efpeglenatide at 
selected clinical visits. See Section 8.5. 
For efpeglenatide participants who consent to postdose 
PK, at least 1 additional postdose sample will be taken 
3 days (±1 day) after administration of efpeglenatide, 
preferably between Week 8 and Week 12, but other 
weeks are also acceptable (eg, the after 1st dose, 4th 
dose, and 12th dose). See Section 8.5.” 
Postdose PK sampling time 
changed from 4 days (±1 day) to 
3 days (±1 day) in order to collect 
more PK data in the absorption 
phase. 
Sample collection time points 
(only in efpeglenatide treated 
patients) have been clarified; 
sample collection time points have 
been specified to allow higher 
flexibility with regard to postdose 
sample collection window in order 
to facilitate additional postdose 
sampling.  
A preferred interval for PK 
postdose sampling (between 
Week 8 and Week 12) was 
defined considering the balance 
between two requirements: PK 
steady state and limited risk of 
anti-drug antibodies (ADA) 
formation. 
Section 3 Table 1 - Objectives 
and endpoints 
The PK endpoint regarding serum concentration of 
efpeglenatide at postdose has been modified from:  
“Serum concentration of efpeglenatide at postdose (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 in a 
subset of participants, at least 10% of total under 
efpeglenatide treatment: [N= 30 per efpeglenatide 
group])” 
To:  
“Serum concentration of efpeglenatide at 
postadministration of efpeglenatide in participants who 
consent” 
The endpoint has been updated to 
remove the operational instruction 
language. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.5 Pharmacokinetics 
The following text has been added pertaining to postdose 
PK sampling: 
 
“Blood samples for measurement of serum 
concentrations of efpeglenatide should only be 
collected and analyzed for participants in 
efpeglenatide arms.” 
The following text has been modified from: 
 
“For a subset of participants, 10% of total 
(N=30 per group): 1 additional postdose sample 
will be taken either 4 days (±1 day) after the 
1st IMP dose, or 4 days (±1 day) after the 
4th dose, or 4 days (±1 day) after the 12th dose. 
To reach this number and due to the blinded 
design of the study, PK post-dose sample will 
be collected in the first 80 randomized 
participants who will accept this additional 
sampling, sign the separate section of the main 
consent form and provide a valid post-dose 
sample.” 
To: 
 
“For participants who consent to postdose PK 
sampling, at least 1 additional postdose sample 
will be taken 3 days (±1 day) after 
administration of efpeglenatide, preferably 
between Week 8 and Week 12, but other 
weeks are also acceptable (eg, after the 
1st dose, 4th dose, or 12th dose). Ideally 
a minimum of 180 evaluable postdose samples 
(including the samples already collected at 
4 days [±1 day] window as required in the initial 
protocol) from efpeglenatide treated patients 
are required to ensure a meaningful PK 
analysis. It is anticipated to collect as many 
samples as possible while considering the 
participants agreement to the optional 
sampling.” 
To clarify the general PK sampling 
process. 
To collect more PK data in the 
absorption phase and to allow 
higher flexibility with regard to 
postdose sample collection 
window in order to facilitate 
additional postdose sampling. 
Section 8.5 Pharmacokinetics 
Section 6.1, Table 2 Overview 
of Study Interventions 
Administered 
The following text has been modified from: 
“Participants will be asked to perform the single dose 
injection at the same injection site twice (eg, at Week 2 
and Week 3 before the planned PK visit for Week 4)” 
To: 
“Participants will be asked to administer the 
last 2 consecutive weekly dose injections prior to PK 
sampling at the same injection region (eg, at Week 2 and 
Week 3 before the planned PK visit at Week 4).” 
To clarify the site of 
administration. 
Section 9.4.3, Table 7 Other 
analyses 
Clarified text pertaining to postdose PK samplings 
To reflect the changes made in 
the PK endpoint. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 2.1 Study rationale 
Specified the patient population and mentioned that 
“patients with T2DM that is inadequately controlled with 
metformin” 
Clarification on the studied 
population. 
Section 1.3 Schedule of 
Activities - rescue therapy 
The following detail has been added for rescue therapy 
notes: “Participants must have an unscheduled in-person 
visit prior to rescue therapy initiation, with the 
assessment normally planned for the EOT visit.” 
The note has been updated for 
clarity. The visits and procedures 
are detailed in different cases 
(rescue treatment introduction). 
Section 1.3 Schedule of 
Activities - footnote “a” 
Footnote “a” has been updated from: 
“For safety reasons, participants who wish to terminate 
participation in the study, should be assessed 6 weeks 
(±1week) from the last IMP dose (at the minimum) using 
the procedure normally planned for the post-treatment 
follow-up visit at EOS. At the time corresponding to their 
Week 56 Visit, all attempts will be made to contact the 
participants to inquire about safety/vital status.” 
To: 
“For safety reasons, participants who do not want to 
continue to be followed in the study after IMP 
discontinuation, should be assessed 6 weeks (±1 week) 
from the last IMP dose (at the minimum) using the 
procedure normally planned for the post-treatment follow-
up visit at EOS. At the time corresponding to their 
Week 56 Visit, all attempts will be made to contact the 
participants to inquire about safety/vital status.” 
The footnote has been reworded 
for clarity. 
Section 1.3 Schedule of 
Activities - Antidrug Antibody 
(ADA) sampling 
Section 8.8.1 Immunogenicity 
Assessments 
Added the following wording “applicable for the 
participants assigned to efpeglenatide” 
Clarification provided for sampling 
requirements. 
Section 2.2 Background 
Specified the section numbers of the IB (Section 5 
Non-Clinical Studies and Section 6 Effects in Humans) 
that contains nonclinical and clinical information of 
efpeglenatide, respectively. 
To clarify the reference source of 
information.  
Section 2.3 Benefit/risk 
assessment 
Specified the section numbers of the IB (Section 2 
Summary and Section 7 Summary of Data and Guidance 
for the Investigator) that contains information of known 
and expected benefits and risks and reasonably expected 
AEs of efpeglenatide, respectively. 
To clarify the reference source of 
information. 
Section 5.3.1 Meals and dietary 
restrictions 
Under fasting conditions, the following wording has been 
added to the first and second bullet: 
 
“The participants should not take any 
antidiabetic medication before blood sampling.  
 
“and before administration of antidiabetic 
medication” 
To add clarity on the definition of 
fasting for the purpose of sample 
collection for glycemic 
parameters. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1.1 Investigational 
medicinal products 
Specified the name of reference document “Pharmacy 
Manual”. 
Added following text “In case of emergency only, for 
scheduled or unscheduled visits, the IMP might be 
supplied from the site to the participant via a Sponsor-
approved courier company where allowed by local 
regulations. Direct-To-Patient (DTP) remains an option 
and the participant/Investigator can refuse this option.” 
Clarification.  
To include DTP, a new process 
regarding IMP dispensation in 
case of emergency. 
Section 6.2 Preparation/ 
handling/storage/ accountability 
Specified the name of reference document “Pharmacy 
Manual”. 
Added following text “except for IMP in case of DTP 
shipment, for which a courier company has been 
approved by the Sponsor” 
Section 6.3 measure to 
minimize bias: randomization 
and blinding 
Adjusted the wordings for allocated IMP from: 
“Returned study intervention should not be redispensed 
to the participants.” 
To: 
“Previously allocated IMP should not be redispensed to 
the participants.” 
Clarification.  
Section 6.3.2 Randomization 
code breaking during the study 
Added “independent Sponsor representative” in the list of 
the people who have access to the randomization code to 
allow for the sorting of the efpeglenatide blood samples.  
Clarification. 
Section 6.4.1 Return and/or 
destruction of treatments 
The following sentences were modified from:  
“The Investigator will not destroy the used and unused 
IMPs unless the Sponsor provides written authorization.” 
“Sharp containers containing all used autoinjectors will be 
brought back to the site by the study participant for the 
purpose of destruction.”  
To: 
“The Investigator will not destroy the used and unused 
IMPs unless the Sponsor or delegate provides written 
authorization.” 
“Sharp containers containing all used autoinjectors that 
are not affected by a complaint or the specified return 
process will be brought back to the site by the study 
participants for the purpose of destruction.” 
The following text has been added in order to clarify the 
return process for efpeglenatide autoinjectors:  
“At selected sites in US only, at least 120 used 
efpeglenatide autoinjectors that functioned normally, with 
no Product technical Complaint (PTCs), will be returned 
to the Sponsor using a defined return process. 
Separate instructions will be supplied to the site and 
participants, in accordance with local law regulatory 
requirements”. 
To add clarification for the specific 
investigational medicinal product 
(IMP) return process for 
autoinjectors that functioned 
normally; these will be additionally 
evaluated to comply with 
regulatory requirements. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.1.1 Permanent 
discontinuation 
The following text was modified to clarify the handling of 
participants after permanent IMP discontinuation, from: 
“For participants who discontinue IMP but remain in the 
study, the remaining visits should occur as scheduled 
where possible.” 
To: 
”For participants who discontinue IMP and attend an 
earlier EOT Visit, but who remain in the study, the 
remaining visits should occur as scheduled, where 
possible, until Week 56 (Visit 14), and all procedures 
should be performed with the exception of the 
assessment of ADA”. 
To clarify the schedule of 
assessments after permanent IMP 
discontinuation. 
Section 8.2.2 Vital signs 
Added clarification for heart rate measurement, text 
modified from: 
“Heart rate will be measured at the time of the 
measurement of seated BP” 
To: 
“Heart rate will be measured at the time of the seated BP 
measurement from a pulse point (as per current 
practice)” 
Clarification.  
Section 8.2.5 Hypoglycemia  
Added documented hypoglycemia measured plasma 
glucose concentration range “between 3.0 to 3.9 mmol/L 
(54 to 70 mg/dL)” that will also be analyzed. 
To align with statistical analysis 
plan (SAP).  
Section 8.2.6 Patient-Reported 
Outcomes Measurement 
Information System gastro-
intestinal symptom scales 
Added following text:  
“As with any patient-reported outcome (PRO) 
questionnaire, the PROMIS GI symptom scale captures 
the patient’s perspective related to GI tolerability and its 
impact on day-to-day activities. PROMIS GI symptom 
scale is complementary to the safety evaluation made by 
Investigators and reported in the eCRF. As a result, 
participants’ responses will not be reviewed by 
Investigators and will not need reconciliation with safety 
events reported in the eCRF.” 
To clarify that the review and 
reconciliation by the Investigators 
of participants responses to 
PROMIS GI symptom scale is not 
needed. 
Section 8.3 Adverse Event and 
Serious Adverse Event 
Adjustment of the adverse event of diabetic retinopathy 
requiring specific monitoring bullet point: reference to 
Appendix 1 (Section 10.1.4.3) has been deleted. 
To maintain consistency among 
the sections.  
Section 8.3.1 Time period and 
frequency for collecting AE and 
SAE information 
Added the following text: 
“All SAEs and AESIs will be recorded and reported to the 
Sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated 
in Appendix 3 (Section 10.3). The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of 
it being available.” 
Added per Common Protocol 
Template.  
Section 10.1.7 Source 
documents 
Specified the name of reference document “GCP training 
module” 
Clarification. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.4.3 Independent 
Expert 
Section 10.5.5. Guidance for 
Monitoring of Participants with 
Diabetic Retinopathy  
Section 10.1.4.3 pertaining to independent 
ophthalmologist expert review has been deleted.  
Added the following details of management of 
participants with retinopathy in Section 10.5.5. 
“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 or local standards; this should occur quarterly 
at a minimum for participants at high risk (eg, participants 
with severe non-proliferative diabetic retinopathy, 
proliferative diabetic retinopathy, and/or diabetic macula 
edema).”  
Adverse event of diabetic 
retinopathy complications will be 
reviewed as per current medical 
review process without an 
independent ophthalmologist 
expert review.  
Section 10.3 Appendix 3 
Specified the name of reference document “the site file 
(detailed Study Contact List)”. 
Clarification.  
Throughout 
Editorial, typographical error corrections and document 
formatting revisions 
To improve readability and overall 
quality of the document.  


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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 01  ............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 9 
LIST OF FIGURES ........................................................................................................................................ 13 
1 
PROTOCOL SUMMARY ............................................................................................................... 14 
1.1 
SYNOPSIS ..................................................................................................................................... 14 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 20 
2 
INTRODUCTION............................................................................................................................ 28 
2.1 
STUDY RATIONALE ..................................................................................................................... 28 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 31 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 32 
4 
STUDY DESIGN ............................................................................................................................ 34 
4.1 
OVERALL DESIGN ........................................................................................................................ 34 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 34 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 35 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 35 
5 
STUDY POPULATION .................................................................................................................. 36 
5.1 
INCLUSION CRITERIA .................................................................................................................. 36 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 36 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 39 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 39 
5.4 
SCREEN FAILURES ..................................................................................................................... 39 


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6 
STUDY INTERVENTION ............................................................................................................... 40 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 40 
6.1.1 
Investigational medicinal products ................................................................................................. 41 
6.1.2 
Noninvestigational medicinal products .......................................................................................... 42 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...................................................... 44 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 45 
6.3.1 
Methods of blinding ........................................................................................................................ 46 
6.3.2 
Randomization code breaking during the study ............................................................................. 46 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 47 
6.4.1 
Return and/or destruction of treatments ........................................................................................ 47 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 48 
6.6 
DOSE MODIFICATION .................................................................................................................. 49 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 49 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 50 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 50 
7.1.1 
Permanent discontinuation ............................................................................................................ 50 
7.1.2 
Temporary discontinuation ............................................................................................................. 51 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 52 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 53 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 54 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 54 
8.1.1 
Hemoglobin A1c ............................................................................................................................. 54 
8.1.2 
Fasting plasma glucose ................................................................................................................. 54 
8.1.3 
Body weight .................................................................................................................................... 54 
8.1.4 
Waist circumference ...................................................................................................................... 55 
8.1.5 
7-point self-monitored plasma glucose profiles ............................................................................. 55 
8.1.6 
Use of rescue therapy .................................................................................................................... 55 
8.1.7 
Patient qualitative assessment of treatment .................................................................................. 56 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 56 
8.2.1 
Physical examinations ................................................................................................................... 56 
8.2.2 
Vital signs ....................................................................................................................................... 57 


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8.2.3 
Electrocardiograms ........................................................................................................................ 57 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 57 
8.2.5 
Hypoglycemia ................................................................................................................................. 58 
8.2.6 
Patient-reported outcomes measurement information system gastrointestinal symptom 
scales ............................................................................................................................................. 59 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 60 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 61 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 62 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 62 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 62 
8.3.5 
Pregnancy ...................................................................................................................................... 62 
8.3.6 
Cardiovascular and death events .................................................................................................. 63 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 63 
8.3.8 
Guidelines for reporting product complaints/medical device incidents (including 
malfunctions) .................................................................................................................................. 63 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 63 
8.5 
PHARMACOKINETICS .................................................................................................................. 63 
8.6 
PHARMACODYNAMICS ............................................................................................................... 64 
8.7 
GENETICS ..................................................................................................................................... 64 
8.8 
BIOMARKERS ............................................................................................................................... 64 
8.8.1 
Immunogenicity assessments ........................................................................................................ 65 
8.9 
HEALTH ECONOMICS .................................................................................................................. 65 
9 
STATISTICAL CONSIDERATIONS  ............................................................................................. 66 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 66 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................ 66 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 66 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 67 
9.4.1 
Efficacy analyses ........................................................................................................................... 67 
9.4.2 
Safety analyses .............................................................................................................................. 70 
9.4.3 
Other analyses ............................................................................................................................... 71 
9.5 
INTERIM ANALYSES  ................................................................................................................... 72 
9.5.1 
Data monitoring committee ............................................................................................................ 72 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 73 


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10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 73 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 73 
10.1.2 
Informed consent process .............................................................................................................. 73 
10.1.3 
Data protection ............................................................................................................................... 74 
10.1.4 
Committees structure ..................................................................................................................... 75 
10.1.5 
Dissemination of clinical study data ............................................................................................... 75 
10.1.6 
Data quality assurance .................................................................................................................. 76 
10.1.7 
Source documents ......................................................................................................................... 76 
10.1.8 
Study and site closure .................................................................................................................... 76 
10.1.9 
Publication policy ........................................................................................................................... 77 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 77 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 78 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 83 
10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 86 
10.5.1 
Laboratory abnormalities ............................................................................................................... 86 
10.5.2 
Monitoring of participants with increased lipase and/or amylase >2 × ULN .................................. 91 
10.5.3 
Management of participants with increased calcitonin values ....................................................... 92 
10.5.4 
Gastrointestinal events in relation to acute renal failure ................................................................ 93 
10.5.5 
Guidance for monitoring participants with diabetic retinopathy ..................................................... 93 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 93 
10.7 
APPENDIX 7: HYPOGLYCEMIA CLASSIFICATION .................................................................... 94 
10.8 
APPENDIX 8: PATIENT QUALITATIVE ASSESSMENT OF TREATMENT VERSION 2 ............. 95 
10.9 
APPENDIX 9: PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION 
SYSTEM (PROMIS) GASTROINTESTINAL SYMPTOM SCALES VERSION 1.0 ....................... 97 
10.10 
APPENDIX 10: ABBREVIATIONS ............................................................................................... 103 
10.11 
APPENDIX 11: PROTOCOL AMENDMENT HISTORY .............................................................. 105 
11 
REFERENCES............................................................................................................................. 106 
 


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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 31 
Table 2 - Overview of study interventions administered ............................................................................... 40 
Table 3 - Rescue criteria ............................................................................................................................... 43 
Table 4 - Populations for analyses ................................................................................................................ 66 
Table 5 - Efficacy analyses ........................................................................................................................... 67 
Table 6 - Safety analyses .............................................................................................................................. 71 
Table 7 - Other analyses ............................................................................................................................... 72 
Table 8 - Protocol-required safety laboratory assessments .......................................................................... 77 
Table 9 - Highly effective contraceptive methods ......................................................................................... 84 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
Figure 2 - Hypoglycemia classification .......................................................................................................... 94 
 


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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A 56-week, Multicenter, Open-label, Active-controlled, Randomized Study to 
Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly Compared to 
Dulaglutide Once Weekly in Patients with Type 2 Diabetes Mellitus Inadequately 
Controlled with Metformin 
Short title: 
Efficacy and Safety of Efpeglenatide Versus Dulaglutide in Patients with Type 2 
Diabetes Mellitus Inadequately Controlled with Metformin (AMPLITUDE-D) 
Rationale: 
The aim of the present study is to compare efpeglenatide once weekly versus dulaglutide once 
weekly in addition to metformin in a population of patients with type 2 diabetes mellitus (T2DM) 
that is inadequately controlled with metformin, in terms of glycemic control, weight control, and 
other efficacy and safety parameters.  
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To demonstrate the noninferiority of once-weekly injection of 
efpeglenatide 4 or 6 mg in comparison to once-weekly injection 
of dulaglutide 1.5 mg on HbA1c change from baseline to 
Week 56 in participants with T2DM inadequately controlled with 
metformin 
 
Change from baseline to Week 56 in HbA1c 
Secondary 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 4 and 6 mg with once-weekly injection of 
dulaglutide 1.5 mg on glycemic control 
 
Change from baseline to Week 56 in fasting plasma 
glucose (FPG) 
 
Number of participants with HbA1c <7.0% at 
Week 56 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 4 and 6 mg with once-weekly injection of 
dulaglutide 1.5 mg on body weight 
 
Change from baseline to Week 56 in body weight 
To evaluate the safety of once-weekly injection of efpeglenatide 
4 and 6 mg and once-weekly injection of dulaglutide 1.5 mg 
 
Number of participants with at least 
one hypoglycemic event during treatment period 
 
Number of hypoglycemic events per participant-year 
during treatment period 
 
Number of participants with AEs (see Section 8.3) 
AE: adverse event, FPG: fasting plasma glucose, HbA1c: hemoglobin A1c, T2DM: type 2 diabetes mellitus 


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Overall design: 
This study is a Phase 3, multicenter, 56-week, randomized, open-label for the drug (efpeglenatide 
and dulaglutide) and double-blind for the doses of efpeglenatide, active-controlled, 3-arm, parallel 
group study in participants with T2DM inadequately controlled with metformin. 
The randomization (1:1:1) to efpeglenatide 4 mg, efpeglenatide 6 mg, or dulaglutide 1.5 mg will 
be stratified by screening HbA1c (<8%, ≥8%) and Visit 3 (Day 1) body mass index (BMI; 
<30 kg/m2 and ≥30 kg/m2). 
An independent Data Monitoring Committee (DMC) will review clinical study safety data and an 
Independent Clinical Endpoint Committee [CEC] will review, assess and/or adjudicate all events 
of death, selected cardiovascular (CV) 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 900 randomized participants assigned to study 
intervention (300 participants per treatment group). All randomized participants will be included 
in the population analyzed for efficacy endpoints. Section 9.2 gives details of the sample size 
determination. 
Intervention groups and duration: 
The study will be comprised of 3 periods as follows: 
 
An up to 3-week Screening Period (with a minimum 11 days) 
 
A 56-week open-label, active-controlled Treatment Period, for efficacy and safety 
assessments 
 
A 6-week post-treatment Follow-up Period to collect safety information after last dose of 
Investigational Medicinal Product (IMP; treatment completed or permanent treatment 
discontinuation) 
The maximum study duration per participant will be 65 weeks. 
Study interventions 
Investigational medicinal product 
Efpeglenatide 
 
Formulation: 500 μL of a sterile, nonpyrogenic, clear, colorless solution in a disposable 
single-dose autoinjector 
 
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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Dulaglutide (Trulicity™): 
 
Formulation: 0.5 mL of a sterile, nonpyrogenic, clear, colorless solution in a single-dose 
pen 
 
Route of administration: SC 
 
Dose regimen: SC injection once-weekly on the same week day (eg, each Monday) at any 
time of the day 
The dose will be titrated as shown in the table below. From Week 4 (Visit 5) through the rest of 
treatment period, participants will remain on the randomized IMP dose until the end of treatment 
(EOT) at Week 56 (Visit 14). 
Investigational medicinal product dose schedule 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 onward 
 
Day 1 
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 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  
Dulaglutide 1.5 mg 
0.75 mg 
0.75 mg 
1.5 mg  
1.5 mg  
1.5 mg  
 
Noninvestigational medicinal products  
Metformin 
 
Route of administration: Oral 
 
Dose regimen: Administered as per the Investigator’s prescription and in accordance with 
local labeling. Participants are enrolled with metformin at a stable dose (≥1500 mg/day, 
maximum tolerated dose, or as per country regulation if less) for at least 3 months prior to 
the Screening Visit. The dose should be kept stable throughout the study unless dose 
reduction is needed for safety reasons. 
Rescue therapy 
 
Route of administration: oral or 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 RA) 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, open-label Treatment Period should be continued 
and the efpeglenatide dose must remain blinded until the end of the study. Refer to 
Section 6.1.2.2 for full details of rescue therapy (unless the Investigator considers a change 
necessary for safety reasons). 


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Statistical considerations: 
 
Primary analysis: 
Analysis of the primary efficacy endpoint (change from baseline to Week 56 in HbA1c) will be 
performed using the intent-to-treat (ITT) population, using HbA1c measurements obtained during 
the study, including those obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from baseline to Week 56 will be analyzed 
with missing values imputed by baseline observation carried forward (BOCF)-like multiple 
imputation (MI) method for both efpeglenatide and dulaglutide groups, under the missing not at 
random frame work (MNAR). For participants with missing HbA1c values at Week 56, the 
missing values will be imputed using a random draw from a normal distribution with mean equal 
to their baseline HbA1c and the standard deviation equal to the pooled standard deviation 
calculated from the square root of the mean square error estimated from a regression model with 
baseline HbA1c as the dependent variable and randomization strata and treatment as the 
covariates. 
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data sets 
with completed data. Each of the complete datasets after the imputation will be analyzed by the 
analysis of covariance (ANCOVA) model with the treatment groups (efpeglenatide 4 or 6 mg, 
dulaglutide 1.5 mg), randomization stratum of screening HbA1c (<8%, ≥8%), Visit 3 (Day 1) 
BMI (<30 kg/m2 and ≥30 kg/m2), and geographical region as fixed effects, and baseline HbA1c 
value as a covariate. The baseline value is defined as the last available value prior to the first dose 
administration of IMP or the last available value on or before the date of randomization if not 
treated with the open-label IMP. Results from each complete dataset will be combined to provide 
the adjusted mean change in HbA1c from baseline to Week 56 (regardless of treatment 
discontinuation or initiation of rescue therapy) for each treatment group, as well as the 
between-group difference (comparing each efpeglenatide group versus dulaglutide group) and the 
95% confidence intervals (CI) for the difference. If the upper bound (UB) of the 2-sided 95% CI 
for the adjusted mean difference (efpeglenatide versus dulaglutide) in HbA1c change from 
baseline to Week 56 is ≤0.3%, the noninferiority will be declared.  
If noninferiority is demonstrated on the primary endpoint for both efpeglenatide groups, ie, the 
UB of the 2-sided 95% CI <0.3%, the superiority of each efpeglenatide group versus dulaglutide 
for the primary endpoint will be tested in a hierarchical fashion, with efpeglenatide 6 mg tested 
first and then efpeglenatide 4 mg.  
Summary statistics (for screening value, baseline value, observed values, and observed changes 
from baseline) at scheduled visits will be provided for each treatment group. 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 [OCs]). 


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 
Analysis of secondary endpoints and other efficacy endpoints: 
The continuous secondary efficacy endpoints of change in fasting plasma glucose (FPG) and body 
weight from baseline at Week 56 will be analyzed using the same ANCOVA model with missing 
values imputed by MI analysis method as the method used for the primary efficacy endpoint 
analysis. Differences between treatment groups and CIs will be estimated by this method. 
The categorical efficacy endpoint of HbA1c <7.0% at Week 56 (yes/no) will be analyzed by 
Cochran-Mantel-Haenszel method stratified by the randomization strata. The proportion in each 
treatment group will be provided, as well as the differences of proportions between groups (each 
efpeglenatide dose versus dulaglutide) with associated 2-sided 95% CI. For the categorical 
secondary endpoint in which HbA1c is assessed at Week 56, all values at Week 56 will be used to 
determine whether a participant is a responder or not, even if they are measured after IMP 
discontinuation or introduction of rescue therapy. If no assessment is available at Week 56 at all, 
participants will be treated as non-responders in the ITT population. 
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 randomization, stratified by screening HbA1c (<8.0% and ≥8.0%) and baseline (Day 1) BMI (<30 kg/m2 and ≥30 kg/m2) 
Visit schedule: from Visit 1 (Week -3) to Visit 15 (Week 56/EOT + 6 weeks) 
BMI: body mass index, EOS: end of study, EOT: end of treatment, HbA1c: hemoglobin A1c, R: Randomization 
 
56 weeks
Open-label, active-controlled Treatment  Period
Week: 
Visit:   
Baseline
-3
1
2
4
-1
2
Phone call visit
On site visit
if HbA1c is ≥7.0% to <10.0%
R
8
6
0
3
56
Primary 
Endpoint
End of
Treatment 
(EOT)
14
3 weeks
12
7
18

8
30
10
Follow-up
period
+ 6 weeks
15
6 weeks
Efpeglenatide 4 mg; N = 300
Efpeglenatide 6 mg; N = 300
Dulaglutide 1.5 mg; N = 300
24
9
4
5
36

11
43
12
50

13
2 mg
Efpeglenatide 4 mg
2 mg
4 mg
Efpeglenatide 6 mg
Dulaglutide 1.5 mg
Screening 
Period
R
End of
Study  
(EOS)
0.75


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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 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 
 
 
 
 
 
Participants 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 
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 V2 and before 
randomization 
Demography, medical/surgical history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes diabetes complications, CV and 
allergy history, alcohol and smoking 
habits. 
Physical examination  
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
Vital signs  
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
BP and HR in sitting position after at least 
5 minutes of rest. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Waist circumference  
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Section 8.1.4 
12-lead ECG 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
The 12-lead ECG recording should be 
obtained in supine position prior to IMP 
dose administration. See Section 8.2.3. 
IMP injection training/retraining as 
needed 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
See Section 6.1.1. 
Inspection of injections sites 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Diary dispensation 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Diary review and collection 
 
 
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 counseling 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
As per current practice, to be documented. 
See Section 5.3.1 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
IMP dispensation 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
At V2, training kit(s) will be allocated; self-
injection will be done at site. 
IMP collection and accounting 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
Training kit(s) will be collected and 
accounted at V2. 
Compliance  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMPG, IMP, diary 
Efficacy: 
HbA1c 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
FPG  
 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
For these visits, participants need to come 
in fasting condition as described in 
Section 5.3.1 
C-peptide (fasting) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
For these visits, participants need to come 
in fasting condition as described in 
Section 5.3.1 
7-point SMPG 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
Performed on at least 1 day in the week 
prior to visits indicated. See Section 8.1.5 
for details. 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
Fasting (prebreakfast) SMPG 
 
 
X 
X 
X 
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 
weeks prior to other visits indicated. 
See Section 8.1.2 for details. 
Safety: 
Hematology 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
See Appendix 2 (Section 10.2). 
Clinical chemistry 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
See Appendix 2 (Section 10.2). 
Calcitonin 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
See Appendix 2 (Section 10.2). 
Lipid profile 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2). 
Urinalysis 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2). 
Pregnancy test (WOCBP) 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Serum pregnancy testing (β-HCG) at 
screening for WOCBP (Appendix 4 
[Section 10.4]), urine pregnancy testing 
subsequently (at on-site visits and monthly 
at home in between visits).  . If the urine 
test is positive, serum β-HCG should be 
tested for confirmation of the pregnancy. 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
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]). 
Antidrug antibody (ADA) sampling 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Participants positive for ADA at EOS, 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 end 
of the treatment. Blood samples are to be 
collected to assess the efpeglenatide ADA 
status (positive or negative) and level 
(titer) applicable for the participants 
assigned to efpeglenatide.  
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
IMP concentration (PK) sampling 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
All participants assigned to efpeglenatide 
will have 1 blood sample collected just 
before their weekly injection (and at least 6 
days after last dose administration) for the 
predose serum concentration (Ctrough) of 
efpeglenatide at selected clinical visits. 
See Section 8.5. 
For efpeglenatide participants who 
consent, at least 1 additional postdose 
sample will be taken 3 days (±1 day) after 
administration of efpeglenatide, preferably 
between Week 8 and Week 12, but other 
weeks are also acceptable (eg, after the 
1st dose, 4th dose, or 12th dose). 
Participant will need to provide separate 
consent. See Section 8.5. 
Patient-reported Outcomes 
PQATv2  
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
PQATv2 should be completed by 
participants as far as possible at home 
before on-site visits. See Section 8.1.7. 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
PROMIS GI symptoms scale, version 1 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
This questionnaire will have to be 
completed by participants as far as 
possible at home before on-site visits after 
randomization and additionally at Weeks 
1, 3, 5, 6, 7, and 18. 
Rescue therapy assessment 
 
 
Continuous assessment and recording during treatment periods 
After randomization, the need of rescue 
treatment should be assessed by the 
Investigators via fasting SMPG performed 
by the participants and/or the central 
laboratory alerts received on FPG and on 
HbA1c (from Week 12 [Visit 7] onwards). 
Participants must have an unscheduled in-
person visit prior to rescue therapy 
initiation, with the assessments normally 
planned for the EOT visit. See 
Section 6.1.2.2 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the screening 
eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days after 
V1 (to allow IMP to be sent to the site) and 
no later than 21 days after V1 
Concomitant medication recording 
Continuous assessment and recording throughout the study 
 
AE/SAE recording 
 
Reporting hypoglycemia (symptoms, 
SMPG) 
Hypoglycemia eCRF page must be filled in 
for all SMPG values ≤3.9 mmol/L 
(≤70 mg/dL) and/or in case of symptoms 
suggesting hypoglycemia (between V1 
and V2, SMPG values measured with non-
study glucometer can be used) 
a In case of premature permanent IMP discontinuation, participants should have a visit as soon as possible after last IMP administration with the assessments normally planned for EOT visit (including a PK sample if 
the visit can be scheduled 7 days after the permanent IMP discontinuation). Afterwards, the participants should continue in the study up to the scheduled date of study completion and be followed up according to 
the study procedures as specified in the protocol. Every effort should be made to have the participant complete the Week 56 Visit assessments (primary and main secondary endpoints) as the minimum.  
For safety reasons, participants who do not want to continue to be followed in the study after IMP discontinuation, should be assessed 6 weeks (±1 week) from the last IMP dose (at the minimum) using the 
procedure normally planned for the post-treatment follow-up visit at EOS. At the time corresponding to their Week 56 Visit, all attempts will be made to contact the participants to inquire about safety/vital status. 
Abbreviations: ADA: antidrug antibody, AE: adverse event, β-HCG: beta-human chorionic gonadotropin, BP: blood pressure, CV: cardiovascular, ECG: electrocardiogram, EOS: end of study, EOT: end of treatment, 
FPG: fasting plasma glucose, FSH: follicle-stimulating hormone, HbA1c: hemoglobin A1c, GI: gastrointestinal, HR: heart rate, IMP: investigational medicinal product, IRT: interactive response technology, PK: 
pharmacokinetics, PQATv2: Patient´s Qualitative Assessment of Treatment version 2; PROMIS: Patient-Reported Outcomes Measurement Information System; R: Randomization; SAE: serious adverse event, SMPG: 
self-monitored plasma glucose, WOCBP: women of childbearing potential
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2 
INTRODUCTION  
Efpeglenatide is a GLP-1 RA that is being developed for once-weekly treatment of T2DM. 
2.1 
STUDY RATIONALE  
The aim of the present study is to compare efpeglenatide once weekly versus dulaglutide once 
weekly in addition to metformin, in a population of patients with T2DM inadequately controlled 
with metformin, in terms of glycemic control, weight control, and other efficacy and safety 
parameters. 
2.2 
BACKGROUND  
Several classes of pharmacological treatments are approved for glucose control in T2DM, but 
good glycemic control remains challenging for many patients, and new therapeutic options are 
necessary. 
Although lifestyle changes, including diet, exercise, and education, 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 (sulfonylurea, 
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 injections. Glucagon-like peptide 
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 once-weekly GLP-1 RA administered by SC injection, is a novel 
long-acting exendin-4 (exenatide) analogue that is being developed for the treatment of T2DM. 
In total, 7 clinical studies (two Phase 1 studies and five Phase 2 studies) in 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 subjects, 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 


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tolerability profile consistent with currently available GLP-1 RAs. Based on Phase 1 and Phase 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. 
Details of nonclinical and clinical information on efpeglenatide can be found in Section 5 Non-
Clinical Studies and Section 6 Effects in Humans, respectively, 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 EFC14829: 
 
Gastrointestinal (GI) disorders such as nausea/vomiting and rarely pancreatitis are the 
most common AEs of GLP-1 RAs. 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 EFC14829 will reduce intensity and frequency of 
GI events, such as nausea and vomiting. 
 
Increase in heart rate is a known side-effect of GLP-1 RAs. In study EFC14829, 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 EFC14829, participants 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). Patients with a recent or planned retinal treatment for retinopathy or 
maculopathy will be excluded from the current study. Diabetic retinopathy complications 
will be monitored throughout the study. 
 
Additional safety monitoring in study EFC14829 includes the collection of AEs, antidrug 
antibodies (ADA) (immunogenicity, [3, 4]) as well as safety laboratory tests 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) 


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elevation ≥3 × upper limit of normal (ULN) and most had confounding factors (2). In this 
study, patients with elevated liver enzymes >3 × 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. 
Efpeglenatide concentrations will also be sampled in study EFC14829. These sparse 
pharmacokinetic (PK) samples will be used for population PK analyses to determine the PK 
characteristics of efpeglenatide in the target T2DM population.   
The risks to the study participants will be minimized by careful participant selection according to 
appropriate inclusion and exclusion criteria based on existing nonclinical and clinical data. During 
the study, participants will be closely monitored at the regular visits, including physical 
examinations and laboratory tests to monitor the glucose-lowering effects and to early detect 
eventual adverse reactions. Suggested actions and follow-up measurements for laboratory 
abnormalities and other safety findings are provided in Appendix 5 (Section 10.5) of the protocol. 
All participants will receive active treatment which is expected to contribute to lower the plasma 
glucose. Participation in the study may also increase motivation and result in an improvement of 
glycemic control. The HbA1c and FPG tests will be performed approximately every 3 to 
4 months. Participants will be provided with a glucose meter and test strips to regularly 
self-measure their plasma glucose. Central laboratory alerts on FPG and on HbA1c (from 
Week 12 onwards) will be set up to ensure that glycemic parameters remain under predefined 
rescue thresholds. Close monitoring throughout the study will detect deterioration of glycemic 
control and allow initiation of “rescue therapy” as deemed necessary. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of efpeglenatide may be found in Section 2 Summary and Section 7 Summary of 
Data and Guidance for the Investigator, respectively, of the IB (2), and the according information 
related to dulaglutide may be found in the prescribing information for TRULICITY (5). 


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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
To demonstrate the noninferiority of once-weekly injection of 
efpeglenatide 4 or 6 mg in comparison to once-weekly injection 
of dulaglutide 1.5 mg on HbA1c change from baseline to 
Week 56 in participants with T2DM inadequately controlled with 
metformin 
 
Change from baseline to Week 56 in HbA1c 
Secondary 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 4 and 6 mg with once-weekly injection of 
dulaglutide 1.5 mg on glycemic control 
 
Change from baseline to Week 56 in fasting plasma 
glucose (FPG) 
 
Number of participants with HbA1c <7.0% at 
Week 56 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 4 and 6 mg with once-weekly injection of 
dulaglutide 1.5 mg on body weight 
 
Change from baseline to Week 56 in body weight 
To evaluate the safety of once-weekly injection of efpeglenatide 
4 and 6 mg and once-weekly injection of dulaglutide 1.5 mg 
 
 
Number of participants with at least 
one hypoglycemic event during treatment period 
 
Number of hypoglycemic events per participant-year 
during treatment period 
 
Number of participants with AEs (see Section 8.3) 
Tertiary/exploratory 
To evaluate the immunogenicity of once-weekly injection of 
efpeglenatide 4 and 6 mg 
 
Number of participants by ADA status 
(positive/negative) at scheduled visits 
 
Number of participants with treatment-induced ADAs 
(among the participants ADA negative or missing at 
baseline) during the study period 
 
Number of participants with treatment-boosted ADAs 
(among the participants with ADA positive at 
baseline) during the study period 
 
ADA titer at scheduled visits 
 
Number of participants by ADA cross-reactivity to 
endogenous GLP-1 at scheduled visits 
 
Number of participants by ADA cross-reactivity to 
endogenous glucagon at scheduled visits 
 
Number of participants with ADAs directed against 
PEG linker of efpeglenatide at scheduled visits 
To characterize the PK of efpeglenatide 
 
Serum concentration (Ctrough) of efpeglenatide at 
predose (Weeks 4, 12, 24, 30) 
 
Serum concentration of efpeglenatide at 
postadministration of efpeglenatide in participants 
who consent 


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Objectives 
Endpoints 
To characterize the effect of once-weekly injection of 
efpeglenatide 4 and 6 mg and once-weekly injection of 
dulaglutide 1.5 mg on participant perspective on the benefit/risk 
of the treatment and to compare the patient GI tolerability 
profile  
 
Participant perspective on benefit/risk of the drug 
using the PQATv2 at Week 30 and Week 56 
 
Evolution of GI symptoms from the participant 
perspective using 3 PROMIS GI Symptom scales 
version 1.0 (nausea and vomiting, diarrhea, and belly 
pain) at Day 1, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 18, 30, 
43, and 56 
To compare the effects of once-weekly injection of 
efpeglenatide 4 and 6 mg with once-weekly injection of 
dulaglutide 1.5 mg on additional measures of glycemic control 
 
Number of participants with HbA1c <7.0% at 
Week 30 
 
Change from baseline to Week 30 in HbA1c 
 
Change from baseline to Week 30 in FPG 
 
Change from baseline to Week 30 and Week 56 in 
mean 24-hour SMPG (7-point profile) 
 
Change from baseline to Week 30 and Week 56 in 
plasma glucose excursions (2-hours PPG minus 
preprandial plasma glucose at breakfast, lunch, and 
dinner) based on 7-point SMPG data 
 
Number of participants with rescue therapy used until 
Week 30 and Week 56 
 
Time to initiation of rescue therapy 
To compare the effect of once-weekly injection of efpeglenatide 
4 and 6 mg with once-weekly injection of dulaglutide 1.5 mg on 
body weight at different time points 
 
Change from baseline to Week 30 in body weight 
 
Number of participants with ≥5% change from 
baseline to Week 56 in body weight 
 
Number of participants with ≥10% change from 
baseline to Week 56 in body weight 
To compare the effect of once-weekly injection of efpeglenatide 
4 and 6 mg with once-weekly injection of dulaglutide 1.5 mg on 
waist circumference 
 
Change from baseline to Week 30 and Week 56 in 
waist circumference 
ADA: antidrug antibody, AE: adverse event, FPG: fasting plasma glucose, GI: gastrointestinal, GLP-1: glucagon-like peptide 1, HbA1c: 
hemoglobin A1c, PK: pharmacokinetics, PEG: polyethylene glycol, PPG: post prandial glucose, PQATv2: Patient’s Qualitative Assessment of 
Treatment version 2, PROMIS: patient-reported outcome measurement information system, SMPG: self-monitored plasma glucose, T2DM: 
type 2 diabetes mellitus 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The primary efficacy analysis will test non-inferiority of efpeglenatide compared to dulaglutide in 
terms of change of HbA1c from baseline to Week 56. The 56-week duration of study treatment is 
considered appropriate to demonstrate maintenance of efpeglenatide effect over at least 
12 months, as recommended by current guidelines (6).  
Hemoglobin A1c reflects the glycemic history of the previous 120 days and is thus an index of 
mean glycemia, documenting glycemic control over the past 2 to 3 months. Hemoglobin A1c has 
also been shown to correlate with the development of long-term complications of diabetes, and 
reduction of HbA1c is known to reduce the risk of long-term microvascular complications. 
Therefore, HbA1c is considered an appropriate primary endpoint for assessing the effect of 
a treatment on glycemic control. 


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Parameters defining main secondary efficacy endpoints, including percentage of participants who 
reach HbA1c targets, changes in FPG, and change in weight, are all assessments of glycemic or 
weight control that are recognized and accepted by regulatory agencies to support assessment on 
clinical relevance of the observed effect. 
As all biological proteins, efpeglenatide has the potential to be immunogenic. Therefore, 
immunogenicity will be assessed by evaluating anti-efpeglenatide antibody status 
(positive/negative) and titers, as well as cross-reactivity to endogenous glucagon and 
glucagon-like peptide 1 (GLP-1) at various time points throughout the study (also 4 and 6 months 
after last IMP dose for participants with treatment-induced or treatment-boosted anti-
efpeglenatide antibodies and who experienced severe hypersensitivity events on treatment). 
Safety will be evaluated by regular clinical monitoring of AEs and standard laboratory 
measurements, including safety parameters of special interest for GLP-1 RA class (eg, GI 
tolerability, amylase and lipase, calcitonin) and for the diabetic patients in general (hypoglycemia, 
liver and renal function, retinopathy complications, neoplasms, hypersensitivity reactions). 


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This study is a Phase 3, multicenter, 56-week, randomized, open-label for the drug (efpeglenatide, 
dulaglutide) and double-blind for the doses of efpeglenatide, active-controlled, 3-arm, parallel 
group study. 
Eligible participants will be randomized 1:1:1 ratio to receive 1 of 2 dose levels of efpeglenatide 
(4 or 6 mg) or dulaglutide (1.5 mg), to be administered SC once weekly. Randomization will be 
stratified by HbA1c (<8%, ≥8%) at screening and BMI (<30 kg/m2 and ≥30 kg/m2) at Visit 3 
(Day -1). Masked dose escalation over the course of 4 weeks will be used to reach the assigned 
4 and 6 mg efpeglenatide weekly doses. For efpeglenatide arms, the escalation will start from 
2 mg once weekly to the maximum of 4 or 6 mg once weekly, as assigned at randomization. 
Participants randomized to the dulaglutide 1.5 mg dose arm will initiate dosing at 0.75 mg once 
weekly and will increase after 2 weeks to 1.5 mg once weekly for the treatment duration.  
The study will be comprised of 3 periods as follows: 
 
An up to 3-week Screening Period (with a minimum 11 days) 
 
A 56-week open label, active controlled Treatment Period, for efficacy and safety 
assessments 
 
A 6-week post-treatment Follow-up Period to collect safety information after last dose of 
IMP (treatment completed or permanent treatment discontinuation) 
The maximum study duration per participant will be 65 weeks. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This study is designed to demonstrate the efficacy and safety of efpeglenatide in comparison to 
dulaglutide, in participants with T2DM inadequately controlled with metformin.  
Dulaglutide was chosen as the comparator as it is dosed once weekly (the same frequency as 
efpeglenatide), provides HbA1c lowering similar to liraglutide, weight reduction similar to 
exenatide, and has similar safety profile to exenatide and liraglutide (7). 
The study is also designed to assess and compare the tolerability and participant’s perspective on 
treatment benefit and risk.  
Bias will be minimized by randomizing the participants to treatment groups, blinding the 
participants and the Investigators to efpeglenatide dose allocations, and by adjudicating the 
selected AEs in a blinded fashion. 


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A parallel-group, randomized, active-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. 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 4 mg 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. The once-weekly 4 mg 
dose has shown clinically relevant efficacy (studies HM-EXC-202 and HM-EXC-203). 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. 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.  
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. The 2 mg dose demonstrated good GI tolerability has been selected as the starting dose of 
both, the 4 and 6 mg efpeglenatide treatment groups in this study. Based on the observed general 
decrease of GI event incidence after the first week of treatment with efpeglenatide, dose increases 
to achieve 4 and 6 mg (in the corresponding arm) will be in 2 mg step intervals every 2 weeks in 
order to minimize the GI adverse effects. The escalation step of 2 mg is small enough to 
contribute to improvement of GI tolerability at dose increase. With this dose escalation schedule, 
the dose of 4 mg once-weekly will be achieved 2 weeks and the maximal dose of 6 mg 
once-weekly will be achieved only 4 weeks after the first dose of efpeglenatide. 
Dulaglutide will be administered at 1.5 mg once weekly, as per approved label following an 
initiation to be started at 0.75 mg once weekly (5).  
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 stable dose of at least 1500 mg/day of metformin, or maximum tolerated 
dose, or as per country regulation if less, 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 which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this protocol 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. 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 02. 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 


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E 03. 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 04. Personal or family history of MTC or genetic conditions that predisposes to MTC 
(eg, multiple endocrine neoplasia syndromes)  
E 05. Body weight change of ≥5 kg within the last 3 months prior to screening 
E 06. Systolic BP >180 mmHg and/or diastolic BP >100 mmHg at randomization 
E 07. 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 08. Laboratory findings at the Screening Visit: 
- 
Alanine aminotransferase (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 09. Known presence of factors that interfere with the HbA1c measurement (eg, specific 
hemoglobin variants, hemolytic anemia) compromising the reliability of HbA1c 
assessment or medical conditions that affect interpretation of HbA1c results (eg, blood 
transfusion or severe blood loss in the last 3 months prior to randomization, any condition 
that shortens erythrocyte survival) 
E 10. Any clinically significant abnormality identified either in medical history or during 
screening evaluation (eg, physical examination, laboratory tests, 12-lead 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 11. Participants having received any antidiabetic drug other than metformin within 3 months 
prior to screening 
E 12. Participants having received any type of insulin for more than 30 consecutive days at any 
time (except for treatment of gestational diabetes) 
E 13. 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 14. Participant not at a stable anti-obesity treatment (if taken) at least 3 months prior to the 
screening and not willing to maintain the dose stable during the study  


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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/SAR439977 
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. Hypersensitivity to any of the study treatments, or components thereof, or to any GLP-1 
RAs  
E 20. History of drug or alcohol abuse within 6 months prior to screening 
E 21. Pregnant (confirmed by serum pregnancy test at screening) or breast-feeding women 
E 22. Women of childbearing potential (WOCBP) not willing to use highly effective method(s) 
of birth control (Appendix 4 [Section 10.4]) or who are unwilling to be tested for 
pregnancy during the study period and for at least 5 weeks after the last dose of study 
intervention 
E 23. 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 24. Any country-related specific regulation that would prevent the subject from entering the 
study  
E 25. 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 26. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol 
E 27. Participants who withdraw consent during the screening period (starting from signed ICF) 


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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 [8]). 
Fasting conditions 
 
For Visits 3 (Day 1), 6 (Week 8), 7 (Week 12), 10 (Week 30), 12 (Week 43), and 
14 (Week 56), participants need to come to the study center in a fasting condition after 
an overnight fast of no less than 8 hours which consists of no food or liquid intake, other 
than water. The participants should not take any antidiabetic medication before blood 
sampling. 
 
Fasting (before breakfast and before administration of antidiabetic medication) 
self-monitored plasma glucose (SMPG) must be performed per SoA (Section 1.3). 
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 intervention). A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once in cases where the original screen failure was due to reasons expected to change 
at rescreening (based upon the Investigator’s clinical judgment). A participant should not be 
randomized more than once (ie, entering the randomized period twice). 


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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
The IMP includes efpeglenatide in 3 doses (2, 4, and 6 mg; the 2 mg dose will be used for titration 
only) and dulaglutide in 2 doses (0.75 mg and 1.5 mg solution; the 0.75 mg dose will be used for 
titration only). 
Non-IMP (NIMP) includes metformin administered as per Investigator prescription and in 
accordance with local labeling, and 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. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
Study intervention 
name 
Efpeglenatide 
Dulaglutide (Trulicity™) 
Dosage formulation 
Sterile, non-pyrogenic, clear, colorless solution in a 
disposable single-dose autoinjector 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 single-dose pen in the 
formulation buffer (containing citric acid 
anhydrous, mannitol, polysorbate 80, 
trisodium citrate dehydrate in water for 
injection) 
Unit dose 
strength(s)/Dosage 
level(s) 
2 mg/500 μL, 4 mg/500 μL, and 6 mg/500 μL 
0.75 mg/0.5 mL and 1.5 mg/0.5 mL 
Route of administration 
SC injection 
SC injection 


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Dosing instructions 
The injection interval of the IMP is once weekly, preferably on the same week day 
(eg, each Monday) at any time of the day. Injections should be administered SC to any of the 
following body regions: abdomen, thigh, or upper arm. Within any selected region, the site of 
injection should be changed (rotated) at each time to prevent skin reactions. The region, date, and 
time of administration should be recorded for each injection administered. 
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 study 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, the participant should skip the 
missed dose and administer the next dose on the regularly scheduled day. In each case, 
participants can 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 (see Section 7.1.2.1). 
Participants will be asked to administer the last 2 consecutive weekly dose injections prior to PK 
sampling at the same body region (eg, at Week 2 and Week 3 before the planned PK visit at 
Week 4; see Section 8.5). 
Predose PK samples are expected to be collected at least 6 to 7 days after last dose of IMP. The 
corresponding study visits (Visit 5, Visit 7, Visit 9 and Visit 10) 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 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  
Dulaglutide 1.5 mg 
0.75 mg 
0.75 mg 
1.5 mg  
1.5 mg  
1.5 mg  
 
From Week 4 (Visit 5) through the rest of the treatment period, participants will remain on the 
randomized IMP dose until the EOT at Week 56 (Visit 14). 
Storage conditions 
Store between +2°C and +8°C (36°F and 46°F). Do not freeze, protect from light. 
Packaging and labeling 
Study treatment will be provided in 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 6.1.2.  
EOT: end of treatment, IMP: investigational medicinal product, PK: pharmacokinetics, 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 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 autoinjector by the study staff at Visit 2 (Day -7 
[±3 days]) and provided with an “instructions for use” leaflet, which will describe the handling 
procedures for the autoinjector and administration technique. Injection training pads can be used, 
if needed. Initial injection technique training at Visit 2 (Day -7 [±3 days]) will include 
self-injection with a training autoinjector and assessment of participant’s skills and understanding 
by observing teach-back (if needed). Also, if needed, an additional training autoinjector 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, under close supervision).  
Review of injection sites will be performed at all on-site visits. 
Autoinjector-related issues (malfunctions) should be reported to the Sponsor by the means of 
a procedure on Product Technical Complaint (PTC) forms, which are described in the Pharmacy 
Manual. 
In case of emergency only, for scheduled or unscheduled visits, the IMP might be supplied from 
the site to the participant via a Sponsor-approved courier company where allowed by local 
regulations. Direct-To-Patient (DTP) remains an option and the participant/investigator can refuse 
this option. 
6.1.2 Noninvestigational medicinal products  
6.1.2.1 Background medication  
Metformin 
 
Route of administration: Oral 
 
Dose regimen: Administered as per the Investigator’s prescription and in accordance with 
local labeling. Participants are enrolled with metformin at a stable dose (≥1500 mg/day, 
maximum tolerated dose, or as per country regulation if less) for at least 3 months prior to 
the Screening Visit. The dose should be kept stable throughout the study unless dose 
reduction is needed for safety reasons. 
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. 


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Table 3 - Rescue criteria  
Time in Study 
Threshold 
From randomization up through the scheduled Week 8 visit (Visit 6) 
FPG >15.0 mmol/L (>270 mg/dL) 
After the Week 8 visit (Visit 6) up through the scheduled Week 12 visit 
(Visit 7) 
FPG >13.3 mmol/L (>240 mg/dL) 
After the Week 12 visit (Visit 7) through the end of Week 30 visit (Visit 10) 
FPG >11.1 mmol/L (>200 mg/dL) or HbA1c ≥8.5% 
After the Week 30 visit (Visit 10) through the end of the treatment period 
(Week 56 [Visit 14]) 
FPG >10.1 mmol/L (>180 mg/dL) or HbA1c ≥8.0% 
FPG: fasting plasma glucose, HbA1c: hemoglobin A1c 
Routine fasting SMPG and central laboratory alerts on FPG (and HbA1c at Week 12 [Visit 7] 
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 [Visit 7] onwards) should be 
performed as soon as possible for confirmation. 
 
Upon receipt of a central laboratory alert for either FPG or HbA1c, a central laboratory 
re-test must be completed and confirmed as exceeding the threshold for rescue before 
rescue therapy is initiated. The re-test confirmation should be performed as soon as 
possible during an unscheduled visit.  
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 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: 
 
Assess FPG (ie, after the participant has fasted for ≥8 hours) 
 
Initiate an evaluation and treatment of intercurrent disease (to be reported in 
AE/concomitant medication parts of the electronic Case Report Form [eCRF] and the 
medical record) 


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 
Stress the absolute need for the participants to be compliant with treatment 
 
Organize a specific interview with the participants 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 and/or 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 and/or HbA1c to 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 pre-rescue assessments (which are the same as those specified for EOT; Week 56 
[Visit 14]), 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 standards of care and prescribing practice. With the 
exception of other GLP-1 RAs and 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, open-label 
Treatment Period should be continued (unless the Investigator considers a change necessary for 
safety reasons) and the efpeglenatide dose must remain blinded until the end of the study. 
All concomitant antidiabetic medications (background metformin 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 IMPs in 
a secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
Control of IMPs storage conditions, especially control of temperature (eg, refrigerated storage) 
and information on in-use stability and instructions for handling should be managed according to 
the rules provided by the Sponsor. 
The expiry date is mentioned on the IMPs labels (when required by country regulation), and 
storage conditions are written on the IMPs labels and in the instruction leaflet.  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
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, 


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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 
the Pharmacy Manual.  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMPs will be responsible for ensuring that the IMPs used in the clinical trial are 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 IMPs issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP/NIMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure 
(see Section 8.3.8). 
A potential defect in the quality of IMP/NIMP/device may be subject to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor, in order to recall the IMP/NIMP/device and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP/device to a third party (except for 
IMP in case of DTP shipment, for which a courier company has been approved by the Sponsor), 
allows 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 intervention 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 allocated to a randomized intervention 
regardless whether the intervention kit was used or not. A participant cannot be randomized more 
than once in the study. 
Previously allocated IMP should not be redispensed to the participants. 


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6.3.1 Methods of blinding  
The entire treatment period will be open-label for the drug (efpeglenatide, dulaglutide) and 
double-blind (for Investigators and participants) for the active doses (4 mg, 6 mg) of 
efpeglenatide. Efpeglenatide will be provided as a single-dose autoinjector and dulaglutide as 
a single-dose pen for self-injection. Each titration and treatment kit will be labeled with a unique 
number. The list of kit numbers will be generated by Sanofi. 
In accordance with the study design, Investigators will remain blinded for the doses of 
efpeglenatide and will not have access to the randomization (dose) 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 Baseline/Randomization visit (Day 1; Visit 3) as those data will be masked. If 
the central laboratory detects FPG above the rescue thresholds, the Investigator will receive 
an alert from the central laboratory (see Section 6.1.2.2). The HbA1c alerts will also be sent if 
a value is above threshold at the Week 12 visit (Visit 7) and onwards. 
6.3.2 Randomization code breaking during the study  
This section is applicable to those participants assigned to efpeglenatide arm.  
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 study dose assignment. The Sponsor must be notified before the 
blind is broken unless identification of the study treatment 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 condition (eg, antidote available). In this case, the Sponsor must 
be notified within 24 hours after breaking the blind. The date and reason that the blind was broken 
must be recorded in the source documentation and 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 detail to the Sponsor’s representative 
or to any staff members until database closure. Furthermore, when completing forms (eg, AE, 
SAE, adjudication information), the efpeglenatide dose 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],) and start analyzing the samples (verum group only) while the study is still 
ongoing. Only the independent Sponsor representative, Project Manager, and lead scientist at the 
Bioanalytical laboratory, as well as the population PK analyst, will have access to the 


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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 drug reaction unblinding by the 
Sponsor. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Measures taken to ensure and document treatment compliance and IMP accountability include the 
following: 
 
Proper recording of treatment kit number as required on appropriate eCRF page for 
accounting purposes 
 
All medication treatment kits (whether empty or unused) will be returned by the 
participant at each visit when a treatment dispensing is planned 
 
The Investigator or his/her delegate tracks treatment accountability/compliance comparing 
the treatment kit number recorded on the participant diary with the treatment kit number of 
returned treatment kits (whether empty or unused) and completes in the participant 
treatment log 
 
The monitor in charge of the study will then checks 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 IMPs 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 IMPs unless the Sponsor or delegate provides written 
authorization. For NIMP reimbursed by the Sponsor, tracking and reconciliation will be 
completed by the Investigator (or the pharmacist, if appropriate) as per local requirements. 
Destruction of IMP is strongly encouraged at site level, nevertheless, if the site is not able to 
destroy IMP or destruction of IMP is not allowed in the country, all treatment kits will be 
retrieved by the Sponsor. 


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At selected sites in US only, at least 120 used efpeglenatide autoinjectors that functioned normally 
(with no PTCs) will be returned to the Sponsor using a defined return process. 
Sharp containers containing all used autoinjectors that are not affected by a complaint or the 
specified return process will be brought back to the site by the study participants for the purpose 
of destruction. 
Separate instructions will be supplied to the site and participants, in accordance with local law as 
well as regulatory requirements.  
6.5 
CONCOMITANT THERAPY  
The following treatments are prohibited during the study (including during screening and the 
56 weeks of the treatment period): 
 
Initiation of any antidiabetic agents other than the IMP or change in dose or preexisting 
oral anti-diabetic(s) (OAD) 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, 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, ophthalmic, 
nasal spray, inhaled, or intra-articular applications are allowed) 
 
Any investigational drug other than IMP for this study 
Glucagon-like petide-1 receptor agonists are known to decelerate gastric emptying. The delay of 
gastric emptying may impact absorption of concomitantly administered oral medicinal products. 
As drug-drug interaction data are not yet available for efpeglenatide, caution should be exercised. 
Drug levels of oral medications with narrow therapeutic index should be adequately monitored. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 
Reason for use 
 
Dates of administration including start and end dates 
 
Dosage information including dose and frequency 


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6.6 
DOSE MODIFICATION  
Up-titration of IMP from randomization to Week 4 is described in Table 2. From Week 4 (Visit 2) 
throughout the rest of the treatment period (open-label for the study treatment and double-blind 
for the doses of efpeglenatide), participants will remain on the randomized IMP (efpeglenatide 
assigned dose or dulaglutide) until the EOT at Week 56 (Visit 14).  
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, to preserve the scientific integrity of the study, participants 
who discontinue IMP should be asked to remain in the study as long as possible and at minimum 
should be evaluated at Week 56 (Visit 14) and undergo the scheduled end of study efficacy and 
safety assessments.  
7.1.1 Permanent discontinuation  
Permanent intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP whatever the reason.  
The participants may withdraw from treatment with IMP if they decide to do so, at any time and 
irrespective of the reason. Participants should discuss stopping study treatment 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 condition that requires discontinuation of IMP: eg, laboratory abnormalities 
(see decision tree and general guidance for the follow up of laboratory abnormalities in 
Appendix 5 [Section 10.5.1]), diagnosis of acute pancreatitis confirmed by 
gastroenterologic evaluation and imaging, unless a clear cause unrelated to IMP is 
confirmed and the participant has recovered from pancreatitis (see Appendix 5 
[Section 10.5.2]), or calcitonin value ≥50 pg/mL (see Appendix 5 [Section 10.5.3]). 
 
If, in the Investigator’s opinion, continuation with the administration of IMP would be 
detrimental to the participant’s well-being  
 
Pregnancy (in female participants) 
 
Confirmed intolerance to the allocated dose of IMP 
 
Any code breaking requested by the Investigator (applicable to efpeglenatide arms only) 
 
At the specific request of the Sponsor 


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As all randomized participants, under treatment or not, will be included in the study data analyses, 
it is important to collect efficacy and safety data from all participants, during the entire 56 weeks 
of the study. A high rate of missing data could jeopardize robustness of efficacy and safety 
findings and should be avoided. Refer to the SoA (Section 1.3) for data to be collected at the time 
of intervention discontinuation and follow-up and for any further evaluations that need to be 
completed. 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation (as soon as possible, preferably in 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 who discontinue IMP will be assessed using the procedure normally 
planned for the EOT Visit including a PK sample if the visit can be scheduled 7 days after the 
permanent discontinuation of intervention.  
For participants who discontinue IMP and attend an earlier EOT Visit, but who remain in the 
study until Week 56, the remaining visits should occur as scheduled, where possible, until 
Week 56 (Visit 14), and all procedures should be performed with the exception of the assessment 
of ADA. The Investigators should discuss with them 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 treatment. 
The value of all their study data collected during their continued involvement will be emphasized 
as important to the public health value of the study.  
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All cases of permanent study intervention discontinuation must be recorded by the Investigator in 
the appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary intervention discontinuation corresponds to at least 1 dose not administered to the 
participants. 
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol (see Section 7.1), and the Investigator should make 
best effort to resume IMP treatment as early as practically possible. There is no defined limit to 
the duration of temporary discontinuation. 


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Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs (including intolerance to the IMP planned dose). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF. 
7.1.2.1 Re-challenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that it is safe for the participant to re-start the IMP. In case of IMP intolerance, 
a one-time re-challenge is recommended following temporary discontinuation before deciding to 
permanently discontinue the IMP. 
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. 
Efpeglenatide 
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 re-initiated 
(Table 2). 
Dulaglutide 
If only 1 dose is missing, the IMP can be resumed at the last dose given. If 2 or more consecutive 
doses are missed, the IMP can be restarted at the Investigator’s discretion with either the previous 
dose or with the titration re-initiated (Table 2). 
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. 


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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 participant’s medical record, at least the date 
of the withdrawal and the reason should be documented. 
Participants who have withdrawn from the study cannot be re-randomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
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/contract research 
organization (CRO) immediately upon occurrence or awareness to determine if the 
participant should continue or discontinue study intervention. 
 
Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
 
All screening evaluations must be completed and reviewed prior to randomization to 
confirm that potential participants meet all eligibility criteria. The Investigator will 
maintain a screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  
8.1 
EFFICACY ASSESSMENTS   
8.1.1 Hemoglobin A1c  
The primary efficacy endpoint and 2 secondary efficacy endpoints are assessed by measurement 
of HbA1c. For the eligibility and efficacy assessments of the study, HbA1c is measured at 
different time points during study, by a certified level I “National Glycohemoglobin 
Standardization Program” central laboratory (Section 1.3).  
If a participant needs to receive rescue therapy (see Section 6.1.2.2), 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 re-test 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 determination of change from baseline to Weeks 30 
and 56 in body weight. 
Body weight is measured according to the schedule detailed in the SoA (Section 1.3), with the 
participant wearing only undergarments or very light clothing and no shoes, and with an empty 
bladder. 


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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 Waist circumference  
Waist circumference will be measured at the midpoint between the lower rib margin and the iliac 
crest in centimeters (cm) according to the schedule detailed in SoA (Section 1.3). 
The calibrated metric tape will be held firmly in a horizontal position and will be placed around 
the waist. It is recommended that the observer sits beside the participant while taking the 
measurements. 
The tape should be loose enough to allow the recorder to place 1 finger between the tape and the 
participant’s body. 
Participants will be asked to breathe normally and the measure is taken at the end of a normal 
exhalation, while ensuring that the participant does not contract the abdominal muscles. 
8.1.5 7-point self-monitored plasma glucose profiles  
The 7-point SMPG profile will be performed over a single 24-hour period prior to administration 
of antidiabetic medication, 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. Participant 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 done, the fasting prebreakfast SMPG profile will be 
considered as the first point of measurement, ie, “prebreakfast” time point. 
8.1.6 Use of rescue therapy  
The use of rescue medications for hyperglycemia will be assessed and reported throughout the 
treatment period to allow determination of the start of rescue therapy and the percentage of 
participants using rescue therapy at Weeks 30 and 56. Routine fasting SMPG profiles will be 
measured by the participants, and alerts on FPG and/or HbA1c from the central laboratory will be 


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sent 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 greater than the 
predefined thresholds, refer to Section 6.1.2.2. 
8.1.7 Patient qualitative assessment of treatment  
The Patient Qualitative Assessment of Treatment version 2 (PQATv2; see Appendix 8 
[Section 10.8]) is intended for the collection of participant-perceived benefit/risk balance of 
glucose-lowering treatment with IMP. 
This patient qualitative assessment includes 6 items (3 of them being open-ended questions) and 
its completion is expected to take approximately 10 to 20 minutes. The participants will be asked 
to complete the PQATv2 electronically from home just before the on-site visits planned at 
Weeks 30 and 56. Participants will be asked to complete the assessment by themselves without 
any help from friends or relatives. The use of the PQATv2 will be limited to participants in 
countries where the PQATv2 available in the local language. See SoA, Section 1.3. 
Participant responses to open-ended questions may contain information about their treatment 
reaction, which may potentially be an SAE/adverse event of special interest (AESI). The 
participant responses should be reviewed by a person not delivering the patient’s care. If any text 
identified at the time of reading the answer may be indicative of a potential SAE or AESI, this 
should be reported by the reviewers to the Investigator for assessment and follow-up, as needed, 
with the participant. If the Investigator confirms the occurrence of the SAE/AESI, the event will 
be reported in the CRF if not already reported.  
In case of early IMP discontinuation, the participant will be asked to complete the PQATv2 at the 
time of discontinuation. Even if he/she remains in the study, the participant will not need to 
complete it again at the following scheduled visits: Week 30 and/or Week 56. 
8.2 
SAFETY ASSESSMENTS   
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. 


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8.2.2 Vital signs  
 
Blood pressure measurements will be assessed while participant in a seated position using 
the same device (automated BP monitor or a manual sphygmomanometer) for 
each participant.  
 
Heart rate will be measured at the time of the seated BP measurement from a pulse point 
(as per current practice). 
 
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). 
8.2.3 Electrocardiograms  
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 printout, and record it in the eCRF. Each ECG trace must be analyzed in 
comparison with the baseline 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 
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 
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 decisions for response 
evaluation or for diagnosis/follow-up an AE, then the results must be recorded in the 
eCRF.  
Recommended decision trees for the management of certain laboratory abnormalities are provided 
in Appendix 5 (Section 10.5). 
8.2.5 Hypoglycemia  
During the study, participants must be instructed to document any hypoglycemic episodes in their 
study diary. Hypoglycemia will be reported on the specific hypoglycemia event information form 
of the eCRF with onset date and time, symptoms and/or signs, the SMPG value if available, and 
treatment. Hypoglycemia fulfilling the seriousness criteria must be documented in addition on the 
SAE form in the eCRF. 
Hypoglycemic events will be categorized (6, 9, 10) as follows (also see Appendix 7 
[Section 10.7]): 
 
Severe hypoglycemia: Severe hypoglycemia is an event that requires the assistance of 
another person to actively administer carbohydrate, glucagon, or other resuscitative 
actions. These episodes may be associated with sufficient neuroglycopenia to induce 
seizure, unconsciousness or coma. Plasma glucose measurements may not be available 
during such an event, but neurological recovery attributable to the restoration of plasma 
glucose to normal is considered sufficient evidence that the event was induced by a low 
plasma glucose concentration. The definition of severe symptomatic hypoglycemia 
includes all episodes in which neurological impairment was severe enough to prevent 
self-treatment and which were thus thought to place participants at risk for injury to 
themselves or others. Note that “requiring assistance of another person” means that the 
participant could not help himself or herself. Assisting a participant out of kindness, when 
assistance is not required, should not be considered a “requiring assistance” incident. 
Severe hypoglycemia will qualify as an SAE only if it fulfills SAE criteria 
(see Appendix 3 [Section 10.3]). For example, events of seizure, unconsciousness or coma 
must be reported as SAEs. 
 
Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia is 
an event during which typical symptoms of hypoglycemia are accompanied by a measured 
plasma glucose concentration ≤3.9 mmol/L (≤70 mg/dL). Clinical symptoms that are 
considered to result from a hypoglycemic episode are, eg, increased sweating, 


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nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
 
Asymptomatic hypoglycemia: Asymptomatic hypoglycemia is an event not accompanied 
by typical symptoms of hypoglycemia but with a measured plasma glucose concentration 
≤3.9 mmol/L (≤70 mg/dL).  
 
Probable symptomatic hypoglycemia: Probable symptomatic hypoglycemia is an event 
during which symptoms of hypoglycemia are not accompanied by a plasma glucose 
determination, but was presumably caused by a plasma glucose concentration 
≤3.9 mmol/L (≤70 mg/dL); symptoms are treated with oral carbohydrate.  
 
Relative hypoglycemia: (recently termed “pseudo-hypoglycemia”) is an event during 
which the person with diabetes reports any of the typical symptoms of hypoglycemia, and 
interprets the symptoms as indicative of hypoglycemia, but with a measured plasma 
glucose concentration greater than 3.9 mmol/L (70 mg/dL). 
In addition to the threshold of plasma glucose of ≤3.9 mmol/L (70 mg/dL), documented 
hypoglycemia with a measured plasma glucose concentration between 3.0 to 3.9 mmol/L (54 to 
70 mg/dL) and less than 3.0 mmol/L (<54 mg/dL) will also be analyzed (6). 
Hypoglycemic events will be evaluated regardless of the time of onset during the study and time 
of the day. 
In addition, hypoglycemia events will be evaluated at the following time periods defined by time 
of the day: 
 
Nocturnal hypoglycemia defined by time of the day: any hypoglycemia of the above 
categories that occurs between 00:00 and 05:59, regardless of whether 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 
8.2.6 Patient-reported outcomes measurement information system gastrointestinal 
symptom scales  
Eight Patient-Reported Outcome Measurement Information System (PROMIS) GI symptom 
scales have been developed and validated to capture the breadth and depth of GI symptoms 
experienced by people with a wide range of digestive disorders (11). In this study, only nausea 
and vomiting (4 items), diarrhea (6 items), and belly pain (5 items) symptom scales will be 
collected (see Appendix 10 [Section 10.9]). In order to have a comprehensive evaluation of the 
evolution of these GI symptoms, participants will be asked to complete these 3 scales 
electronically, at the time points indicated in the SoA (Section 1.3).  
Participants can complete the PROMIS GI symptom scales from home, by themselves without 
any help from friends or relatives, or at the site at the start of the visit before any other procedures 
or tests, in a quiet place and independently from the Investigator or other site staff. 


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As with any patient-reported outcome (PRO) questionnaire, the PROMIS GI symptom scale 
captures the patient’s perspective related to GI tolerability and its impact on day-to-day activities. 
PROMIS GI symptom scale is complementary to the safety evaluation made by Investigators and 
reported in the eCRF. As a result, participants’ responses will not be reviewed by Investigators 
and will not need reconciliation with safety events reported in the eCRF. In case of early IMP 
discontinuation, the PROMIS GI symptom scales will be completed by the participant at the time 
of discontinuation and afterwards as normally planned.  
The use of the PROMIS GI symptom scales will be limited to participants in countries where the 
scales are available in local language. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An 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, 2 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 must 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). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention and/or study (see Section 7).  


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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 specific 
eCRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria). 
The AE requiring specific monitoring for this study are:  
 
Severe GI events 
 
Severe hypoglycemia (see Section 8.2.5) 
 
Pancreatic events (including abnormal values of pancreatic enzymes (see Appendix 5 
[Section 10.5.2]) - will be adjudicated by CEC 
 
Major adverse cardiovascular events (MACE, CV death, MI, or stroke) and other specific 
CV events (eg, heart failure leading to hospitalization) - will be adjudicated by CEC 
 
Calcitonin increase ≥5.9 pmol/L (≥20 pg/mL) and thyroid C-cell neoplasm (see 
Appendix 5 [Section 10.5.3]) 
 
Acute renal failure (see Appendix 5 [Section 10.5.1] for definition) 
 
Diabetic retinopathy complications; 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). 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available.  
Investigators are not obligated to actively seek 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 intervention 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 Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file the report along with IB and will notify the IRB/IEC, if appropriate according 
to local requirements. 
8.3.5 Pregnancy  
 
Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the Follow-up Visit 
(Visit 15). 
 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 


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 
In the event of pregnancy in a female participant, IMP should be discontinued. 
 
A pregnancy will be qualified as an SAE only if it fulfills 1 of the seriousness criteria (see 
Appendix 3 [Section 10.3]). 
 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Cardiovascular and death events  
For CV events, see details of AEs requiring specific monitoring above (Section 8.3). 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.8 Guidelines for reporting product complaints/medical device incidents (including 
malfunctions)  
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within 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. 
8.5 
PHARMACOKINETICS  
 
Blood samples for measurement of serum concentrations of efpeglenatide should only be 
collected and analyzed for participants in efpeglenatide arms. 


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 
Participants will be asked to administer the last 2 consecutive weekly dose injections prior 
to PK sampling at the same injection region (eg, at Week 2 and Week 3 before the planned 
PK visit at Week 4).  
 
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 date, time, and body region 
(abdomen, thigh, or arm) of drug administration. Samples not collected, missed, or lost, 
for any reason should be recorded. 
 
For participants who consent to postdose PK sampling, at least 1 additional postdose 
sample will be taken 3 days (±1 day) after administration of efpeglenatide, preferably 
between Week 8 and Week 12, but other weeks are also acceptable (eg, after the 1st dose, 
4th dose, or 12th dose). Ideally a minimum of 180 evaluable postdose samples (including 
the samples already collected at 4 days [±1 day] window as required in the initial protocol) 
from efpeglenatide treated participants are required to ensure a meaningful PK analysis. It 
is anticipated to collect as many samples as possible while considering the participant’s 
agreement to the optional sampling. 
 
The collected blood samples will be used to determine concentrations of efpeglenatide in 
serum and these concentration data will be summarized and reported in the CSR.  
 
The concentrations will be used to perform a population PK (popPK) analysis by 
non-linear mixed effects modeling and the results will be reported in a 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 to be collected to assess the efpeglenatide ADA status (positive or negative) 
and level (titer) for the participants assigned to efpeglenatide. 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 EOS, and who experienced severe injection site or 
hypersensitivity reaction at any time during the study, will be asked to provide samples for 
anti-efpeglenatide antibodies assessments 4 and 6 months after the end of the treatment. 
8.9 
HEALTH ECONOMICS  
Not applicable. 


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9 
STATISTICAL CONSIDERATIONS   
9.1 
STATISTICAL HYPOTHESES  
For the primary efficacy endpoint of change from baseline to Week 56 in HbA1c, the following 
null and alternative hypotheses will be tested: 
H0: efpeglenatide - dulaglutide ≥0.3% 
H1: efpeglenatide - dulaglutide <0.3% 
The null hypothesis will be tested at a 1-sided alpha level of 0.025 using a non-inferiority margin 
of 0.3%. 
9.2 
SAMPLE SIZE DETERMINATION   
The sample size and power calculations were performed based on the primary variable, change 
from baseline to Week 56 in HbA1c (%).  
Assuming a common standard deviation of 1.1%, and the true difference between efpeglenatide 
and dulaglutide is zero, 300 participants per arm will ensure that the UB of the 2-sided 95% CI of 
the adjusted mean difference would not exceed 0.3% with 91% power. 
Hence, there are 3 parallel dosing arms as follows: 
 
Efpeglenatide 4 mg, N = 300 
 
Efpeglenatide 6 mg, N = 300 
 
Dulaglutide 1.5 mg, N = 300 
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 randomized participants irrespective of rescue therapy use and compliance with 
the study protocol and procedures. Participants will be analyzed in the treatment 
group to which they are randomized. 


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Population 
Description 
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: antidrug antibody, ICF: informed consent form, IMP: investigational medicinal product, IRT: interactive response technology, ITT: intent to 
treat, PK: pharmacokinetic. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) 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 56 in HbA1c 
Analysis of the primary efficacy endpoint (change from baseline to Week 56 in HbA1c) will be performed 
using the ITT population, using HbA1c measurements obtained during the study, including those obtained 
after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from baseline to Week 56 will be analyzed with missing 
values imputed by BOCF-like MI method for both efpeglenatide and dulaglutide groups, under the MNAR 
frame work: 
 
For participants with missing HbA1c values at Week 56, the missing values will be imputed using 
a random draw from a normal distribution with mean equal to their baseline HbA1c and the 
standard deviation equal to the pooled standard deviation calculated from the square root of the 
mean square error estimated from a regression model with baseline HbA1c as the dependent 
variable and randomization strata and treatment as the covariates. 
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data sets with 
complete data. Each of the complete datasets after the imputation will be analyzed by the ANCOVA model 
with the treatment groups (efpeglenatide 4 or 6 mg, dulaglutide 1.5 mg), randomization stratum of screening 
HbA1c (<8%, ≥8%), Visit 3 (Day 1) BMI (<30 kg/m2 and ≥30 kg/m2), and geographical region as fixed 
effects, and baseline HbA1c value as a covariate.  
The baseline value is defined as the last available value prior to the first dose administration of IMP or the 
last available value on or before the date of randomization if not treated with the open-label IMP. 
Results from each complete dataset will be combined to provide the adjusted mean change in HbA1c from 
baseline to Week 56 (regardless of treatment discontinuation or initiation of rescue therapy) for each 
treatment group, as well as the between-group difference (comparing each efpeglenatide group versus 
dulaglutide group) and the 95% CI for the difference. If the UB of the 2-sided 95% CI for the adjusted mean 
difference (efpeglenatide versus dulaglutide) in HbA1c change from baseline to Week 56 is ≤0.3%, the 
non-inferiority will be declared.  
If noninferiority is demonstrated on the primary endpoint for both efpeglenatide groups, ie, the UB of the 
2-sided 95% CI ≤0.3%, the superiority of each efpeglenatide group versus dulaglutide for the primary 


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endpoint will be tested in a hierarchical fashion, with efpeglenatide 6 mg tested first and then efpeglenatide 
4 mg.  
Summary statistics (for screening value, baseline value, observed values, and observed changes from 
baseline) at scheduled visits will be provided for each treatment group. The summary will include the 
number of observations, mean, SD, SE, minimum, median, and maximum. Graphical presentations will also 
be used to examine trends over time using mean values (±SE) and mean changes from baseline (±SE) at 
each of the scheduled visits (using OC). 
Sensitivity analysis: 
Tipping point analysis based on the same MI method as described 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 (4 or 6 mg) who have no HbA1c data at Week 56. The penalty will be gradually 
increased to evaluate at which level the conclusion of the analyses in terms of non-inferiority 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 56 creates a shift in the treatment effect of 
efpeglenatide from the demonstration of non-inferiority to the failure of non-inferiority. Least square mean 
difference between each efpeglenatide dose and dulaglutide will be provided for each penalty level. 
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 as follows: 
 
Pattern 1: participants without baseline values, if any 
 
Pattern 2: participants with baseline values but without postbaseline value during the 56-week 
Core Treatment Period 
 
Pattern 3: participants with baseline values and at least 1 postbaseline value during the 56-week 
Core Treatment Period but not at Week 56, 
 
Pattern 4: participants with baseline values and Week 56 values during the 56-week Treatment 
Period 
The 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) 
 
Baseline HbA1c (<8.0%, ≥8.0%) 
 
Baseline BMI (<25 kg/m2, 25-30 kg/m2, ≥30 kg/m²) 
 
Diabetes duration (<10 years; ≥10 years) 
 
Country 
 
United States/non-United States 
 
Baseline estimated GFR categories (mL/min/1.73m²): (<30; [30-60]; ≥60) 
The treatment effects (efpeglenatide 4 or 6 mg, dulaglutide 1.5 mg) across the subgroups defined for each 
of these factors will be estimated for the change from baseline to Week 56 in HbA1c in the ITT population, 
and using a similar approach (ie, BOCF-like MI method under MNAR framework) as applied to the analysis 


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for the primary efficacy endpoint. The ANCOVA model will include treatment groups (efpeglenatide  4, or 
6 mg, dulaglutide) and randomization stratum of Screening HbA1c (<8%, ≥8%), randomization stratum of 
Visit 3 (Day 1) BMI (<30 kg/m2, ≥30 kg/m2), subgroup factor, treatment-by-subgroup factor, and region as 
fixed factors and using the baseline HbA1c value as a covariate. The adjusted estimates of treatment mean 
differences (each efpeglenatide dose versus dulaglutide) with SE and 95% CIs will be provided as 
appropriate across the subgroups. A graphical presentation of the results (ie, forest plot) will also be 
provided. 
In the case that the subgroup factor is identical or similar to a randomization strata factor (eg, baseline 
HbA1c, baseline BMI), only the subgroup factor (as a single factor or an interaction term) will be included in 
the model in order to avoid the issue of collinearity in the analysis. The corresponding strata factor will not 
be included in the model. In case that the subgroup factor is country, the region will not be included in the 
model.  
Secondary  
Change from 
baseline to 
Week 56 in: FPG 
and body weight 
Number of 
participants with 
HbA1c <7.0% at 
Week 56 
The continuous secondary efficacy endpoints of change in FPG and body weight from baseline at Week 56 
will be analyzed using the same ANCOVA model with missing values imputed by MI analysis method as the 
method used for the primary efficacy endpoint analysis. Differences between treatment groups and CIs will 
be estimated by this method. 
The categorical efficacy endpoint of HbA1c <7.0% at Week 56 (yes/no) will be analyzed by the 
Cochran-Mantel-Haenszel method stratified by the randomization strata. The proportion in each treatment 
group will be provided, as well as the differences of proportions between groups (each efpeglenatide dose 
versus dulaglutide) with associated 2-sided 95% CI. For the categorical secondary endpoint in which HbA1c 
is assessed at Week 56, all values at Week 56 will be used to determine whether a participant is 
a responder or not, even if they are measured after IMP discontinuation or introduction of rescue therapy. If 
no assessment is available at Week 56 at all, participants will be treated as non-responders in the ITT 
population. 
Multiplicity 
considerations 
After MI for the primary endpoint of change in HbA1c from baseline to Week 56 was established for both 
efpeglenatide 4 and 6 mg, the secondary endpoints will be tested in the prioritized order as follows: 
1. 
Change from baseline to Week 56 in HbA1c for efpeglenatide 6 mg versus dulaglutide 
(Superiority)   
2. 
Change from baseline to Week 56 in body weight for efpeglenatide 6 mg versus dulaglutide 
(Superiority) 
3. 
HbA1c <7% at Week 56 for efpeglenatide 6 mg versus dulaglutide (yes/no) (Superiority) 
4. 
Change from baseline to Week 56 in body weight for efpeglenatide 4 mg versus dulaglutide 
(Superiority)  
5. 
Change from baseline to Week 56 in HbA1c for efpeglenatide 4 mg versus dulaglutide 
(Superiority) 
6. 
HbA1c <7% at Week 56 for efpeglenatide 4 mg versus dulaglutide (yes/no) (Superiority) 
7. 
Change from baseline to Week 56 in FPG or efpeglenatide 6 mg versus dulaglutide (Superiority) 
8. 
Change from baseline to Week 56 in FPG or efpeglenatide 4 mg versus dulaglutide (Superiority) 
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 dulaglutide than those mentioned earlier in 
this section. 


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Tertiary/ 
Exploratory  
(refer Section 3) 
The analysis of the exploratory endpoints will be descriptive with no formal testing, unless otherwise 
specified. Summary statistics at scheduled visits using OC will be provided by each treatment group. 
For the continuous exploratory endpoints, descriptive summary statistics will be provided, including the 
number of observations, mean, SD, SE, minimum, median, and maximum. Graphical presentations will also 
be provided as appropriate. 
For the categorical exploratory endpoints, the summary will include the count and percentage for each 
treatment group. 
The time to initiation of rescue therapy will be analyzed using the Cox proportional hazards regression 
model with the treatment groups (efpeglenatide 4 or 6 mg, dulaglutide 1.5 mg), randomization stratum of 
screening HbA1c (<8%, ≥8%), Visit 3 (Day 1) BMI (<30 kg/m2 and ≥30 kg/m2), and geographical region as 
the factors. 
Details of the analyses for exploratory endpoints will be described in the SAP finalized before database 
lock. 
ANCOVA: analysis of covariance, BMI: body mass index, BOCF: baseline observation carried forward, CI: confidence interval, FPG: fasting 
plasma glucose, HbA1c: hemoglobin A1c, IMP: investigational medicinal product, ITT: intent to treat, MI: multiple imputation, MNAR: missing not 
at random, OC: observed cases, SAP: statistical analysis plan, SD: standard deviation, SE: standard error, UB: upper bound. 
9.4.2 Safety analyses  
All safety analyses will be performed on the safety population.  
The observation period of safety data is divided into 3 main segments as follows: 
 
The pretreatment period is defined as the time from informed consent up to the time of the 
first injection of IMP. 
 
The whole on-treatment period is defined as the time from the first injection of IMP up to 
30 days (7 days for hypoglycemia) after the last injection of IMP. 
 
The post-treatment period is defined as the time starting 31 days (8 days for 
hypoglycemia) after the last injection of IMP (after the whole on-treatment period). 
The AE observations will be classified per the observation periods of safety data as defined above 
into the following: 
 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
 
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became 
serious during the on-treatment period. 
 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
In addition, the on-study period is defined from the 1st injection of IMP up to the last study visit 
of the participants or the date of last available information if participants discontinued the study 
prematurely. 


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Table 6 - Safety analyses  
Endpoint 
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 used by the Sponsor at the time of database lock. 
Adverse event incidence table 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. 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all TEAEs, 
all treatment-emergent SAEs, all TEAEs leading to permanent treatment discontinuation, and all 
TEAEs leading to death. 
The AE, SAE, and AE leading discontinuation table will also be presented for the on-study period. 
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 and laboratory 
data 
ECG  
For quantitative safety parameters based on central laboratory/reading measurements, descriptive 
statistics will be used to summarize results and change from baseline values by visit and treatment 
group.  
The incidence of 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. 
AE: adverse event, ECG: electrocardiogram, HLGT: high-level grouped term, HLT: high-level term, LLT: lowest-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 time point will be summarized by visit using descriptive statistics 
by number (n), median, quartiles, minimum, and maximum 
 
Number and percentage of participants by ADA cross-reactivity to endogenous GLP-1 
(positive or 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 in the PK population, using descriptive statistics by n, 
geometric mean, coefficient of variation, median, minimum and maximum.  
PRO endpoints  
(refer Section 3) 
The analysis of PRO endpoints (PQATv2 and 3 PROMIS GI symptoms scales v1) will be 
descriptive with no formal testing, and conducted on the ITT population. Summary statistics at 
scheduled visits will be provided by treatment group. Graphical presentation will also be used to 
illustrate trends over time as appropriate. 
All participants’ answers to open-ended questions of the PQATv2 will be analyzed qualitatively 
and quantitatively, as relevant, using appropriate data analysis software. The analysis method for 
this exploratory analysis will be provided in a separate SAP and results will be documented in a 
separate report. 
ADA: anti-drug antibody, GI: gastrointestinal, GLP-1: glucagon-like peptide 1, PK: pharmacokinetic, PEG: polyethylene glycol, PQATv2: Patient 
Qualitative Assessment of Treatment version 2, PRO: patient-reported outcome, PROMIS: patient-reported outcome measurement information 
system, SAP: statistical analysis plan. 
 
9.5 
INTERIM ANALYSES   
Not applicable. 
9.5.1 Data monitoring committee  
See Appendix 1 (Section 10.1) for details. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
 
This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
- 
Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
 
The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European Regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
10.1.2  Informed consent process  
 
The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  
 
Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  


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 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 
Participants must be 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 sub-study.  
 
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. 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.  
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; 
ethnicity: Hispanic, not Hispanic) will be collected in this study because these data are 
required by several regulatory authorities (eg, on African American population for US 
FDA).  
 
The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). 
They may be further processed if they have been anonymized. 


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10.1.4 Committees structure  
10.1.4.1 Data monitoring committee  
An independent DMC with members who are independent from the Sponsor and the Investigators 
will meet on a regular basis and will be responsible for 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 cardiovascular events (nonfatal MI, stroke, 
unstable angina leading to hospitalization, and heart failure leading to hospitalization), pancreatic 
events, and other selected AEs (to be defined in the CEC Charter). This review will be conducted 
in a blinded manner with regard to IMP. 
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, EU clinical trial register (eruct), and sanofi.com, as well as 
some national registries. 
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 continues 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. 


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10.1.6 Data quality assurance  
 
All participant data relating to the study will be recorded on printed or electronic case 
report form (CRF) unless transmitted to the Sponsor or designee electronically 
(eg, laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the Sponsor. No 
records may be transferred to another location or party without written notification to the 
Sponsor.  
10.1.7 Source documents  
 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 
The definition of what constitutes source data can be found in the GCP training module. 
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. 


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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 locally 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 make a study treatment decision or response evaluation or to diagnose 
and/or follow-up an AE, the results must be entered into the eCRF.  
Table 8 - Protocol-required safety laboratory assessments  
Laboratory 
assessments 
Parameters 
Hematology 
Platelet count 
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 


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Laboratory 
assessments 
Parameters 
Clinical chemistrya 
Creatinine 
Potassium 
AST 
Total bilirubin (in case of values 
above the normal range, 
differentiation in conjugated and 
nonconjugated bilirubin) 
 
Sodium 
Alkaline phosphatase  
 ALT 
eGFR (MDRD formula) 
 
Amylase 
Lipase 
 
 
Routine urinalysis 
pH, glucose, protein, blood/hemoglobin, ketones, leukocyte, by dipstick 
Lipid profile 
Triglycerides 
Cholesterol: 
Total cholesterol 
Low-density lipoprotein cholesterol 
High-density lipoprotein cholesterol 
Anti-drug antibodies 
Serum antidrug antibody 
Calcitonin 
Calcitonin  
Other screening tests 
 
FSH and estradiol (as needed in unconfirmed postmenopausal women) 
 
NOTE: For women not of childbearing potential (Appendix 4 [Section 10.4]), FSH 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 WOCBP)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. 
ALT: alanine aminotransferase, AST: aspartate aminotransferase, β-HCG: beta-human chorionic gonadotropin, eGFR: estimated glomerular 
filtration rate, FSH: follicle-stimulating hormone, MDRD: Modification of Diet in Renal Disease, RBC: red blood cell, 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. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 


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 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
Events NOT meeting the AE definition 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 
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). 


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An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
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. 


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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 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 
the Sponsor representative. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor representative. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 
The Investigator will submit any initial SAE/AESI data to the Sponsor representative 
within 24 hours of its acknowledgement 
Assessment of intensity 
The Investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
 
The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 
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. 


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 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 
The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor representative. However, it is 
very important that the Investigator always assess the causality of 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 post 
mortem findings including histopathology.  
 
New or updated information will be recorded in the originally completed eCRF. 
 
The Investigator will submit any updated SAE/AESI data to the Sponsor representative 
within 24 hours of receipt of the information. 
REPORTING OF SAEs and AESIs 
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. 


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 
If a site receives a report of a new SAE/AESI from a study participant or receives updated 
data on a previously reported SAE/AESI after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE/AESI form or to 
the Sponsor representative by telephone. 
 
Contacts for SAE/AESI reporting can be found in the site file (detailed Study Contact 
List). 
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 one of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone 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 highly effective nonestrogen hormonal 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. 


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In addition, WOCBP must refrain from donating ova for the duration of the study and at least 
5 weeks after last dose of IMP. 
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. 
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 ±7 days after the last dose of study 
intervention), and as required locally. 
 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 


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COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive IMP. 
 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of 
a participant’s pregnancy. The participant will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the participant and 
the neonate and the information will be forwarded to the Sponsor. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 
Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting.  
 
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 


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10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
10.5.1 Laboratory abnormalities  
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
Neutrophils < 1500/mm3 or according to ethnic 
group
NEUTROPENIA
Repeat immediately a full blood count if value 
close to 1500/mm3
Neutrophils < 1500/mm3 confirmed 
with signs of infection  
Neutrophils < 1500/mm3 confirmed 
with no signs of infection  
1.
DISCONTINUE
Investigational Medicinal 
Product, hospitalization 
should be considered
2.
PERFORM biological 
investigations for infection
1.
DISCONTINUE
Investigational 
Medicinal Product
2.
INVESTIGATE for 
infection
In both situations
3.
INFORM the local monitor
4.
INVESTIGATE previous treatments particularly long-term, even a long time ago, 
exposure to toxic agents, e.g., benzene, X-rays, etc.
5.
PERFORM and collect the following investigations (results): 
•
RBC and platelet counts
•
Serology: EBV, (HIV), mumps, measles, rubella
6.
DECISION for bone marrow aspiration: to be taken in specialized unit
7.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
8.
MONITOR the leukocyte count 3 times per week for at least one  week, then twice a 
month until it returns to normal
Note: 
•The procedures described in the above flowchart are to be discussed with the patient only in case 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.
•For individuals of African descent, the relevant value of concern is <1000/mm3


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aPTT: activated partial thromboplastin time, EBV: Epstein-Barr Virus, EDTA: ethylenediaminetetraacetic acid, HIV: human 
immunodeficiency virus, INR:  international normalized ratio, PK: pharmacokinetic, PT: prothrombin time  
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
Platelets < 100 000/mm3 (rule out EDTA – induced 
pseudo-thrombocytopenia)
THROMBOCYTOPENIA
Repeat immediately the count (rule out EDTA 
anticoagulant in the sample)
Platelets  < 100 000/mm3 confirmed 
with bleeding  
Platelets  < 100 000/mm3 confirmed 
with no bleeding
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
HOSPITALIZATION
should be considered
1.
DISCONTINUE
Investigational Medicinal 
Product
2.
INVESTIGATE for 
bleeding
In both situations
3.
INFORM the local Monitor
4.
QUESTION about last intake of quinine (drinks), alcoholism, heparin administration
5.
PERFORM or collect the following investigations: 
•
Complete blood count, schizocytes, creatinine
•
Bleeding time and coagulation test (fibrinogen, INR or PT, aPTT), Fibrin 
Degradation Product
•
Viral serology: EBV, HIV, mumps, measles, rubella
6.
COLLECT/STORE one sample following handling procedures described in PK 
sections (for studies with PK sampling) and freeze one serum sample (5 mL) on 
Day 1 (cessation of investigational medicinal product) and Day 5 (for further 
investigations)
7.
DECISION for bone marrow aspiration: to be taken in specialized unit
•
On Day 1 in the case of associated anemia and/or leukopenia
•
On Day 8 if platelets remain < 50 000/mm3
8.
MONITOR the platelet count every day for at least one week and then regularly 
until it returns to normal
Note: 
The procedures above flowchart are to be discussed with the patient only in case described in the 
the event occurs. If applicable (according to local regulations), an additional consent (e.g., for 
HIV testing) will only be obtained in the case the event actually occurs.


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*If unable to retest in 72 hours, use original laboratory results to decide on further reporting/monitoring/discontinuation.  
ALT: alanine aminotransferase, AST: aspartate aminotransferase, CMV: cytomegalovirus, CPK: creatine phosphokinase, HAV: Hepatitis A virus, 
HCV: Hepatitis C virus, IgM: immunoglobulin M, IMP: investigational medicinal product, INR: international normalized ratio, LFT: liver function 
test, LKM: liver kidney microsomal; ULN: upper limit of normal   
Note: 
 
“Baseline” refers to ALT sampled at the 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 8.3 for guidance on safety reporting. 
 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 


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ARF: acute kidney failure, BP: blood pressure, CPK: creatine phosphokinase, DIC: disseminated intravascular coagulation, ECG: 
electrocardiogram, HR: heart rate, PK: pharmacokinetic     
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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CPK: creatine phosphokinase, CPK-MB-MM: creatine phosphokinase muscle/brain, ECG: electrocardiogram, PK: pharmacokinetic, ULN: upper 
limit of normal  
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 
intervention 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 leukocytosis, 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 Appendix 5 
[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 Appendix 5 (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 in Appendix 5 (Section 10.5.2.1 and Section 10.5.2.2), all 
laboratory or clinical documentations must be collected. If the retest result 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 (≥5.9 pmol/L): 
 
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 RA. 
Acute renal impairment is not thought to be caused directly by GLP-1 RA (including 
efpeglenatide) without dehydration. 
In case of prolonged or severe nausea and vomiting, if clinically indicated, serum creatinine 
measurement should be performed at the central laboratory. If there is an acute increase of serum 
creatinine, metformin must be discontinued (if concomitantly taken) until resolution of renal 
dysfunction. Please also refer to Appendix 5 (Section 10.5.1), increase in serum creatinine 
flowchart for further recommendations. 
10.5.5 Guidance for monitoring participants with diabetic retinopathy  
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 or local standards; this should occur quarterly at 
a minimum for participants at high risk (eg, participants with severe non-proliferative diabetic 
retinopathy, proliferative diabetic retinopathy, and/or diabetic macula edema). 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 


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10.7 
APPENDIX 7: HYPOGLYCEMIA CLASSIFICATION  
Figure 2 - Hypoglycemia classification  
 
PG: plasma glucose, SAE: serious adverse event 


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10.8 
APPENDIX 8: PATIENT QUALITATIVE ASSESSMENT OF TREATMENT VERSION 2  
The following questions ask for your opinion on the drug you received during this clinical 
study.  
There are no right or wrong answers; we would like to better understand your own experience of 
the drug. 
1. 
During this trial, what were the main benefits you experienced with the drug you received?  
Free-text 
 
 
 
 
 
 
 
 
 
2. 
On a scale of 0 to 10, how beneficial was the drug you received during this trial? 
 
 
 
3. 
During this trial, what were the main disadvantages you experienced with the drug you received?  
Free-text 
 
 
 
 
 
 
 
 
 
 


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4. 
On a scale of 0 to 10, how disadvantageous was the drug you received during this trial? 
 
 
5. 
After this trial, would you be willing to continue using the drug you received during this trial?  
Yes  
 
No  
Please explain why? 
Free-text 
 
 
 
 
 
 
 
 
 
6. 
Based on your own experience in this trial, please select a response on the scale below 
 
- 3 
 
- 2 
 
- 1 
 
0 
 
1 
 
2 
 
3 
The disadvantages 
of the drug I 
received 
significantly 
outweigh the 
benefits 
 
 
There were 
equal benefits 
and 
disadvantages 
of the drug I 
received 
 
 
The benefits of 
the drug I 
received 
significantly 
outweigh the 
disadvantages 


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10.9 
APPENDIX 9: PATIENT-REPORTED OUTCOMES MEASUREMENT INFORMATION 
SYSTEM (PROMIS) GASTROINTESTINAL SYMPTOM SCALES VERSION 1.0  
 
 


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10.10 APPENDIX 10: ABBREVIATIONS  
 
ADA: 
antidrug antibody 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
BOCF: 
baseline observation carried forward 
BP: 
blood pressure 
CEC: 
Clinical Endpoint Committee 
CI: 
confidence interval 
CRF: 
case report form 
CRO: 
contract research organization 
CT: 
computed tomography 
CV: 
cardiovascular 
DMC: 
Data Monitoring Committee 
DPP-4: 
dipeptidyl peptidase 4 
DTP: 
Direct-To-Patient 
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 
ICH: 
International Council for Harmonisation 
ICO: 
International Council of Ophthalmology 
IEC: 
Independent Ethics Committee 
IMP: 
Investigational Medicinal Product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
MACE: 
major adverse cardiovascular event 
MDRD: 
Modification of Diet in Renal Disease 


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MEN-2: 
multiple endocrine neoplasia syndrome type-2 
MI: 
multiple imputation 
MNAR: 
missing not at random 
MRI: 
magnetic resonance imaging 
MTC: 
medullary thyroid cancer 
NIMP: 
noninvestigational medicinal product 
OAD: 
oral anti-diabetic 
OC: 
observed case 
PEG: 
polyethylene glycol 
PK: 
pharmacokinetic 
popPK: 
population PK 
PQATv2: 
Patient Qualitative Assessment of Treatment version 2 
PRO: 
patient-reported outcome 
PROMIS: 
Patient-Reported Outcome Measurement Information System 
PTC: 
Product Technical Complaint 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SD: 
standard deviation 
SE: 
standard error 
SGLT2: 
sodium/glucose cotransporter 2 
SMPG: 
self-monitored plasma glucose 
SoA: 
Schedule of Activities 
SUSAR: 
suspected unexpected serious adverse reaction 
T2DM: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse events 
UB: 
upper bound 
ULN: 
upper limit of normal 
WOCBP: 
women of childbearing potential 
 


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10.11 APPENDIX 11: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 


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11 
REFERENCES  
1. American Diabetes Association. Standards of Medical Care in Diabetes - 2017. Diabetes Care. 
2017;40(Suppl 1):S4-S5. 
2. Investigator's Brochure, SAR439977, latest edition. 
3. Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (US). Draft guidance. Assay development and validation 
for immunogenicity testing of therapeutic protein products. 2016. Available from: 
https://www.fda.gov/downloads/Drugs/Guidances/UCM192750.pdf 
4. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on immunogenicity assessment of biotechnology-derived therapeutic 
proteins. London, 18 May 2017. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2017/06/WC5
00228861.pdf 
5. TRULICITY (dulaglutide injection, solution) [prescribing information] TRU-0007-USPI-
20170825. Eli Lilly and Company. Indianapolis, (IN). 2017:1-22. 
6. European Medicines Agency (EMA). Committee for Medicinal Products for Human Use 
(CHMP). Guideline on clinical investigation of medicinal products in the treatment or 
prevention of diabetes mellitus. London, 14 May 2012. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC5
00129256.pdf 
7. Thompson AM, Trujillo JM. Dulaglutide: the newest GLP-1 receptor agonist for the 
management of type 2 diabetes. Ann Pharmacother. 2015;49(3):351-9. 
8. 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–S43. 
9. Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (US). Draft guidance: Diabetes mellitus: developing drugs 
and therapeutic biologics for treatment and prevention. February 2008. Available from: 
https://www.fda.gov/downloads/Drugs/.../Guidances/ucm071624.pdf 
10. American Diabetes Association. Glycemic Targets. Sec. 6. In Standards of Medical Care in 
Diabetes 2017. Diabetes Care. 2017;40(Suppl. 1):S48-56. 
11. Speigel BMR, Hays RD, Bolus R, Melmed GY, Chang L, Whitman C, et al. Development of 
the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) 
gastrointestinal symptom scales. Am J Gastroenterol. 2014;109(11):1804-14. 
 


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Page 1 
STATISTICAL ANALYSIS PLAN 
A 56-week, Multicenter, Open-label, Active-controlled, Randomized Study to 
Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly Compared to 
Dulaglutide Once Weekly in Patients with Type 2 Diabetes Mellitus Inadequately 
Controlled with Metformin 
EFC14829/AMPLITUDE-D 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 02-Oct-2020 
Total number of pages: 
83 
NCT03684642


Statistical Analysis Plan 
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................. 8 
1.6 
STATISTICIAL MODIFICATIONS MADE IN STATISTICAL ANALYSIS PLAN .............................. 9 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 10 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 10 
2.1.1 
Demographic and Baseline characteristics .................................................................................... 10 
2.1.2 
Prior or concomitant medications ................................................................................................... 12 
2.1.3 
Efficacy endpoints .......................................................................................................................... 13 
2.1.3.1 
Primary efficacy endpoint ............................................................................................................... 13 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................ 13 
2.1.3.3 
Exploratory efficacy endpoint(s) ..................................................................................................... 13 
2.1.4 
Safety endpoints ............................................................................................................................ 14 
2.1.4.1 
Adverse events variables ............................................................................................................... 15 
2.1.4.2 
Deaths ............................................................................................................................................ 16 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 16 
2.1.4.4 
Vital signs variables ....................................................................................................................... 17 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 17 
2.1.4.6 
Hypoglycemia ................................................................................................................................. 17 
2.1.4.7 
Gastrointestinal (GI) symptoms from the participant perspective .................................................. 18 
2.1.5 
Immunogenicity endpoints ............................................................................................................. 18 
2.1.5.1 
Anti-drug (efpeglenatide) antibody ................................................................................................. 18 
2.1.6 
Pharmacokinetic endpoints ............................................................................................................ 20 
2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 20 


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2.2 
DISPOSITION OF PARTICIPANTS............................................................................................... 20 
2.2.1 
Protocol Deviations ........................................................................................................................ 21 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 21 
2.3.1 
Efficacy populations ....................................................................................................................... 22 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 22 
2.3.1.2 
Modified Intent–to-treat population ................................................................................................ 22 
2.3.2 
Safety population ........................................................................................................................... 22 
2.3.3 
ADA population .............................................................................................................................. 23 
2.3.4 
PK population ................................................................................................................................. 23 
2.4 
STATISTICAL METHODS ............................................................................................................. 23 
2.4.1 
Demographics and Baseline characteristics .................................................................................. 23 
2.4.2 
Prior or concomitant medications ................................................................................................... 24 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 24 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 24 
2.4.3.2 
Compliance .................................................................................................................................... 25 
2.4.3.3 
Frequency of injections .................................................................................................................. 25 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 25 
2.4.4.1 
Analysis of primary efficacy endpoint ............................................................................................ 26 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 30 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 31 
2.4.4.4 
Exploratory efficacy analysis .......................................................................................................... 32 
2.4.5 
Analyses of safety data .................................................................................................................. 34 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 35 
2.4.5.2 
Analysis of Hypoglycemia .............................................................................................................. 41 
2.4.5.3 
Deaths ............................................................................................................................................ 41 
2.4.5.4 
Analyses of laboratory variables .................................................................................................... 42 
2.4.5.5 
Analyses of vital sign variables ...................................................................................................... 43 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 43 
2.4.5.7 
Analyses of other safety endpoints ................................................................................................ 44 
2.4.6 
Analyses of pharmacokinetic variables .......................................................................................... 45 
2.4.7 
Analyses of quality of life/health economics variables ................................................................... 45 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 45 
2.5.1 
General conventions ...................................................................................................................... 45 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 46 
2.5.3 
Missing data ................................................................................................................................... 46 
2.5.4 
Windows for time points ................................................................................................................. 48 
2.5.5 
Unscheduled visits ......................................................................................................................... 49 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 49 
2.5.7 
Statistical technical issues ............................................................................................................. 49 
3 
INTERIM ANALYSIS ..................................................................................................................... 50 


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4 
DATABASE LOCK ........................................................................................................................ 51 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 52 
6 
REFERENCES............................................................................................................................... 53 
7 
LIST OF APPENDICES ................................................................................................................. 54 
APPENDIX A 
EFFICACY ANALYSIS SAS PSEUDO CODE .................................................................... 55 
APPENDIX B 
CRITERIA FOR POTENTIALLY SIGNIFICANT ABNORMALITIES – FOR PHASE 
2/3 STUDIES (ONCOLOGY EXCEPTED) ..................................................................................... 66 
APPENDIX C 
DIAGRAM FOR IDENTIFYING MISSING DATA DUE TO COVID-19 ................................ 72 
APPENDIX D 
SCHEDULE OF ACTIVITIES (SOA) ................................................................................... 73 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
anti-drug antibody 
AE: 
adverse event 
AERSM: 
adverse event requiring specific monitoring 
AESI: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
BMI: 
body mass index 
CMH: 
Cochran-Mantel-Haenszel 
ECG: 
electrocardiogram 
EOS: 
end of study 
EOT: 
end of treatment 
GI: 
gastrointestinal 
HbA1C: 
hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high-level term 
IMP: 
Investigational Medicinal Product 
IRT: 
Interactive Response Technology 
LLT: 
lower-level term 
mITT: 
modified intent-to-treat 
NIMP: 
noninvestigational medicinal product 
PCSA: 
potentially clinically significant abnormality 
PRO: 
patient reported outcome 
PT: 
preferred term 
R: 
randomization 
SAE: 
serious adverse event 
SOC: 
system organ class 
T2DM: 
Type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
UB: 
upper bound 
WHO-DD: 
World Health Organization-Drug Dictionary 
 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a Phase 3, multicenter, 56-week, randomized, open-label for the drug (efpeglenatide and 
dulaglutide) and double-blind for the doses of efpeglenatide, active-controlled, 3-arm, parallel 
group study in participants with type 2 diabetes mellitus (T2DM) inadequately controlled with 
metformin. 
After a Screening phase of up to 3 weeks, participants will be centrally randomized (using 
permuted block randomization schedule) via Interactive Response Technology (IRT) in a 1:1:1 
ratio to 1 of the following 3 treatment groups: 
• efpeglenatide 4 mg  
• efpeglenatide 6 mg  
• dulaglutide 1.5 mg 
Randomization will be stratified by Screening hemoglobin A1c (HbA1c) (<8.0%, ≥8.0%) and 
Visit 3 (Baseline, Day 1) body mass index (BMI) (<30 kg/m2 and ≥30 kg/m2). Participants will 
receive open-label, active-controlled treatment for 56 weeks. Additional details on the study 
design and plan are provided in  
Section 1.4. 
Approximately 900 participants (300 participants per treatment group [details in Section 1.3] will 
be randomized. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate the noninferiority of once-weekly injection 
of efpeglenatide 4 or 6 mg in comparison to once-weekly injection of dulaglutide 1.5 mg on 
HbA1c change from Baseline to Week 56 in participants with T2DM inadequately controlled with 
metformin. 
1.2.2 Secondary objectives 
The secondary objectives of this study are: 
• 
To demonstrate the superiority of once-weekly injection of efpeglenatide 4 and 6 mg with 
once-weekly injection of dulaglutide 1.5 mg on glycemic control. 


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• 
To demonstrate the superiority of once-weekly injection of efpeglenatide 4 and 6 mg with 
once-weekly injection of dulaglutide 1.5 mg on body weight. 
• 
To evaluate the safety of once-weekly injection of efpeglenatide 4 and 6 mg and once-
weekly injection of dulaglutide 1.5 mg. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are performed based on the primary endpoint, change in HbA1c (%) 
from Baseline to Week 56. 
Assuming a common standard deviation of 1.1%, and the true difference between efpeglenatide 
and dulaglutide is zero, 300 participants per arm will ensure that the upper bound (UB) of the 
2-sided 95% CI of the adjusted mean difference would not exceed 0.3% with 91% power. 
Hence, there are 3 parallel dosing arms as follows: 
• Efpeglenatide 4 mg, N=300 
• Efpeglenatide 6 mg, N=300 
• Dulaglutide 1.5 mg, N=300 
1.4 
STUDY PLAN 
This is a multicenter, 56-week, randomized, open-label for the drug (efpeglenatide and 
dulaglutide) and double-blind for the doses of efpeglenatide, active-controlled, 3-arm, parallel 
group Phase 3 study consisting of 3 study periods: 
• An up to 3-week Screening Period (with a minimum of 11 days) 
• A 56-week open-label, active-controlled Treatment Period, for efficacy and safety 
assessments 
• A 6-week post-treatment Follow-up Period to collect safety information after last dose of 
Investigational Medicinal Product (IMP) after treatment is completed or permanent 
treatment discontinued  
The maximum study duration per participant will be 65 weeks with treatment lasting for 
56 weeks. The graphical study design is shown in Figure 1. 


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Figure 1 - Study Design Overview 
 
Abbreviations: EOS, end of study; EOT, end of treatment; R, Randomization. 
Note: The telephone symbol is used to designate visits conducted by telephone interview. 
 
The end of the study is defined as the date of the last visit of the last participant in the study. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
The statistical section of the protocol was never changed in an amendment.  


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1.6 
STATISTICIAL MODIFICATIONS MADE IN STATISTICAL ANALYSIS PLAN 
The statistical analysis plan history table below provides the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan and/or protocol.  
Table 1 - Statistical analysis plan Statistical changes 
SAP Version 
Number 
Date 
Approved 
Rationale 
Description of Statistical Changes 
2 
02-Oct-2020 
Additional analyses provided due 
to Covid-19 pandemic. 
2.2.1 Added analyses for COVID-19 related PDs 
2.4.4.4.2 Added HbA1c sensitivity analysis due 
to COVID-19 at Week 56. COVID-19 impact on 
disposition data will be presented. Assessment 
of missing data due to COVID-19 added 
2.4.5.1 COVID-19 related AEs have been added 
Appendix C Added diagram for identifying 
missing data due to COVID-19 
 
 
 
 
 
 
Clarification on- and post-study 
periods; Updated definition of 
actual treatment group for as-
treated analysis; clarified AERSM 
definitions; Added definitions of 
ADA responses.  
 
2.1.4 Clarified on-study and post-study 
observation periods 
2.3.2 Updated definition of actual treatment 
group 
2.4.5.1 Updated definitions of AERSM 
2.1.5.1 Added definitions for Persistent, 
Transient and indeterminate ADA response   
 
 
 
 
 
 
Since the study was terminated 
early, the mITT was added and 
defined; Added additional 
sensitivity analysis using retrieved-
dropout multiple imputation 
method and back-up multiple 
imputation method on the primary 
endpoint; Removed model-based 
analyses for the change from 
baseline in mean 24-hour SMPG 
and time to initiation of rescue 
medication; Clarified analysis 
window for efficacy endpoints.  
2.3.1. Added mITT population 
2.4.4.1 Added sensitivity analyses using the 
retrieved-dropout multiple imputation method 
and the back-up multiple imputation method (in 
case of insufficient retrieved dropouts).  
2.4.4.1 descriptively summarized HbA1c at 
Week 56 by ADA status only 
2.4.4.4.3 Removed ANCOVA analysis for 
changes from baseline in mean 24-hour SMPG. 
Removed Cox proportional hazard model for 
time to initiation of rescue analysis. 
2.5.4 Clarified analysis window for efficacy 
endpoints at Weeks 30 and 56 in case of 
missing scheduled visits 
 
 
 
  
 


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and Baseline characteristics 
The Baseline value (except for serum creatinine and eGFR) is defined as the last available value 
prior to the first dose administration of open-label IMP or the last available value on or before the 
date of randomization if not treated with the open-label IMP. Note: any assessment undertaken on 
the day of first dose administration of open-label IMP with missing assessment time will be 
considered as Baseline. 
For serum creatinine and eGFR, baseline is defined as the average of all values before the first 
dose of the open-label IMP for those randomized and exposed or before randomization for those 
who were randomized but never exposed to open-label IMP. 
All Baseline safety parameters (apart from those listed below) are presented along with the 
on-treatment summary statistics in the safety sections (Section 2.4.5).  
Summary statistics of baseline efficacy parameters by treatment group and overall will be 
provided in randomized population.  
Demographic characteristics 
Demographic variables are gender (Male, Female), race (Asian, Black or African American, 
White, Multiple, Other, Not reported, Unknown), age in years (quantitative and qualitative 
variable: <50, ≥50 and <65, ≥65 and < 75, ≥75 years), ethnicity (Hispanic or Latino, not Hispanic 
or Latino, Not reported, Unknown), region (North America, Eastern Europe (including Hungary 
and Poland)), and randomization strata (Baseline BMI (quantitative and qualitative variable: <30, 
≥30 and <40, ≥40 kg/m2), HbA1c at screening (<8.0, ≥8.0%)).  
Participants counted as multiple races will not be counted in other race categories. 
Medical history 
Medical history includes medical or surgical history, alcohol and smoking habits.  
Medical and surgical history will be coded using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at the time of database lock. 


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Alcohol and smoking habit variables include: 
• Alcohol status in the last 12 months (Never, Occasional, At least monthly, At least weekly, 
At least daily) 
• Smoking status (Never, Current, Former) 
• 
Cigarettes smoked (per day) 
Disease characteristics at Screening or Baseline  
Diabetes history includes: 
• Duration of diabetes (years) derived as: (Date of informed consent – Date of diagnosis of 
diabetes + 1)/365.25; 
• Categories of duration of diabetes (<10, ≥10 years); 
• Age at diagnosis of diabetes (years) derived as: Year of diagnosis of diabetes – Year of 
birth; 
• Baseline diabetic microvascular complications (Yes, No) (neuropathy, nephropathy, 
retinopathy) and retinopathy history (Proliferative, Non-proliferative, Macular Edema); 
• Use of anti-diabetic medication, duration of Metformin (years), and daily dose of 
Metformin (mg) at screening; 
• Estimated Glomerular Filtration Rate (eGFR) at baseline (ml/min/1.73m2); 
• Estimated glomerular filtration rate (eGFR) categories at baseline (<15 ml/min/1.73m2 
[End stage renal Disease], ≥15 to <30 ml/min/1.73m2 [Severe decrease in glomerular 
filtration rate (GFR)], ≥30 to <60 ml/min/1.73m2 [Moderate decrease in GFR], ≥60 to 
<90 ml/min/1.73m2 [Mild decrease in GFR], and ≥90 ml/min/1.73m2 [Normal]). 
Baseline efficacy variables 
The baseline efficacy variables include: 
• HbA1c (% , mmol/mol); 
• HbA1c category (<8.0, ≥8.0%) 
• FPG (mmol/L, mg/dL); 
• Body weight (kg);  
• Waist Circumference (cm) 
• Mean 24-hour SMPG (mmol/L, mg/dL) 


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Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
2.1.2 Prior or concomitant medications  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or during the 
study must be recorded in the corresponding case report form page. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at the time of database lock. 
Medications will be classified into the following 3 groups: 
• Prior medications are those the participant used prior to first open-label IMP 
administration. Prior medications can be discontinued before first open-label IMP 
administration or can be ongoing during treatment phase.  
• Concomitant medications are any treatments received by the participant concomitantly to 
the IMP(s), from first dose to the end of treatment + 30 days (+ 7 days for antidiabetic 
drugs). A given medication can be classified both as a prior medication and as a 
concomitant medication. Concomitant medications do not include medications started 
during the posttreatment period (as defined in the observation period in Section 2.1.4).  
• Post-treatment medications are those the participant took in the period running from the 
31st day (8 days for antidiabetic drugs) after the last injection of IMP up to the end of the 
study. 
Background medication  
Metformin tablets, administered as per Principal Investigator prescription and in accordance with 
local labeling, and rescue medication(s) that will be used to treat hyperglycemia if a participant’s 
glycemic values reach the applicable rescue threshold. 
The doses of metformin at randomization should be maintained throughout the study unless 
down-titration is required for safety reasons. 
Rescue medication(s) is considered Non-IMP (NIMP) treatment. Except for GLP-1 RA and 
DDP-4i, any approved medication(s) including oral antidiabetic drugs or insulin can be prescribed 
at the Investigator’s discretion to treat the hyperglycemia. 
The background medication and rescue medications will be included in the concomitant 
medication summaries. A special list of rescue therapy medications will be generated. 
Prohibited medication(s) 
All prohibited medications are based on sponsor-defined Customized Drug Grouping (CDG).  


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The following treatments are prohibited during the Screening Period and the 56 weeks of 
treatment period. 
• Initiation of any antidiabetic agents other than the IMP or change in dose or preexisting 
oral anti-diabetic(s) (OAD) 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, or semaglutide) and DPP-4 
inhibitors (eg, sitagliptin, saxagliptin, vildagliptin, or linagliptin) 
• Initiation of any prescription weight loss drugs (eg, phentermine, lorcaserin, or orlistat) 
• Gastric surgery or other gastric procedures for weight loss 
• Systemic use of glucocorticoids for more than 10 consecutive days (topical, nasal spray, 
and inhaled or intra-articular applications are allowed) 
• Any investigational drug other than IMP for this study 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints 
Efficacy endpoints are defined in Section 2.1.3.1, Section 2.1.3.2 and Section 2.1.3.3. 
Efficacy variables will be summarized in both standard international units and conventional units 
when applicable. 
2.1.3.1 Primary efficacy endpoint 
• Change in HbA1c (%) from Baseline to Week 56 
2.1.3.2 Secondary efficacy endpoints 
• Number of participants with HbA1c < 7.0% at Week 56 (yes/no) 
• Change in FPG from Baseline to Week 56  
• Changes in body weight from Baseline to Week 56 
2.1.3.3 Exploratory efficacy endpoint(s) 
• Participant perspective on benefit/risk of the drug using the Patient qualitative assessment 
of treatment version 2 (PQAT v2) at Weeks 30 and 56 
• Number of participants with HbA1c < 7.0% at Week 30 (yes/no) 


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• Change in HbA1c from Baseline to Week 30 
• Change in FPG from Baseline to Week 30 
• Changes in 7-point SMPG profiles (mmol/L, mg/dL: mean 24-hour SMPG) from Baseline 
to Weeks 30 and 56 
• Change in plasma glucose excursions (2-hours PPG minus preprandial plasma glucose at 
breakfast, lunch, and dinner) based on 7-point SMPG data from baseline to Week 30 and 
Week 56 
• Number of participants with rescue therapy used during the treatment period until 
Weeks 30 and 56 (yes/no) 
• Time to initiation of rescue therapy (weeks) 
• Change from baseline to week 30 in body weight 
• Number of participants with change in body weight ≥ 5% from Baseline to Week 56 
(yes/no) 
• Number of participants with change in body weight ≥ 10% from Baseline to Week 56 
(yes/no) 
• Change in waist circumference from Baseline to Weeks 30 and 56 
Mean 24-hour SMPG is the average over the available plasma glucose values from the 7 time 
points and can only be calculated if at least 4 points are available. 
Prandial glucose excursions are calculated by subtracting the preprandial value from the 
postprandial value respectively for breakfast, lunch, and dinner. 
2.1.4 Safety endpoints 
The safety analysis will be based on the reported adverse events (AE), hypoglycemia and other 
safety information, such as clinical laboratory data, vital signs, and ECG.  
Observation period  
The period related to treatment will be divided into 3 main segments: 
• The pre-treatment period is defined as the time from informed consent up to the time of 
first injection of open-label IMP 
• The on-treatment period is defined as the time from the first injection of the open-label 
IMP up to 30 days (7 days for hypoglycemia) after the last injection of the IMP 
• The post-treatment period is defined as the period from the end of the on-treatment 
period.  


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The on-study observation period is defined as the time from first injection of open-label IMP up 
to either the last protocol-planned visit or the date of last available information if participants 
discontinue the study prematurely, whichever is later.  
The post-study observation period is defined as the time after the end of the on-study 
observation period until the date of resolution/stabilization of SAE, AESI, and AERSM, up to 
database lock. 
2.1.4.1 Adverse events variables 
Adverse event observation period  
• Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period  
• Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became 
serious during the on-treatment period 
• Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period 
All AEs (including SAEs, AEs of special interest and AEs requiring specific monitoring) will be 
coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), high-level group 
term (HLGT), and associated primary system organ class (SOC) using the version of MedDRA 
currently in effect at the time of database lock. 
Adverse events of special interest (AESIs) include the following: 
• 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. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
• Increase in alanine aminotransferase (ALT) >3 x upper limit normal (ULN) 
Adverse events requiring specific monitoring include the following terms: 
• Severe gastrointestinal (GI) events 
• Severe hypoglycemia 
• Pancreatic events (including abnormal values of pancreatic enzymes, pancreatitis and 
pancreatic neoplasm) 
• Selected cardiovascular events (CV death, MI, stroke, heart failure leading to 
hospitalization, unstable angina, and transient ischemic attack (TIA)) 
• Calcitonin increase (≥5.9 pmol/L (≥20 pg/mL)) and thyroid C-cell neoplasm 
• Acute renal failure 
• Diabetic retinopathy complications 


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• Severe injection site reaction 
• Severe allergic reactions 
• Severe immune complex disease 
Independent Clinical Endpoint Committee(s) [CEC(s)] will review, assess and/or adjudicate all 
events of death, selected CV events and pancreatic events. 
2.1.4.2 Deaths 
The death observation periods are per the observation periods defined below.  
• Death on-study: deaths occurring during the on-study observation period  
• Death on-treatment: deaths occurring during the on-treatment period 
• Death post-study: deaths occurring after the end of the study  
2.1.4.3 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry and 
urinalysis. Clinical laboratory values will be summarized in both standard international units and 
conventional units (US) when applicable.  
Blood samples for clinical laboratories will be collected at designated visits (see Schedule of 
Activities in Appendix D). The following laboratory parameters will be measured at central 
laboratory:  
• Hematology  
- 
Red blood cells and platelets: Platelet count, Red blood cell count, Hemoglobin, 
Hematocrit;  
- 
White blood cells: White blood cell count, differential count (Neutrophils, 
Lymphocytes, Monocytes, Eosinophils, Basophils). 
• Clinical chemistry  
- 
Pancreatic enzymes: Amylase, Lipase; 
- 
Electrolytes: Potassium, Sodium;  
- 
Renal function: Creatinine, Estimated glomerular filtration rate (MDRD formula);  
- 
Liver function: Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), 
Alkaline phosphatase (ALP), Total bilirubin. 
- 
Lipid profile: Triglyceride, Total cholesterol, Low-density lipoprotein cholesterol, 
High-density lipoprotein cholesterol 
For triglycerides, only values assessed in fasted patients will be analyzed. 
- 
Calcitonin 


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Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables 
Vital signs include sitting heart rate (bpm), as well as sitting systolic and diastolic blood pressures 
(mmHg). 
2.1.4.5 Electrocardiogram variables 
ECG variables will include 12-lead ECG interpretation (normal/abnormal) provided by the 
investigator. 12-lead ECG recording will be performed locally at Randomization, Week 12 and 
Week 56. Investigator’s interpretation of normal and abnormal will be reported in the eCRF. 
2.1.4.6 Hypoglycemia 
During the study, participants are to be instructed to document any hypoglycemic episodes in their 
study diary. Hypoglycemia will be reported in the specific eCRF page with onset date and time, 
symptoms and/or signs, the SMPG value if available, and the treatment of the hypoglycemia. 
Hypoglycemia fulfilling the seriousness criteria will be documented, in addition, on the SAE form 
in the eCRF. 
Hypoglycemic events will be categorized as follows: 
• Severe hypoglycemia: Severe hypoglycemia is an event requiring assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure, 
unconsciousness or coma. Plasma glucose measurements may not be available during such 
an event, but neurological recovery attributable to the restoration of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration. The definition of severe symptomatic hypoglycemia includes all 
episodes in which neurological impairment was severe enough to prevent self-treatment 
and which were thus thought to place participants at risk for injury to themselves or others. 
Note that “requiring assistance of another person” means that the participant could not 
help himself or herself. Assisting a participant out of kindness, when assistance is not 
required, should not be considered a “requiring assistance” incident. 
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria. 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. 


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• 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 treated with oral carbohydrate. 
• Relative hypoglycemia: (recently termed “pseudo-hypoglycemia”) is an event during 
which the person with diabetes reports any of the typical symptoms of hypoglycemia, and 
interprets the symptoms as indicative of hypoglycemia, but with a measured plasma 
glucose concentration greater than 3.9 mmol/L (>70 mg/dL). 
In addition to the threshold of plasma glucose of less than or equal to 3.9 mmol/L (≤70 mg/dL), 
documented symptomatic and asymptomatic hypoglycemic events with measured plasma glucose 
concentration ≥3.0 and <3.9 mmol/L (≥54 and <70 mg/dL), and less than 3.0 mmol/L 
(<54 mg/dL) will also be analyzed. 
Hypoglycemic events will be evaluated regardless of the time of onset during the study and time 
of the day. 
In addition, hypoglycemia events will be evaluated at the following time periods defined by time 
of the day: 
• Nocturnal hypoglycemia defined by time of the day: any hypoglycemia of the above 
categories that occurs between 00:00 and 05:59, regardless of whether 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. 
2.1.4.7 Gastrointestinal (GI) symptoms from the participant perspective 
The evolution of GI symptoms will be evaluated from the participant perspective using 3 
PROMIS GI Symptom scales version 1.0 (nausea and vomiting, diarrhea, and belly pain) at 
Day 1, Weeks 1, 2, 3, 4, 5, 6, 7, 8, 12, 18, 30, 43, and 56. 
2.1.5 Immunogenicity endpoints 
2.1.5.1 Anti-drug (efpeglenatide) antibody 
Blood samples are taken to assess the Anti-drug antibody (ADA) status (positive/negative) and 
level (titer). Mapping the ADA epitopes of confirmed positive samples to different moieties of 
efpeglenatide, (ie, HMC001, exendin-4 and polyethylene glycol (PEG)) and cross-reactivity to 
endogenous GLP-1 (positive/negative), endogenous glucagon (positive/negative), neutralizing 
capacity of ADAs will also be evaluated for efpeglenatide groups in serum, at the time points 
specified in protocol. 


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Subjects with pre-existing ADAs are those with a positive ADA at Baseline. Non-missing post-
Baseline titer values are deemed treatment-induced ADAs if the subject had a negative or missing 
ADA status at Baseline. Treatment-boosted ADAs are defined as a post-Baseline minimum 2-fold 
increase in Baseline titer value for subjects with pre-existing ADA at Baseline. 
Persistent ADA response is defined as: Treatment-induced or treatment-boosted ADA detected at 
two or more sampling time points during the study (ie, including post-study observation period), 
where the first and last treatment-induced or treatment-boosted ADA samples (irrespective of any 
negative samples in between) are separated by at least 16 weeks. 
Transient ADA response is defined as: (1) Treatment induced or treatment-boosted ADA detected 
only at 1 sampling time point during the study (excluding the last sampling time point); or (2) 
Treatment induced or treatment-boosted ADA detected at 2 or more sampling time points during 
the study, where the first and last treatment-induced or treatment-boosted ADA samples 
(irrespective of any negative samples in between) are separated by a period less than 16 weeks 
and the last time point is ADA-negative. 
Indeterminate ADA response is defined as: (1) Only the last sampling time point is positive; or (2) 
the last two samples, separated by a period less than 16 weeks are positive. 
The data will be presented as: 
• Number of participants by ADA status (positive/negative) at scheduled visits 
• Number of participants with treatment-induced ADAs among the participants with ADA 
negative or missing at Baseline 
• Number of participants with treatment-boosted ADAs among the participants with ADA 
positive at Baseline 
• ADA titer at scheduled visits 
• Number of participants by ADA cross-reactivity to endogenous GLP-1 (positive/negative) 
at scheduled visits 
• Number of participants by ADA cross-reactivity to endogenous glucagon 
(positive/negative) at scheduled visits 
• Number of participants with ADAs directed against PEG linker of efpeglenatide at 
scheduled visits 
• Number of participants with ADAs directed against the HMC001 moiety of efpeglenatide 
at scheduled visits 
• Number of participants with ADAs directed against the exendin-4 moiety of efpeglenatide 
at scheduled visits 
• Number of participants by status of anti-efpeglenatide neutralizing antibodies 
(positive/negative) at scheduled visits 
o Number of participants by status of neutralizing antibodies against endogenous GLP-1 
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o Number of participants by status of neutralizing antibodies against endogenous 
glucagon (positive/negative) 
2.1.6 Pharmacokinetic endpoints 
Pharmacokinetic variables include the concentration of efpeglenatide in the efpeglenatide groups 
• Serum concentration (Ctrough) of efpeglenatide at pre-dose (Weeks 4, 12, 24, 30) 
• Serum concentration of efpeglenatide at least 1 additional postdose (3 days [±1 day] after 
administration of efpeglenatide, preferably between Week 8 and Week 12, but other weeks 
are also acceptable [eg, after 1st dose, 4th dose, or 12th dose]) in a subset of participants. All 
valid efpeglenatide samples collected will be sent to the laboratory to be analyzed, even if 
out of the specified window. 
2.1.7 Pharmacodynamic/genomics endpoints 
Pharmacodynamic parameters are not evaluated in this study. 
2.2 
DISPOSITION OF PARTICIPANTS 
This section describes participants’ disposition for both participant study status and the participant 
analysis populations. 
Screened participants are defined as any participants who signed the informed consent form. 
Randomized participants consist of all participants with a signed informed consent form who have 
had an open-label kit number allocated and recorded in the IRT database, regardless of whether 
the treatment kit was used or not. 
The total number of participants in each of the following categories will be presented in the 
clinical study report using a flowchart diagram or summary table: 
• Screened participants  
• Screen failure participants and reasons for screen failure 
• Nonrandomized but treated participants  
• Randomized participants  
• Randomized but not treated participants  
• Randomized and treated participants  
• Participants who have completed the 56-week study treatment period as per protocol 
• Participants who did not complete the 56-week study treatment period, and main reasons 
for permanently treatment discontinuation  
• Participants who completed the study as per protocol 


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• Participants who discontinued the study by main reasons for permanent study 
discontinuation 
• Status at last study contact  
For all categories of participants (except for the screened, screen failure, and nonrandomized but 
treated categories) percentages will be calculated using the number of randomized participants as 
the denominator. Reasons for treatment and study discontinuation will be supplied in tables giving 
numbers and percentages by treatment group. This summary will be provided by treatment group. 
List of participants who discontinued treatment and/or study will be provided with reasons for 
discontinuation (including each specific reason categorized as ‘OTHER’), including reasons 
related to COVID-19. 
Kaplan-Meier cumulative incidence of early IMP withdrawal, premature discontinuation of 
treatment due to AE and study discontinuation will be provided. 
Additionally, the following analysis populations will be summarized in a table by number of 
participants in the randomized population.  
• Efficacy population: intent-to-treat (ITT) population, modified ITT (mITT) population  
• Safety population 
• ADA population 
• Pharmacokinetics (PK) population 
2.2.1 Protocol Deviations 
All significant deviations, potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, as well as other selected significant deviations will be summarized 
in tables giving numbers and percentages of deviations by treatment group in randomized 
population. Listing of participants with at least one significant deviation will be provided. 
Additionally, participants with any protocol deviations due to COVID-19 will be summarized and 
listed separately. 
2.3 
ANALYSIS POPULATIONS 
Participants treated without being randomized will not be considered randomized and will not be 
included in any efficacy population.  
The randomized population includes any participant who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used or not. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population. The safety experience associated with any 
later randomization will be assessed separately. 


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The safety experience of participants treated and not randomized will be reported separately, and 
these participants will not be in the safety population. 
2.3.1 Efficacy populations 
The efficacy analysis population will be the ITT population. 
2.3.1.1 Intent–to-treat population 
The ITT population is defined as all randomized participants, irrespective of compliance with the 
study protocol and procedures analyzed according to the treatment group allocated by 
randomization.  
2.3.1.2 Modified Intent–to-treat population 
Due to the study terminated early by sponsor on September 9, 2020 (hereinafter referred to as 
“early termination”), the efficacy analyses will be performed in mITT population instead of ITT 
population originally planned. The mITT population is defined as,  
• Participants who have completed the study treatment, or 
• Participants who discontinued the study treatment AND completed/discontinued the study 
before the early termination, or 
• Participants who discontinued treatment before early termination and discontinued the 
study due to early termination within 30 days of the target Week 56 visit (Day 392), or 
• Participants who discontinued treatment due to early termination within 30 days of the 
target Week 56 visit (Day 392). 
Participants will not be included in mITT if they discontinued study due to termination and 
discontinued study treatment (before or due to early termination) and had visits performed more 
than 30 days before the target Week 56 visit (Day 392). 
By-visit summary will be provided for ITT population in addition for mITT population.  
2.3.2 Safety population 
The safety population is defined as:  
• Randomized population who received at least 1 dose or part of a dose of the IMP, 
analyzed according to the treatment actually received 
In addition:  
• Nonrandomized but treated participants will not be part of the safety population; however, 
their safety data will be presented separately 
• Randomized participants for whom it is unclear whether they took the IMP will be 
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• For participants receiving 1 or more injections during the trial, the treatment group 
allocation for as-treated analysis will be included in the treatment group that they are 
exposed for longer duration. In case of tie, highest dose group of efpeglenatide will be 
used. When calculating the Dulaglutide treatment duration, the Dulaglutide 0.75 mg 
duration will be combined with Dulaglutide 1.5 mg 
• Participants, who premature discontinued study treatment during the titration phase, will 
be summarized in their planned treatment group for as-treated analysis too.  
• Randomized participants will be excluded from the safety population only if there is 
documented evidence (ie, all study dates recorded as no medication taken) that participants 
have not taken the study treatment. If a participant is dispensed IMP and is lost to follow-
up without any documented evidence, the participant will be considered exposed. 
2.3.3 ADA population 
ADA population is defined as:  
• All efpeglenatide participants from the safety population with at least 1 post-Baseline valid 
ADA sample after drug administration. 
2.3.4 PK population 
PK population is defined as: 
• All participants from the safety population with at least 1 measurable serum efpeglenatide 
concentration available for PK analysis. 
2.4 
STATISTICAL METHODS 
In general, descriptive statistics of quantitative efficacy and safety endpoints (result and change 
from baseline) by scheduled visit will be provided on observed cases (OC), ie, only including 
participants having a non-missing assessment at a specific visit. 
2.4.1 Demographics and Baseline characteristics 
Parameters described in Section 2.1.1 will be summarized on the ITT population by randomized 
treatment group and overall using descriptive statistics.  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group. Categorical and 
ordinal data will be summarized using the number and percentage of participants in each 
treatment group. Missing data will not be categorized in the summaries. 
Medical history will be summarized on the ITT population by treatment group (and overall), 
primary SOC, and HLT, with events sorted by primary SOC in internationally agreed order and 
decreasing frequency of HLT in the overall group.  


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Technical formulas are described in Section 2.5.1. 
P-values on demographic and Baseline characteristic data will not be calculated.  
2.4.2 Prior or concomitant medications 
The prior, concomitant, and post-treatment medications will be presented for the ITT population 
and the following two summaries will be produced for each: 
• All medications (excluding anti-diabetic), and 
• Anti-diabetic medications.   
Medications will be summarized by treatment group (and overall) according to the WHO-DD, 
considering the first digit of the ATC class (anatomic category) and the first 3 digits of the ATC 
class (therapeutic category). All ATC codes corresponding to a medication will be summarized, 
and participants will be counted once in each ATC category (anatomic or therapeutic) linked to 
the medication. Therefore, participants may be counted several times for the same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence across treatment group. In case of equal 
frequency regarding ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant and posttreatment medications will be sorted by decreasing frequency 
of ATC followed by all other therapeutic classes based on the incidence in the Efpeglenatide 6 mg 
treatment group. In case of equal frequency regarding ATCs (anatomic or therapeutic categories), 
alphabetical order will be used.  
Similar to concomitant medications, prohibited medications will be sorted by decreasing 
frequency of ATC followed by all other therapeutic classes based on the incidence in the 
Efpeglenatide 6 mg treatment group. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
within the safety population (Section 2.3.2).  
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of open-label IMP exposure will be assessed by cumulative exposure (patient years), 
duration (days), and category (weeks). 
Duration of open-label IMP exposure is defined as last dose date – first dose date + 7, regardless 
of unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data). 


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Duration of open-label IMP exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum). In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
following categories and cumulatively according to these categories: 1 to 2 weeks, 3 to 4 weeks, 
5 to 8 weeks, 9 to 12 weeks, 13 to 18 weeks, 19 to 24 weeks, 25 to 30 weeks, 31 to 43 weeks, 
44 to 56 weeks, and >56 weeks. The duration of treatment exposure in weeks will be the duration 
(in days)/7, rounded to the nearest integer. 
Duration of study will be summarized separately and analyzed descriptively as a quantitative 
variable (number, mean, SD, median, minimum, and maximum). The study duration is defined as 
date of completion or discontinuation – date of first open-label IMP + 1. If the date of first open-
label IMP is missing, then the date of randomization will be used. 
2.4.3.2 Compliance 
A given administration will be considered noncompliant if the participant did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for participants with 
missing or incomplete data. 
Percentage of compliance for a participant will be defined as the number of injections (partial 
injection will be counted as 1 injection) that the participant was compliant divided by the total 
number of injections that the participant was planned to take during the treatment period defined 
from the first to the last dose injection. Number of planned injections is calculated as following:  
1 + (last dose date – first dose date + 1)/7, rounded to the nearest integer. 
Treatment compliance will be summarized descriptively as quantitative variables (number, mean, 
SD, median, minimum, and maximum). The percentage of participants whose compliance is 
<60%, ≥ 60% and < 80%, ≥ 80% and ≤ 100%, or > 100% will be summarized.  
Cases of overdose will constitute AESIs and will be listed as such. 
2.4.3.3 Frequency of injections 
The frequency of injections during the on-treatment period will be summarized separately by time 
of day (morning, afternoon, evening, night) and location of injection (Abdomen, Arm, Thigh, 
Other, Missing). For analysis purposes, morning is defined as the time between 06:00-11:59, 
afternoon as between 12:00-17:59, evening as between 18:00-23:59, and night as between 
00:00-05:59.  
2.4.4 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population using efficacy assessment collected 
during the study, including those obtained after IMP discontinuation and/or introduction of rescue 
therapy, unless otherwise specified (see Section 2.5.4). 


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Due to COVID-19 pandemic, participants may not be able to maintain their regular clinical visits 
according to the study protocol, with the closure of facilities, safety concern for the participants to 
go to the sites, unavailability of the investigators for treating participants, interruption of 
transportation or other COVID-19 related reasons. Data missingness due to these reasons is likely 
to be missing at random. For a continuous endpoint, all observed data of participants within the 
same treatment group can be used for imputation in an MAR approach. Sensitivity analyses will 
be performed to take into consideration of the impact of COVID-19 if the number of participants 
with missing endpoint data due to COVID-19 is above the threshold as specified in the following 
sections.  
2.4.4.1 Analysis of primary efficacy endpoint 
Hypothesis Testing of the Primary Endpoint: 
For the primary efficacy variable of change from Baseline to Week 56 in HbA1c, the following 
statistical null hypothesis and alternative will be tested as: 
• H0: efpeglenatide - dulaglutide ≥ 0.3% 
• H1: efpeglenatide - dulaglutide < 0.3% 
The null hypothesis will be tested at a 1-sided alpha level of 0.025 using a non-inferiority margin 
of 0.3%. 
Primary Analysis:  
The statistical analysis for the primary endpoint is described below. 
The Baseline value is defined in Section 2.1.1.  
Analysis of the primary efficacy endpoint (change from Baseline to Week 56 in HbA1c) will be 
performed using the ITT population, using HbA1c measurements obtained during the study, 
including those obtained after IMP discontinuation or introduction of rescue therapy. 
The primary efficacy endpoint of change in HbA1c from Baseline to Week 56 will be analyzed 
with missing values imputed by BOCF-like MI method for both efpeglenatide and dulaglutide 
groups, under the MNAR framework: 
• For participants with missing HbA1c values at Week 56, the missing values will be 
imputed using a random draw from a normal distribution with mean equal to their Baseline 
HbA1c and the standard deviation equal to the pooled standard deviation calculated from 
the square root of the mean square error estimated from a regression model with Baseline 
HbA1c as the dependent variable and randomization strata and treatment as the covariates.  
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data sets 
with complete data. Each of the complete datasets after the imputation will be analyzed by the 
ANCOVA model with the treatment groups (efpeglenatide 4 or 6 mg, dulaglutide 1.5 mg), 
randomization stratum of screening HbA1c (<8.0, ≥8.0%), Visit 3 (Day 1) BMI (<30 and 


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≥30 kg/m2), and geographical region (North America, Eastern Europe (including Hungary and 
Poland)) as fixed effects, and baseline HbA1c value as a covariate. 
In case a baseline value needed for multiple imputations is missing, it will be imputed by the 
population mean at Baseline. 
SAS pseudo-codes are provided in Appendix A.  
Results from each complete dataset will be combined to provide the adjusted mean change in 
HbA1c from baseline to Week 56 (regardless of treatment discontinuation or initiation of rescue 
therapy) for each treatment group, as well as the between-group difference (comparing each 
efpeglenatide group versus dulaglutide group) and the 95% CI for the difference. This will be 
implemented using MIANALYZE procedure in SAS. If the UB of the 2-sided 95% CI for the 
adjusted mean difference (efpeglenatide versus dulaglutide) in HbA1c change from baseline to 
Week 56 is ≤0.3%, the noninferiority will be declared. 
If noninferiority is demonstrated on the primary endpoint for both efpeglenatide groups, ie, the 
UB of the 2-sided 95% CI ≤0.3%, the superiority of each efpeglenatide group versus dulaglutide 
for the primary endpoint will be tested in a hierarchical fashion, with efpeglenatide 6 mg tested 
first and then efpeglenatide 4 mg. 
Summary statistics (for screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided for each treatment group. The summary will 
include the number of observations, mean, SD, SE, minimum, median, and maximum. Graphical 
presentations will also be used to examine trends over time using mean values (±SE) and mean 
changes from Baseline (±SE) at each of the scheduled visits (using OC). 
Sensitivity Analysis: 
Tipping point analysis: 
Tipping point analysis based on the same multiple imputation (MI) method as applied 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 (4 or 6 mg) who have no HbA1c data at Week 56. 
The penalty will be gradually increased to evaluate at which level the conclusion of the analyses 
in terms of non-inferiority 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 56 creates a shift in the treatment effect of efpeglenatide from the demonstration of non-
inferiority to the failure of non-inferiority. The penalty δ will start at 0 and increase by 0.1 (unit: 
%) at each imputation until UB of the 2-sided 95% CI for the adjusted mean difference is > 0.3%. 
Least square mean difference between each efpeglenatide dose and dulaglutide and their 
associated 95% CI will be provided for each penalty level.  
SAS pseudo-codes are provided in Appendix A. 


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Retrieved-dropout multiple imputation method: 
The retrieved-dropout multiple imputation sensitivity analysis will have 2 separates parts as 
follows:  
1. Missing endpoint data in participants who prematurely discontinue the study treatment 
before the Week-56 visit will be imputed using a model built separately in each arm and 
estimated from participants in the same treatment arm who prematurely discontinue the 
study treatment before the Week-56 visit but have the measurement for the endpoint 
(retrieved dropouts). Considering that the number of participants in each treatment arm 
who discontinue the study treatment but have the measurement for the endpoint is 
expected to be small, a simple imputation model will be used, where only the Hb1Ac 
baseline measurements are included as the predictor. Each treatment group will have their 
own imputation model.  
2. Missing endpoint data in all participants who stay on the study treatment until the 
Week-56 visit will be imputed using a model built separately in each arm and estimated 
from participants in the same treatment arm who stay on the study treatment until 
Week-56 visit and have the endpoint measurement, where randomization strata and 
Hb1Ac baseline measurements are included as the predictors. 
In both parts, the missing data will be imputed using the regression method. After imputation, the 
completed data sets will be analyzed using an ANCOVA model similar to the primary analysis. 
If there are no sufficient data to support the imputation approach in item 1 described above (less 
than 5 participants in any arms who prematurely discontinue the study treatment before the 
endpoint visit but have the measurement for the endpoint), a back-up method will be used. In 
particular, missing endpoint data in all participants, regardless of staying on the study treatment or 
not, will be imputed using a model built separately in each arm and estimated from participants in 
the same treatment arm with endpoint data, where randomization strata and corresponding 
baseline values are included as the predictors. 
SAS pseudo-codes are provided in Appendix A. 
Analysis on completers: 
For participants in ITT population who completed the 56-week treatment period and did not start 
any rescue therapy before the end of the period, the primary endpoint will be assessed too by the 
same ANCOVA model as used for the primary analysis using the observed values. 
2.4.4.1.1 Sensitivity analysis due to COVID-19 at Week 56 (HbA1c)  
Sensitivity analysis will be performed using ANCOVA (as specified in Section 2.4.4.1) with 
missing values imputed based upon BOCF-like MI method and MAR approach as described 
below, if there are more than 10 participants in total (regardless of treatment group) with missing 
endpoint data due to COVID-19. Participants with missing endpoint data due to COVID-19 are 
identified in Appendix C. 


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• For participants with missing HbA1c values at Week 56 not due to Covid-19, the missing 
values will be imputed using a random draw from a normal distribution with mean equal 
to their Baseline HbA1c and the standard deviation equal to the pooled standard deviation 
calculated from the square root of the mean square error estimated from a regression 
model with Baseline HbA1c as the dependent variable and randomization strata and 
treatment as the covariates.  
• For participants with missing HbA1c values at Week 56 due to Covid-19 in each group, 
the missing values will be imputed using separate models including the data at all 
scheduled visits within the same treatment group assuming missing at random.  
o Step 1: Use the Markov Chain Monte Carlo method in conjunction with the 
IMPUTE=MONOTONE option in PROC MI to create an imputed data set with a 
monotone missing pattern 
o Step 2: Based on the MONOTONE data sets obtained from Step 1, build the 
imputation model using the regression method sequentially for each scheduled visit. 
The imputation model will include the randomization stratum of Hba1c value at 
Screening (<8.0, ≥8.0%), Visit 3 (Day 1) BMI (<30, ≥30 kg/m²), corresponding 
baseline values and preceding scheduled postbaseline values.  
Participants without data at the endpoint visit will be summarized by treatment status 
(discontinued, completed) and by impact of COVID-19 on participant (yes, no) for each treatment 
group. 
Assessment of missing data: 
The availability of data (yes, no) at the endpoint visit (Week 56) will be summarized by treatment 
status (discontinued, completed) by treatment group. 
Patients without data at the endpoint visit be summarized by treatment status (discontinued, 
completed) and by impact of Covid-19 on participants (yes, no) for each treatment group. Reasons 
for missing primary efficacy endpoint (ie, HbA1c at Week 56) will be listed.  
Assessment of treatment effect by subgroup: 
Primary efficacy endpoint will be further analyzed to examine the consistency of the treatment 
effect across the subgroups defined by the following Screening or 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)  
Note: For all efficacy and safety subgroup analyses, race groups “Not reported”, 
“Unknown”, and participants who report more than one race will be considered “Other”.  
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
• Age group (<50, ≥50 to <65, ≥65) 
• Gender (Male, Female) 


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• Duration of diabetes (<10, ≥10 years) 
• Baseline HbA1c (<8.0, ≥8.0%) 
• Baseline BMI (<30, ≥30 to <40, ≥40 kg/m²) 
• Region (North America, Eastern Europe (including Hungary and Poland)) 
• Baseline estimated GFR categories (mL/min/1.73m²): (<60; ≥60 to <90, ≥90) 
The treatment effects (efpeglenatide 4, or 6 mg, versus dulaglutide 1.5 mg) across the subgroups 
defined for each of these factors will be estimated for the change from Baseline to Week 56 in 
HbA1c in the ITT population, and using a similar imputation approach (ie, BOCF-like MI method 
under MNAR framework) as applied to the analysis of the primary efficacy endpoint. The 
ANCOVA model will include treatment groups (efpeglenatide 4, or 6 mg, dulaglutide 1.5 mg) and 
randomization stratum of Screening HbA1c (<8.0, ≥8.0%), randomization stratum of Visit 3 
(Baseline, Day 1) BMI (<30, ≥30 kg/m2), subgroup factor, treatment-by-subgroup factor, and 
region as fixed factors and using Baseline HbA1c value as a covariate. The adjusted estimates of 
treatment mean differences (each efpeglenatide dose versus dulaglutide) with SE and 95% CIs 
will be provided as appropriate across the subgroups. A graphical presentation of the results (ie, 
forest plot) will also be provided. 
In the case that the subgroup factor (eg, Baseline HbA1c, Baseline BMI) is identical or similar to 
a randomization strata factor, only the subgroup factor (as a single factor or an interaction term) 
will be included in the model in order to avoid the issue of collinearity in the analysis. The 
corresponding strata factor will not be included in the model. In case that the subgroup factor is 
country, the region will not be included in the model. 
Descriptive statistics for change from baseline in Hba1c to Week 30 will be presented by ADA 
status the efpeglenatide groups:  
• ADA status (positive, negative) at Baseline, if ≥ 5% of patients are ADA positive; 
Treatment-emergent ADA status (positive, negative). 
Summary statistics at scheduled visits 
Summary statistics (for Screening value, Baseline value, observed values, and observed changes 
from Baseline) at scheduled visits will be provided by treatment group for HbA1c value over the 
treatment period. The last on-treatment value will be presented in a separate row. The summary 
will include the number of observations, mean, SD, SE, minimum, median, and maximum. 
Graphical presentations will also be used to examine trends over time using mean values (±SE) 
and mean changes from Baseline (±SE) at each of the scheduled visits (using OC). 
2.4.4.2 Analyses of secondary efficacy endpoints 
For secondary efficacy endpoints included in the multiplicity procedure described in  
Section 2.4.4.3, 2-sided statistical tests for the superiority of efpeglenatide versus dulaglutide will 
be performed at the alpha level of 0.05.  


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2.4.4.2.1 HbA1c < 7.0 % at Week 56 (yes/no) 
Proportions of participants achieving the HbA1c target value of <7.0% at Week 56 will be 
compared between each efpeglenatide dose versus dulaglutide using a Cochran-Mantel-Haenszel 
(CMH) test stratified by randomization stratum of Screening HbA1c (<8.0, ≥8.0%) and Visit 3 
(Baseline, Day 1) BMI (<30, ≥30 kg/m2) in the ITT population. For categorial secondary endpoint 
in which HbA1c is assessed at Week 56, all HbA1c values at Week 56 will be used to determine 
whether a participant is a responder (HbA1c <7.0%) or not, even if they are measured after IMP 
discontinuation or introduction of rescue therapy. Participants with missing HbA1c data at 
Week 56 will be considered not achieving HbA1c < 7.0%. The nominal p-value from the CMH 
test will be presented. No rounding for HbA1c will be done. 
2.4.4.2.2 Changes in FPG from Baseline to Week 56 and in body weight from baseline to 
Week 56 
Changes in FPG from baseline to Week 56 and in body weight to Week 56 will each be analyzed 
using the same ANCOVA model with missing values imputed by MI analysis method as the 
method used for the primary efficacy endpoint analysis. Differences between treatment groups 
and CIs will be estimated by this method. The least squares (LS) means, standard errors of LS 
means within each treatment group and the adjusted mean and associated two-sided 95% CI of the 
difference between efpeglenatide 4, 6 mg and 1.5 mg dulaglutide group will be presented.  
Summary statistics at protocol scheduled visits and for the last on-treatment value will also be 
provided for FPG and body weight. 
2.4.4.3 Multiplicity issues 
After noninferiority for the primary endpoint of change in HbA1c from Baseline to Week 56 has 
been established for both efpeglenatide 4 and 6 mg, the secondary endpoints will be tested in the 
prioritized order as follows: 
1. Change from baseline to Week 56 in HbA1c for efpeglenatide 6 mg versus dulaglutide 
(Superiority) 
2. Change from baseline to Week 56 in body weight for efpeglenatide 6 mg versus 
dulaglutide (Superiority) 
3. HbA1c <7.0% at Week 56 for efpeglenatide 6 mg versus dulaglutide (yes/no) (Superiority) 
4. Change from baseline to Week 56 in body weight for efpeglenatide 4 mg versus 
dulaglutide (Superiority) 
5. Change from baseline to Week 56 in HbA1c for efpeglenatide 4 mg versus dulaglutide 
(Superiority) 
6. HbA1c <7.0% at Week 56 for efpeglenatide 4 mg versus dulaglutide (yes/no) (Superiority) 
7. Change from baseline to Week 56 in FPG for efpeglenatide 6 mg versus dulaglutide 
(Superiority) 


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8. Change from baseline to Week 56 in FPG for efpeglenatide 4 mg versus dulaglutide 
(Superiority) 
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 dulaglutide 
than those mentioned earlier in this section. 
2.4.4.4 Exploratory efficacy analysis 
The analysis of the exploratory endpoints will be descriptive in general with no formal testing, 
unless otherwise specified. Summary statistics at scheduled visits using OC will be provided by 
each treatment group. For the continuous exploratory endpoints, descriptive summary statistics 
will be provided, including the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be provided as appropriate. 
2.4.4.4.1 HbA1c < 7.0 % at Week 30 (yes/no) 
Proportions of participants achieving HbA1c target values of <7.0% at Week 30 will be analyzed 
by same approach described in secondary endpoint: HbA1c < 7.0% at Week 56. Participants with 
missing HbA1c data at Week 30 will be considered not achieving HbA1c < 7.0%.   
2.4.4.4.2 Change in HbA1c/body weight/FPG from baseline to Week 30 
Changes from Baseline in HbA1c to Week 30, in body weight to Weeks 30 and in FPG to Week 
30 will each be analyzed by the same ANCOVA model with missing values imputed by MI 
method as described in section 2.4.4.1 the primary analysis.  
2.4.4.4.3 Changes in 7-point SMPG from Baseline to Weeks 30 and 56  
The 7-point SMPG profile should be measured at the following 7 points: pre-breakfast and 
2 hours post-breakfast, pre-lunch, 2-hour post-lunch, pre-dinner, 2-hour post-dinner, and at 
bedtime. Two hours postprandial (breakfast, lunch and dinner) is defined as 2 hours after the start 
of the meal. On days when 7-point profiles are done, fasting pre-breakfast SMPG will be 
considered as the first point of measurement, ie, “pre-breakfast” time point.  
Normally, investigator can only record one entry in the eCRF. In case of multiple records per visit 
for some participants, the most complete one should be selected; in case of a tie, the one closest to 
the visit will be selected for analysis. Descriptive statistics and graphs will be presented by 
treatment group at each visit for each time point. 
2.4.4.4.4 Changes in mean 24-hour SMPG from Baseline to weeks 30 and 56 
The mean 24-hour SMPG (7-point profile) will be calculated as the mean of the plasma glucose 
values over the 7 time points. The daily average data will be calculated only if at least 4 plasma 
glucose values are available. Only available plasma glucose values will be used for the 


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calculation. For example, if the available data are pre-breakfast, post-breakfast, pre-lunch, and 
pre-dinner, then the daily average will be calculated as (pre-breakfast + post-breakfast + pre-lunch 
+ pre-dinner)/4. 
Descriptive statistics and graphical presentations will be presented by treatment group over time. 
2.4.4.4.5 Changes in prandial glucose excursion from Baseline to Weeks 30 and 56  
The prandial glucose excursion, defined as the change in plasma glucose value after each meal 
(breakfast, lunch, or dinner), will be calculated by subtracting the preprandial value from the 
postprandial value. 
Prandial glucose excursion will be summarized by treatment group and over time. Additionally, 
graphical presentations will be provided as appropriate.  
2.4.4.4.6 Rescue therapy used during the treatment period until Weeks 30 and 56 (yes/no) 
Proportions of participants who used rescue therapy during the treatment period until Week 30 
and until Week 56 respectively will be summarized. 
2.4.4.4.7 Time to initiation of rescue therapy (weeks) 
Time to initiation of rescue therapy is defined as the time from the date of randomization to the 
date of first rescue therapy in weeks. Participants who did not take any rescue therapy during the 
study will be censored at the date of study completion/discontinuation. The curve of the 
cumulative incidence of participants with rescue initiation will be estimated using Kaplan-Meier 
method by study treatment group. 
2.4.4.4.8 Patient reported outcome: 
The Patient Qualitative Assessment of Treatment version 2 (PQATv2) is intended for the 
collection of participant-perceived benefit-risk of glucose-lowering treatment with IMP. The 
participants will be asked to complete it from home just before the on-site visits planned at 
Weeks 30 and 56. If a participant discontinues treatment with IMP during the treatment period, 
the participant will be asked to complete the PQATv2 at the time of discontinuation. 
The analysis of participant-reported outcome (PRO) endpoints will be descriptive with no formal 
testing. For categorical data, frequency and percentage will be provided by treatment group and 
overall at scheduled visits. Participants’ answers to the open-ended questions of PQATv2 (items 
#1, 3 and 5) will be analyzed qualitatively and quantitatively, as relevant, using appropriate data 
analysis software. The analysis method for open-ended questions will be provided separately and 
the analyses results will not be included in CSR. 


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2.4.4.4.9 Other exploratory analysis: 
• 
Analysis to investigate whether the HbA1c decrease depends on the decrease in weight 
will be assessed by scatter plots of HbA1c reduction versus weight loss. A cumulative 
distribution plot will be provided for each of changes in HbA1c and in body weight from 
Baseline to Week 30 and 56. 
• Proportion of participants with HbA1c < 7.0% at Week 30 and 56 with no severe or 
documented symptomatic hypoglycemia will be assessed by number of participants and 
percentage by treatment group. 
• Analysis of change in weight as a function of baseline BMI will be assessed by descriptive 
summary statistics at scheduled visits, by baseline BMI categorization (<19, [≥19 to <25], 
[≥25 to <30], [≥30 to <40], ≥40 kg/m2) and by treatment group. 
• Analysis of proportions of participants with 5% and 10% weight loss at Weeks 30 and 56 
will be assessed by number of participants and percentage by treatment group. 
• Descriptive statistics of change in waist circumference from baseline to Week 30 and 56 
will be provided by treatment group. 
• Descriptive statistics of change in the ratio C-peptide (nmol/L)/ FPG (mmol/L) from 
baseline will be provided by scheduled visit and treatment group. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group on the on-treatment period as 
defined in Section 2.1.4.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the common rules noted below. Safety data in participants who do not 
belong to the safety population (eg, treated but not randomized) will be listed separately. 
• The Baseline value is defined in Section 2.1.1. For WBC and differential counts, the 
baseline is defined as the last available value before the first injection of IMP where no 
differential component is missing.  
• Last on-treatment value is defined as the value collected at or just prior to the last IMP 
intake. 


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• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA version 3 date dated 21 May 2014 effective 
date 24 May 2014 [Appendix B]).  
• PCSA criteria will determine which participants had at least 1 PCSA during the 56-week 
on-treatment period, taking into account all evaluations performed during the 56-week 
on-treatment period, including nonscheduled or repeated evaluations. The number of all 
such participants will be the numerator for the 56-week on-treatment period PCSA 
percentage. 
• The treatment-emergent PCSA denominator by group for a given parameter will be based on 
the number of participants assessed for that given parameter in the 56-week on-treatment 
period by treatment group on the safety population. 
• 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 analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned. Relative risks between treatment groups and their 95% CIs may be 
provided, if relevant. 
• Selected safety analyses will be summarized by age group, gender, racial subgroups, and 
any pertinent subgroups as appropriate. 
2.4.5.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAEs. Pretreatment and posttreatment AEs will be 
described separately.  
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pretreatment, treatment-emergent, or 
posttreatment. The algorithm for imputing date/time of onset will be conservative and will classify 
an AE as treatment emergent unless there is definitive information to determine it is pretreatment 
or posttreatment. Details on classification of AEs with missing or partial onset dates are provided 
in Section 2.5.3. 
Incidence tables will present AEs by SOC, HLGT, HLT, and PT, sorted in SOC internationally 
agreed order and HLGT, HLT and PT sorted alphabetically for each treatment group, and the 
number (n) and percentage (%) of participants experiencing an AE. Multiple occurrences of the 
same event in the same participant will be counted only once in the tables within a treatment 
phase. The denominator for computation of percentages is the safety population within each 
treatment group. 


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Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period (pretreatment, treatment-emergent, and posttreatment). For that purpose, the table of all 
TEAEs presented by primary SOC and PT sorted by the internationally agreed SOC order and 
decreasing frequency of PTs within SOCs will define the presentation order for all other tables 
unless otherwise specified. In case of equal frequencies of PTs within a SOC, the alphabetic order 
will be applied. Sorting will be based on the incidence in the efpeglenatide 6 mg group. 
The internationally agreed order of SOCs shown below was described in the Introductory Guide 
MedDRA Version 19.1, September 2016 International Conference on Harmonisation for SOC: 
1. Infections and infestations 
2. Neoplasms benign and malignant (including cysts and polyps) 
3. Blood and lymphatic system disorders 
4. Immune system disorders 
5. Endocrine disorders 
6. Metabolism and nutrition disorders 
7. Psychiatric disorders 
8. Nervous system disorders 
9. Eye disorders 
10. Ear and labyrinth disorders 
11. Cardiac disorders 
12. Vascular disorders 
13. Respiratory, thoracic, and mediastinal disorders 
14. Gastrointestinal disorders 
15. Hepato-biliary disorders 
16. Skin and subcutaneous tissue disorders 
17. Musculoskeletal, connective tissue, and bone disorders 
18. Renal and urinary disorders 
19. Pregnancy, puerperium, and perinatal conditions 
20. Reproductive system and breast disorders 
21. Congenital and familial/genetic disorders 
22. General disorders and administration site conditions 
23. Investigations 
24. Injury, poisoning, and procedural complications 


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25. Surgical and medical procedures 
26. Social circumstances 
27. Product issues 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
• Overview of TEAEs, summarizing number (%) of participants with any 
- 
TEAE 
- 
Serious TEAE 
- 
TEAE leading to death 
- 
TEAE leading to permanent treatment discontinuation 
- 
Treatment-related TEAE 
- 
TEAEs of special interest (AESI) 
- 
TEAEs requiring specific monitoring (AERSM) 
• All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of participants 
with at least 1 TEAE sorted by the SOC internationally agreed order. The other levels 
(HLGT, HLT, PT) will be presented in alphabetical order. This sorting order will be 
applied to all other tables by SOC, HLGT, HLT, and PT, unless otherwise specified.  
• All TEAEs by primary SOC and PT, showing the number (%) of participants with at least 
1 TEAE, sorted by the internationally agreed SOC order and by decreasing incidence of 
PTs within each SOC. This sorting order will be applied to all other tables by SOC and 
PT, unless otherwise specified. 
• All TEAEs related to IMP by primary SOC, HLGT, HLT and PT, showing the number 
(%) of participants with at least 1 TEAE 
• All TEAEs by maximal intensity, presented by primary SOC and PT, showing the number 
(%) of participants with at least 1 TEAE by intensity (ie, mild, moderate, or severe) 
• Summary of common TEAEs (eg, PTs with incidence ≥ 2% in any treatment group) will 
also be presented by primary SOC, and PT 
• Summaries of common TEAEs (eg, PTs with an incidence ≥2% in any treatment group) 
will be provided as appropriate by primary SOC and PT and by demographic factors 
including gender (Male, Female), age group (<50, ≥50 to <65, ≥65 to <75, ≥ 75 years), 
and race (Asian, Black or African American, White, Other); 
Note: For all efficacy and safety subgroup analyses, race groups “Not reported”, 
“Unknown”, and participants who report more than one race will be considered “Other”. 
• Kaplan-Meier curves will be provided, when appropriate, for the time to first onset of the 
following PTs: nausea, vomiting, and diarrhea 


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• The frequency of TEAEs over time will be provided for nausea, vomiting and diarrhea, 
using weekly time intervals up to 56 weeks, ie, [0-1] week, [1-2] weeks, [2-3] weeks, [3-4] 
weeks, etc. In each time interval, the numerator in the calculation of percentages will be 
the number of participants with at least 1 TEAE occurring in this time interval. Two types 
of analyses will be included: (1) only the first event will be counted for each participant 
and all recurrent events will not be included, and the denominator for the calculation of 
percentages will be the number of participants at risk at the beginning of the time interval 
who did not experience a first event in the preceding intervals; and (2) the recurrent events 
in subsequent intervals will be counted once for each participant in the numerator of the 
corresponding interval, and the denominator for the calculation of percentages will be the 
number of participants at risk at the beginning of the time interval. A histogram of the 
frequency over time (by weekly intervals) will also be presented as appropriate. 
• All TEAEs by BMI subgroup (< 30, ≥ 30 kg/m2) 
• All TEAEs by Anti-Efpeglenatide Antibody Status (Positive, Negative) 
Analysis of all treatment emergent serious adverse event(s) 
All serious TEAEs by primary SOC, HLGT, HLT, and PT, showing the number (%) of 
participants with at least 1 serious TEAE.  
• All serious TEAEs related to IMP, by primary SOC and PT, showing the number (%) of 
participants with at least 1 serious TEAE 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of participants 
Analysis of adverse events of special interest and adverse events requiring specific monitoring  
Adverse events of special interest (AESI) and adverse events requiring specific monitoring (AERSM) 
include AE defined in Section 2.1.4.1 and the criteria of AESI and AERSM are in Table 2. 
Table 2 - Criteria for AESI and AERSM 
AE Grouping 
Criteria 
AESI 
 
         Pregnancy 
“Pregnancy” or “Partner pregnancy” checked 
         Symptomatic Overdose 
“Overdose” checked and symptomatic (AEOVSYMP) =”Yes” 
         Increase in ALT >3ULN 
“ALT Increase” checked and Yes to the question “Is the event 
an AESI?” in eCRF form “Adverse Events” 
AERSM 
 
Severe GI event 
AE severity= “severe” using Gastrointestinal disorders CMQ 
Severe hypoglycemia 
Any hypoglycemia event which required assistance (from 
hypoglycemia page) 


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AE Grouping 
Criteria 
Pancreatic event 
Cases reported in eCRF “Suspected or confirmed Pancreatitis” page 
or AE Category=”Pancreatic Neoplasm” 
Selected cardiovascular event 
Cases reported in the following specific eCRF pages: 
• ‘Suspected or confirmed MI/Unstable Angina’  
• 
‘Suspected or confirmed cerebrovascular event’,  
• 
‘Suspected or confirmed heart failure’ led to unplanned 
hospitalization, led to urgent/unscheduled visit to 
emergency room or an urgent/unscheduled outpatient 
heart failure treatment unit, or infusion center, or 
office/practice visit, not followed by hospitalization, or 
occurred while patient was hospitalized for another reason 
• 
Primary cause of death in eCRF “Death (CV)” as Acute MI, 
Sudden cardiac death, Heart failure or cardiogenic shock, 
Stroke, Complication of cardiovascular procedure, Other 
cardiovascular cause, or Undetermined cause of death 
Calcitonin and thyroid C-cell neoplasm 
Using Calcitonin increase CMQ 
Using Medullary thyroid cancer CMQ 
Acute renal failure 
Using Acute renal failure CMQ 
Severe injection site reaction 
Intensity = "Severe" + Using Injection site reaction CMQ. 
Severe allergic reaction 
Intensity = "Severe" + CMQs for anaphylactic reaction, angioedema, 
severe cutaneous adverse reaction, anaphylactic/anaphylactoid 
shock conditions (under SMQ "Shock"), and hypersensitivity. 
Severe immune complex disease 
Intensity = "Severe" using Immune complex disease CMQ  
Diabetic retinopathy complications 
Cases reported in eCRF “Diabetic Retinopathy Complementary 
Form” 
 
The number of participants, and the percent of participants who experienced TEAEs of special 
interest and TEAEs requiring specific monitoring will be presented for each AESI and AERSM 
specified above by PT and treatment group. PTs will be sorted by decreasing frequency in 
Efpeglenatide 6 mg group. 
Analysis of adjudicated events 
All events of death, selected cardiovascular events (MI, stroke, unstable angina leading to 
hospitalization, and heart failure leading to hospitalization), any pancreas related events, and other 
selected AEs (as defined in the CEC charter) will be reviewed, assessed and adjudicated by CEC. 
The number (%) of patients with an event positively adjudicated by CEC will be summarized by 
treatment group.  


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Analysis of pretreatment and posttreatment adverse events  
• All pretreatment AEs by primary SOC and PT, showing the number (%) of participants 
with at least 1 pretreatment AE 
• All posttreatment AEs by primary SOC and PT, showing the number (%) of participants 
with at least 1 posttreatment AE 
• All pretreatment SAEs by primary SOC and PT, showing the number (%) of participants 
with at least 1 pretreatment SAE 
• All posttreatment SAEs by primary SOC and PT, showing the number (%) of participants 
with at least 1 posttreatment SAE 
Analysis of adverse events during the 56-week on study observation period  
The following selected AE will also be summarized for the 56-week on-study observation period 
as defined in Section 2.1.4: 
• Overview of AEs 
• AEs (by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with at least 
1 adverse event) 
• SAE (by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with at 
least 1 serious adverse event) 
• AEs leading to death 
Listings 
Supportive AE listings will be provided for all SAEs, AESIs, AERSM, AEs leading to death, and 
AEs leading to treatment discontinuation. These listings will include at least the following 
information, sorted by treatment, participant identification, and onset date: treatment, participant 
identification, country, age, gender, race, randomization strata, primary SOC, PT, reported term, 
onset date, study day (relative day to the start date of IMP), AE duration, duration of exposure, 
intensity, corrective treatment, action taken with IMP, relationship to IMP/NIMP, outcome, date 
of death (if any), seriousness, seriousness criteria, and AE status (“Pre” for a pre-treatment AE; 
“T” for a TEAE; and “Post” for a post-treatment AE).  
Similar to the AE listing, a listing for all adjudicated AEs will be provided with adjudication 
outcome. 
Analysis of COVID-19 related adverse events  
 
COVID-19 related AEs during the on-treatment period will be presented for the number (%) of 
participants with at least one event and by primary SOC and PT. 


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2.4.5.2 Analysis of Hypoglycemia 
Treatment-emergent hypoglycemia events will be tabulated separately from the AEs. 
Event frequency and incidence of hypoglycemia events will be summarized by treatment for all 
reported hypoglycemia and per type of hypoglycemic event described in Section 2.1.4.6 (ie, 
severe, documented symptomatic, asymptomatic, probable symptomatic, relative) for safety 
population. Incidence of severe or documented symptomatic hypoglycemia events will be 
summarized by study period (≤4 weeks (titration period), >4 weeks to ≤8 weeks, >8 weeks to 
≤30 weeks, >30 weeks) and according to time of occurrence (nocturnal [ie, 00:00 to 05:59 am], 
daytime [ie, 06:00 am to 23:59]) for safety population. Documented hypoglycemia (symptomatic 
or asymptomatic) will be also evaluated for the more stringent plasma glucose threshold of 
<54 mg/dL (3.0 mmol/L), as well as for ≥3.0 and <3.9 mmol/L (≥54 and <70 mg/dL). Frequency 
and percentage of participants with at least one hypoglycemia event will be summarized as well. 
Event rate of hypoglycemia per participant year will be calculated by treatment using the total 
number of hypoglycemia events from all participants (denoted as n) divided by the total exposures 
from all participants expressed in years (ie, participant exposure in days divided by 365.25, 
denoted as t). Multiple events from an individual participant will all be counted. Event rates of 
hypoglycemia per participant year {all reported hypoglycemia, severe, documented symptomatic 
[<54 mg/dL (<3.0 mmol/L),  ≥54 and <70 mg/dL (≥3.0 and <3.9 mmol/L), ≤70 mg/dL(≤3.9 
mmol/L) respectively], asymptomatic, probable symptomatic, relative hypoglycemia} will be 
presented by treatment group during the 56-week on-treatment period. 
The summary of frequency and event rate in participant years for severe or documented 
symptomatic hypoglycemia will be provided as appropriate by gender (Male, Female), age group 
(<50, ≥50 to <65, ≥65 to <75, ≥ 75 years), and race (Asian, Black or African American, White, 
Other). 
A KM curve will also be provided by treatment group for the time to first severe or documented 
symptomatic hypoglycemia during the on-treatment period. 
A listing of participants for all severe or documented symptomatic hypoglycemia events reported 
on the specific eCRF “Hypoglycemic Event Information” page will be provided and sorted by the 
following order: severe, documented symptomatic. 
2.4.5.3 Deaths 
The following summaries of deaths will be generated for the safety population: 
• TEAE leading to death (death as an outcome on the AE case report form page as reported 
by the Investigator) during the on-treatment period by primary SOC, HLGT, HLT, and PT 
showing number (%) of participants (Safety population) 
• AE leading to death (death as an outcome on the AE case report form page as reported by 
the Investigator) during the 56-week on-study observation period by primary SOC, HLGT, 
HLT, and PT showing number (%) of participants (Safety population) 


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• Number (%) of participants who died by study period (on-study period (on-treatment 
period, post-treatment period), post-study period) 
• Pre-treatment AEs, TEAEs and post-treatment AEs leading to death (death as an outcome 
on the AE case report form page as reported by the Investigator) by study period (pre-
treatment period, on-treatment period, and post-treatment period) showing number (%) of 
participants  
2.4.5.4 Analyses of laboratory variables  
All hematology and clinical chemistry results will be listed by treatment group, participants and 
visit, including scheduled and unscheduled/repeat measurements.  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all protocol-required laboratory variables (central laboratory values and changes 
from Baseline) will be calculated for each scheduled visit and last value on treatment by treatment 
group. This section will be organized by biological function as specified in Section 2.1.4.3. 
The incidence of PCSAs at any time during the on-treatment period will be summarized by 
biological function and treatment group whatever the Baseline level and/or according to the 
following Baseline status categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. For calcitonin, no PCSA criterion is defined. Similar summaries will be 
provided using the pre-defined categories: ≤ULN, >ULN - < 20 ng/L, ≥20 - <50 ng/L, and 
≥50 ng/L (Note that ng/L is the standard international unit and is equivalent to pg/mL). 
All measurements collected during the on-treatment period, including values from unscheduled 
visits, will be considered for the PCSA summaries. These summaries will include participants in 
the safety population who have at least 1 assessment performed during the on-treatment period. 
When a PCSA definition involves only a change from baseline value, participants must also have 
a baseline value to be included in the summaries, and when required by the definition of the 
abnormality, participants must also have available laboratory normal ranges. 
For some parameters, such as liver enzymes, the lower limit of normal (LLN) is not considered 
clinically relevant, and values below this limit are considered normal. When there are multiple 
PCSA criteria for a specific parameter (eg, ALT), the participant will be counted once during the 
on-treatment period for the specific parameter in question under the worst/maximum PCSA 
category. 
Elevated liver parameters will be summarized by treatment group in safety population. 
For PCSA, both central and local lab data will be used. 


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A listing of participants with at least 1 post-baseline PCSA (or out of normal range when no 
PCSA criterion is defined) will be provided and will display the entire participants’ profile across 
time for all parameters belonging to the corresponding biological function. Individual data listings 
will include flags when applicable: 
• 
Baseline values will be flagged “B”. 
• 
Normal laboratory ranges, available for most laboratory parameters, will be identified as 
ULN and LLN. Baseline, and individual data will be flagged “L” if the value is below the 
LLN and will be flagged “H” if it is above the ULN. 
• 
Laboratory PCSA criteria will be used for the corresponding laboratory parameters. 
Values reaching a PCSA limit will be flagged (+, ++, -, or – depending upon the direction 
and level of the abnormality). Flags for WBC and differential counts will be determined 
using data expressed in international units. 
For parameters whose PCSA criteria are multiples of the ULN, the parameter’s value will also be 
expressed as a multiple of the ULN in the individual data provided. 
2.4.5.5 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital sign variables will be calculated for each scheduled visit by treatment 
group.  
The incidence of PCSAs at any time during the on-treatment period will be summarized by 
treatment group irrespective of the Baseline level and/or according to the following Baseline 
status categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
A listing of participants with at least 1 post-baseline PCSA will be provided and will display the 
participant’s profile over time of all vital sign parameters. Individual data listings will include the 
following flags: 
• Baseline values will be flagged “B”, 
• Parameter values reaching a PCSA limit will be flagged (+, or - depending of the 
direction). 
2.4.5.6 Analyses of electrocardiogram variables 
The frequency and percentage of 12-lead ECG interpretation (normal, abnormal) will be provided 
at each scheduled visit by treatment group.  


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2.4.5.7 Analyses of other safety endpoints 
Anti-drug Antibody: 
An anti-drug antibody positive participant is defined as a participant with at least one treatment-
induced or treatment-boosted ADA-positive sample at any time. 
Summaries of ADA data will be provided for participants treated with efpeglenatide only. All 
summaries related to kinetics of ADA response (ADA status and magnitude, ADA attributes, 
participant status, ADA incidence) will be descriptive; no statistical significance tests will be 
performed on ADA data. The incidence of ADA status (positive/negative) will be summarized by 
visit, treatment, and individual titer for the ADA population. Incidence of treatment induced and 
treatment-boosted (treatment emergent) ADA during on-study period will be summarized by 
treatment. Incidence of participants with ADA cross-reactivity to endogenous GLP-1 
(positive/negative), and to endogenous glucagon (positive/negative) will be summarized by visit 
and treatment. Incidence of participants with ADA directed against PEG linker, HMC001 moiety 
and exendin-4 moiety (positive/negative) will be summarized by visit and treatment. 
Incidence of participants with neutralizing antibodies against efpeglenatide and against 
endogenous GLP-1 and Glucagon will be summarized by visit and treatment. 
ADA data from unscheduled visits (due to SAE for example) will not be included in summary and 
will be presented only in ADA values listing. 
Patient – Reported Outcomes: 
Eight Patient-Reported Outcome Measurement Information System (PROMIS) GI symptom 
scales have been developed and validated to capture the breadth and depth of GI symptoms 
experienced by people with a wide range of digestive disorders. In this study, only nausea and 
vomiting (4 items), diarrhea (6 items), and belly pain (5 items) symptom scales will be collected. 
The participants will be asked to complete the evaluation electronically from home or at site 
before the start of any procedures or tests, at the timepoints showed in the SoA (Appendix D). In 
case of early IMP discontinuation, the PROMIS GI symptom scales will be completed by the 
participant at the time of discontinuation and afterwards as normally planned. 
The analysis of PROMIS GI symptoms scales v1 will be descriptive with no formal testing and 
conducted on the ITT population. Summary statistics of the raw scores and T-scores of GI 
symptom scales at scheduled visits will be provided by treatment group for each scale (nausea and 
vomiting, diarrhea, belly pain). The raw score for each scale is calculated as the arithmetic sum of 
all the individual item scores according to PROMIS GI symptoms scales v1 documentation. In 
case the participant does not answer every question (has missing data), the raw score can be 
approximately estimated according to following steps: 
• Sum up all scores from the items that were answered  
• Multiply the results obtained above by the total number of questions in that scale 
• Divide the results obtained above by the number of items answered 


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The T-score will be calculated using the association table provided in the PROMIS GI symptoms 
scales v1 documentation between the raw score and T-Score. The T-score has been estimated 
using an item response theory graded response model (GRM) that includes a slope parameter that 
differs across items.  
Plots will be also presented to illustrate trends over visits by treatment group for mean raw scores 
and mean T-scores for each scale. The mean raw scores and mean T-scores for each scale will be 
presented on the y-axis. Schedule visits will be presented on the x-axis.  
2.4.6 Analyses of pharmacokinetic variables 
Serum concentrations of efpeglenatide, pre-dose (Ctrough) and post-dose will be summarized 
(mean, SD, CV%, median, minimum, and maximum) over time and by treatment and by visit.  
Serum concentrations of efpeglenatide, pre-dose (Ctrough) and post-dose, will be listed.  Population 
PK analysis will be discussed in a separate analysis plan. 
2.4.7 Analyses of quality of life/health economics variables 
Not applicable. 
2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
The participant’s duration of diabetes (years) is calculated using the date of informed consent and 
the date of diabetes diagnosis. 
If date of diabetes diagnosis is a complete date, then the duration of diabetes is (date of informed 
consent - date of diabetes diagnosis + 1) / 365.25. If date of diabetes diagnosis is a partial date: 
a) year and month are not missing, but day is missing, then day = 01 
b) year is not missing, but month and date are both missing, then month = January 
and day = 01. 


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Renal function formulas  
eGFR will be calculated using the 4-variable Modification of Diet in Renal Disease (MDRD-4) 
formula below (1): 
• eGFR (mL/min/1.73 m2) = 175×serum creatinine (mg/dL)-1.154×Age(year)-
0.203×1.212 [if black]×0.742 [if female]  
2.5.2 Data handling conventions for secondary efficacy variables 
No special data handling. 
2.5.3 Missing data 
For categorical variables, participants with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of participants with missing 
data is presented. 
Derived variables will be considered missing if any of the original variables required to calculate 
them are missing. For example, if either a baseline assessment or an endpoint assessment is 
missing for a participant, then change from baseline at endpoint will be missing. Depending upon 
the assessment, analyses may not include all participants in the analysis population, because 
certain participants in the intended population may have missing data. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the treatment status case report form page. If this date is 
missing, the exposure duration should be left as missing.  
In the definition of the on-treatment period, the date of the last dose of IMP is equal to the date of 
the last administration reported on the treatment status case report form page. If this date is 
missing, the date of the last IMP injection in the exposure page will be used for participants with 
at least 1 injection or the date of visit 3/randomization visit will be used for participants who were 
lost to follow-up after the initial dispensation of IMP. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 


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For time to event (TTE) analysis, partial rescue medication dates will be imputed using the 
following rules: 
a) If year and month are not missing, but day is missing, then day = 15 
b) If year is not missing, but month and date are both missing, then month = June and 
day = 15. 
Note: if it’s possible that the partial date is within the on-treatment period, but the imputed date 
falls outside of the on-treatment period, then imputed date will be set to the nearest date inside the 
on-treatment period. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial AE/hypoglycemia onset dates and times will be imputed so that if the partial 
AE/hypoglycemia onset date/time information does not indicate that the AE/hypoglycemia started 
prior to treatment or after the on-treatment period, the AE/hypoglycemia will be classified as 
treatment-emergent. No imputation of AE end dates/times will be performed. These data 
imputations are for categorization purpose only and will not be used in listings. No imputation is 
planned for date/time of AE resolution. 
Handling of adverse events/hypoglycemia when date and time of first investigational medicinal 
product administration is missing 
When the date and time of the first open-label IMP administration is missing, all 
AEs/hypoglycemia that occurred on or after the day of randomization should be considered as 
TEAEs. The exposure duration should be kept as missing. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the AE considered as such in the frequency tables of possibly related AEs, but no 
imputation should be done at the data level. 
Handling of missing intensity of adverse events 
If the intensity is missing for 1 of the treatment-emergent occurrences of an AE, the maximal 
intensity on the remaining occurrences will be considered. If the intensity is missing for all the 
occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a participant has a missing Baseline, he or she will be grouped in the category “normal/missing 
at Baseline.” 
For PCSAs with 2 conditions, one based on a change from Baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 


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For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.  
Handling of missing screening value to derive actual randomization strata 
In case of missing data at screening visit for HbA1c and BMI, unscheduled data before 
randomization visit can be used. If the sample is confirmed as being for the purpose of a re-
screen, then the result is sent to be integrated into IRT. In case of several data collected, the 
earliest is used. 
2.5.4 Windows for time points 
Nominal post-baseline visits will be used for descriptive statistics and time course plots. 
Display of safety data by visit (laboratory variables and vital signs) 
Descriptive statistics (N, mean, SD, minimum, median, maximum) of quantitative laboratory 
variables and vital signs (observed data and change from baseline) during the on-treatment period 
for all scheduled visits as per protocol will be provided (ie, only including participants having 
non-missing assessments at a nominal visit). Summaries showing data by visit will be presented 
according to the visit number and labeled with the targeted approximate day/week. 
As specified in the study protocol, laboratory data from scheduled visits are reported by central 
laboratories. When both central and local laboratories report values from the same blood sample 
(ie, sample collected at the same date and time), only measurements from the central laboratory 
will be included in the analyses. When only local laboratory results are reported and central 
laboratory results are unavailable, the local results will not be used in the efficacy analyses. In the 
safety analyses, local results will only be used in the PCSA summary if they are accompanied by a 
local laboratory normal range. 
When a participant has more than 1 measurement from the central laboratory for the same 
laboratory parameter on the same date, the average of the measurements will be used. For the 
same laboratory parameter, if a participant has more than one measurement on different dates for 
the same scheduled visit, the value closest to the scheduled visit will be used for the scheduled 
visit. When the values for the same scheduled visit are equidistant, the last value should be used 
for the scheduled visit. 
Early Treatment Discontinuation (efficacy parameters) 
Subjects who discontinue treatment at or just before a regularly scheduled visit will have the Early 
Treat Term Visit page completed instead of the scheduled visit in the eCRF, and the scheduled visit 
will be reported as not done. For analysis purposes, values from Early Treat Term Visits will be 
mapped directly to the scheduled visit.  


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Efficacy data at Week 30 / Week 56 
The scheduled measurements at the endpoint visit (Week 30 or Week 56) as collected will be used in 
the efficacy analyses including those obtained after IMP discontinuation and/or introduction of rescue 
therapy. For participants whose efficacy measurement is not available at the endpoint visit, the 
measurement at unscheduled visit (including the end of treatment and/or study visit for those 
prematurely discontinued) will be used if the unscheduled measurement is within +/-30 days (7 days 
for FPG and SMPG) of the date of the end point visit [targeted study Day 210 for Week 30 (or 
Day 392 for Week 56)]. If multiple measurements are associated to the same targeted date, the closest 
to the targeted study day will be used. In case of equality, the last measurement will be used. If there 
are still no measurements for a given parameter at an endpoint visit, the data is considered missing for 
efficacy analyses, where multiple imputation would be applied as appropriately as described in 
Section 2.4.4.1. 
Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with a reference identification number that links the new record to the original 
record. An AE that worsened or became serious will be considered a new recurring AE in the 
summary of recurrent events or in the summary of events by time intervals. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will not be included in 
the by-visit summaries, but will be used for computation of Baseline and PCSAs. 
2.5.6 Pooling of centers for statistical analyses 
Not applicable. 
2.5.7 Statistical technical issues 
Not applicable. 


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3 
INTERIM ANALYSIS 
No interim analysis is planned. 


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


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


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6 
REFERENCES 
 
1. FDA Draft Guidance for Industry. Pharmacokinetics in patients with impaired renal function - 
study design, data analysis, and impact on dosing and labeling. Clinical Pharmacology. 2010 
Mar (revision 1). 
 


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7 
LIST OF APPENDICES 
 
Appendix A: 
Efficacy Analysis SAS pseudo code 
Appendix B: 
Criteria for Potentially Significant Abnormalities  
Appendix C 
Diagram for Identifying Missing Data due to COVID-19 
Appendix D 
Schedule of Activities 


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Appendix A 
Efficacy Analysis SAS pseudo code 
Primary Analysis missing data imputation: 
 
1) Multiple imputations in participants who have missing HbA1c values at Week 56  
 
  Step 1: Perform regression to estimate pooled mean and standard deviation of non-missing baseline HbA1c measures 
 
proc glm data=BaseHbA1c; 
class ARM HbA1c_strata BMI_strata; 
model base = ARM HbA1c_strata BMI_strata; 
ods output FitStatistics=basefit; 
run; 
 
proc sql noprint; 
select RootMSE, depmean 
into :std, mean 
from basefit; 
quit; 
 
 
Step 2: For participants with missing HbA1C values at week 56, simulate week 56 HbA1c 10000 times by random draw 
(with seed=14829) from a normal distribution with mean equal to baseline HbA1c and STD equal to the pooled STD from the 
regression model in Step 1. In case baseline HbA1c is missing, pooled mean is used as baseline HbA1c.   
For participants with non-missing HbA1C values at week 56, repeat the same record 10000 times (iteration 1 to 10000) to 
generate 10000 data sets. 
 
 
 
VV-CLIN-0365236 2.0


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data HbA1cW56Complete; 
  set InputData; 
  call streaminit(14829);  
   do _imputation_ = 1 to 10000; 
    if base = . then newbase = &mean;  /* in case of missing baseline HbA1c measure, pooled mean is used as the 
baseline HbA1c*/ 
    else newbase = base ;  
    
   base_simu = rand ('normal', newbase, &std);  
   
   if aval=. then do ;  
      aval=base_simu ; 
      msfl = ‘Y’;   /* Flag missing record for tipping analysis */ 
    end;  
    
   chg_wk56 = aval - newbase ; 
    
   output ;  
end; 
run; 
    
Step 3: Use ANCOVA and Rubin’s formula to obtain the between-group difference and 95% CI. 
 
proc mixed data=HbA1cW56Complete; 
class ARM HbA1c_strata BMI_strata region; 
model chg_wk56 = ARM HbA1c_strata BMI_strata region NEWBASE; 
by _Imputation_; 
VV-CLIN-0365236 2.0


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lsmeans ARM/ pdiff=control (‘Dulaglutide 1.5 mg’) cl; 
ods output LSMeans=lsmeans  diffs=lsmeansdiff; 
run; 
 
proc mianalyze parms=lsmeansdiff; 
  modeleffects ARM; 
  by ARM; 
  ods output parameterestimates=miparm; 
run; 
 
In this sample SAS® (version 9.4) code: 
 
- BaseHbA1c contains one observation per participant in the ITT population with Baseline HbA1c value.  
- InputData contains one observation per participant in the ITT population with Week 56 HbA1c value 
- HbA1cW56Complete is the final output containing 10,000 lines by participant with all observed and simulated data used 
for the ANCOVA.  
- ARM is the randomized treatment group (Dulaglutide 1.5 mg, Efpeglenatide 4mg, Efpeglenatide 6mg).  
- HbA1c_strata is the randomization stratum of screening Hb1Ac (<8.0, ≥8.0%) 
- BMI_strata is the randomization stratum of BMI at Visit 3(<30, ≥30) 
- BASE is the observed baseline HbA1c. 
- BASE_simu contains the simulated baseline HbA1c values. 
- NEWBASE is the baseline HbA1c including observed (If non-missing) and imputed (If missing, pooled mean) data. 
- CHG_WK56 is the change from baseline in HbA1c at Week 56.  
- REGION is the geographical region. 
- The seed is 14829. 
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Sensitivity analysis using retrieved-dropout multiple imputation method: 
1. Multiple imputations in participants who prematurely discontinued the study treatment before the Week-56 visit:  
         proc mi data=data_IN out=data_OUT_DISC  nimpute=10000 seed=14829; 
 
where PEOT56FL = "Y"; 
 
by ARM; 
 
var BASE AVAL_W56; 
 
monotone regression (AVAL_W56= BASE ); 
              run; 
 
2. Multiple imputations in participants who stay on the study treatment until the Week-56 visit:  
                 proc mi data=data_IN out=data_OUT_COMPL_MI  nimpute=10000 seed=14829; 
where PEOT56FL=’N’; 
by ARM; 
 
class HbA1c_strata BMI_strata; 
 
var HbA1c_strata BMI_strata base AVAL_W56; 
 
monotone regression (AVAL_W56 = HbA1c_strata BMI_strata  BASE ); 
                run;  
 
3. Combine multiple imputations from the step 1 and step 2 above 
Data 
dataMI; 
set  
data_OUT_DISC  
data_OUT_COMPL_MI  
run; 
 
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Back-up plan: 
proc mi data =data_IN out=data_OUT_MI  nimpute=10000 seed=14829; 
                               by ARM; 
              class HbA1c_strata BMI_strata; 
              var HbA1c_strata BMI_strata base AVAL_W56; 
 
  monotone regression (AVAL_W56 = HbA1c_strata BMI_strata  BASE ); 
run;  
In this sample SAS® (version 9.4) code: 
- 
DATA_IN is the input dataset including one observation per participant in the ITT population with Baseline HbA1c value 
and change from baseline at Week 56. 
- 
data_OUT_DISC is the output dataset including observed and imputed data for participants who have prematurely 
discontinued the treatment. 
- 
data_OUT_COMPL_MI is the output dataset including observed and imputed data for all participants who have 
completed the 56-week study treatment period.  
- 
Data_OUT_MI is the output dataset including observed and imputed data for all participants using backup plan. 
- 
PEOT56FL is the variable indicating whether the participant prematurely discontinued the study treatment 
(PEOT56FL=”Y” if the participants prematurely discontinued the study treatment before Week 56 visit and 
PEOT56FL=”N” if the participant stay on the study treatment until Week 56 visit). 
- 
ARM is the randomized treatment group (Dulaglutide 1.5 mg, Efpeglenatide 4mg, Efpeglenatide 6mg). 
- 
HbA1c_strata is the randomization stratum of screening Hb1Ac (<8%, ≥8%) 
- 
BMI_strata is the randomization stratum of BMI at Visit 3(<30, ≥30) 
- 
BASE is the baseline HbA1c. 
- 
AVAL_W56 is the HbA1c at Week 56. 
- 
The seed (14829) has been chosen arbitrarily and is based on the study code (EFC14829). 
VV-CLIN-0365236 2.0


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Sensitivity analysis (If more than 10 missing endpoint data impacted by COVID-19): 
 
Step 1: Perform regression to estimate pooled mean and standard deviation of non-missing baseline HbA1c measures 
 
proc glm data=BaseHbA1c; 
class ARM HbA1c_strata BMI_strata; 
model base = ARM HbA1c_strata BMI_strata; 
ods output FitStatistics=basefit; 
run; 
 
proc sql noprint; 
select RootMSE, depmean 
into :std, mean 
from basefit; 
quit; 
 
 
data base_imputed; 
  set InputData; 
    if base = . then newbase = &mean;  /* in case of missing baseline HbA1c measure, pooled mean is used as the 
baseline HbA1c*/ 
    else newbase = base ;  
run; 
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Statistical Analysis Plan 
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Step 2: Multiple imputations 
 
1) Multiple imputations in participants who have missing HbA1c values at Week 56 not due to Covid-19 
 
For participants with missing HbA1C values at week 56, simulate week 56 HbA1c 10000 times by random draw (with 
seed=14829) from a normal distribution with mean equal to baseline HbA1c and STD equal to the pooled STD from the 
regression model in Step 1. In case baseline HbA1c is missing, pooled mean is used as baseline HbA1c.   
For participants with non-missing HbA1C values at week 56, repeat the same record 10000 times (iteration 1 to 10000) to 
generate 10000 data sets. 
 
data data_OUT_MI_MISSING; 
  set base_imputed (where W56_missing = “Y” and COVID = “N”); 
  call streaminit(14829);  
   do _imputation_ = 1 to 10000; 
    
   base_simu = rand ('normal', newbase, &std);  
   
   if aval_W56=. then do ;  
      aval_W56=base_simu ; 
    end;  
    
   chg_wk56 = aval_W56 - newbase ; 
    
   output ;  
end; 
run; 
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Statistical Analysis Plan 
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2) Multiple imputations in participants who have missing HbA1c values at Week 56 due to Covid-19 
 
proc sort data=base_imputed out= data_IN_COVID; 
                        by ARM; 
run; 
 
proc mi data =data_IN_COVID out= monotone nimpute=10000 seed=14829; 
 
 
by ARM; 
where (W56_missing ne “Y” or (W56_missing = “Y” and COVID=“Y”)); 
 
 
mcmc chain=multiple impute=monotone 
 
 
var BASE AVAL_W12 AVAL_W30 AVAL_W43 AVAL_W56; 
run;  
 
    proc mi data= monotone out= OUT_MI_MISSING_COVID nimpute=1 seed=14829; 
              
by ARM _imputation_; 
              
class HbA1c_strata BMI_strata; 
             
 monotone reg (  / details); 
              
var HbA1c_strata BMI_strata BASE AVAL_W12 AVAL_W30 AVAL_W43 AVAL_W56; 
 run; 
 
data data_OUT_MI_MISSING_COVID; 
 
set OUT_MI_MISSING_COVID; 
 
if W56_missing = “Y”; 
run; 
 
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Statistical Analysis Plan 
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3) Identifying observed values 
data_data_OUT_COMPL_MI; 
Set 
base_imputed (where = (AVAL_W56^=.)); 
_imputation_=0; 
do i = 1 to 10 000; 
 
 
 
_imputation_=_imputation_+1; 
output; 
end; 
run;   
 
4) Combine imputation datasets and use ANCOVA and Rubin’s formula to obtain the between-group difference and 95% CI. 
 
data 
dataMI; 
set  
data_OUT_MI_MISSING  
data_OUT_MI_MISSING_COVID 
data_OUT_COMPL_MI; 
run; 
 
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Statistical Analysis Plan 
02-Oct-2020 
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Property of the Sanofi Group - strictly confidential 
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Step 3: ANCOVA analysis 
 
proc mixed data=HbA1cW56Complete; 
class ARM HbA1c_strata BMI_strata region; 
model chg_wk56 = ARM HbA1c_strata BMI_strata region NEWBASE; 
by _Imputation_; 
lsmeans ARM/ pdiff=control (‘Dulaglutide 1.5 mg’) cl; 
ods output LSMeans=lsmeans  diffs=lsmeansdiff; 
run; 
 
proc mianalyze parms=lsmeansdiff; 
  modeleffects ARM; 
  by ARM; 
  ods output parameterestimates=miparm; 
run; 
 
In this sample SAS® (version 9.4) code: 
 
- BaseHbA1c contains one observation per participant in the ITT population with Baseline HbA1c value.  
- InputData contains one observation per participant in the ITT population 
- data_OUT_COMPL_MI is the output dataset including observed values 10,000 times by participant 
- data_OUT_MI_MISSING is the output dataset containing 10,000 lines per participant with missing endpoint data not due 
to COVID-19 
- data OUT_MI_MISSING_COVID is the output dataset containing 10,000 lines per participant with missing endpoint data 
due to COVID-19 
- dataMI is the final output containing 10,000 lines by participant with all observed and simulated data used for the 
ANCOVA.  
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Statistical Analysis Plan 
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Property of the Sanofi Group - strictly confidential 
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- ARM is the randomized treatment group (Dulaglutide 1.5 mg, Efpeglenatide 4mg, Efpeglenatide 6mg).  
- HbA1c_strata is the randomization stratum of screening Hb1Ac (<8.0, ≥8.0%) 
- BMI_strata is the randomization stratum of BMI at Visit 3(<30, ≥30) 
- BASE is the observed baseline HbA1c. 
- BASE_simu contains the simulated baseline HbA1c values. 
- NEWBASE is the baseline HbA1c including observed (If non-missing) and imputed (If missing, pooled mean) data. 
- CHG_WK56 is the change from baseline in HbA1c at Week 56.  
- W56_missing = for each patient, “Y” if the Week 56 value is missing, otherwise W56_missing = “N”.  
- COVID = for each patient, “Y” if the missing data at Week 56 is impacted by COVID-19, otherwise COVID = “N”. 
- REGION is the geographical region. 
- The seed is 14829. 
 
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
 
 
Property of the Sanofi Group - strictly confidential 
Page 66 
Appendix B 
Criteria for Potentially Significant Abnormalities – for Phase 2/3 
studies (oncology excepted)   
 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
 
 
ALT 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
AST 
By distribution analysis: 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed in 
ULN, not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in µmol/L 
or mg/L. Categories are cumulative. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI >1.5 ULN 
Conjugated bilirubin dosed on a case-by-
case basis. 
ALT and Total Bilirubin 
ALT >3 ULN and TBILI >2 ULN 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment 
phase, whatever the interval between 
measurement. 


Statistical Analysis Plan 
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Parameter 
PCSA 
Comments 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
CLcr (mL/min) 
(Estimated creatinine clearance based 
on the Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, 
data analysis, and impact on dosing and 
labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - < 60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, 
data analysis, and impact on dosing and 
labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 


Statistical Analysis Plan 
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Parameter 
PCSA 
Comments 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not 
provided) 
FDA Sept 2005. 
Hematology 
 
 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L 
(Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L 
(Black) 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN 
≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from 
baseline are more relevant than based 
on absolute value. Other categories for 
decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male); ≤0.32 v/v (Female) 
≥0.55 v/v (Male); ≥0.5 v/v (Female) 
 


Statistical Analysis Plan 
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Parameter 
PCSA 
Comments 
RBC 
≥6 Tera/L 
Unless specifically required for particular 
drug development, the analysis is 
redundant with that of Hb. 
Otherwise, consider FDA criteria. 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
Urinalysis 
 
 
pH 
≤4.6 
≥8 
 
Vital signs 
 
 
HR 
≤50 bpm and decrease from baseline 
≥20 bpm 
≥120 bpm and increase from baseline 
≥20 bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline 
≥10 mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
 
Ref.: ICH E14 guidance (2005) and E14 
Q&A (2012), and Cardiac Safety 
Research Consortium White Paper on 
PR and QRS (Nada et al. Am Heart J. 
2013; 165(4): 489-500) 


Statistical Analysis Plan 
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Property of the Sanofi Group - strictly confidential 
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Parameter 
PCSA 
Comments 
HR 
<50 bpm 
<50 bpm and decrease from baseline 
≥20 bpm 
<40 bpm 
<40 bpm and decrease from baseline 
≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline 
≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline 
≥20bpm 
>100 bpm  
>100 bpm and increase from baseline 
≥20bpm 
>120 bpm  
>120 bpm and increase from baseline 
≥20 bpm 
Categories are cumulative 
PR 
>200 ms 
>200 ms and increase from baseline 
≥25% 
> 220 ms 
>220 ms and increase from baseline 
≥25% 
> 240 ms 
> 240 ms and increase from baseline 
≥25% 
Categories are cumulative 
QRS 
>110 ms 
>110 msec and increase from baseline 
≥25% 
>120 ms 
>120 ms and increase from baseline 
≥25% 
Categories are cumulative 
QT 
>500 ms 
 


Statistical Analysis Plan 
02-Oct-2020 
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Parameter 
PCSA 
Comments 
QTc 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
Absolute values categories are 
cumulative 
 
QTc >480 ms and QTc>60 ms are the 
2 PCSA categories to be identified in 
individual subjects/patients listings. 
 
 
 
 


Statistical Analysis Plan 
02-Oct-2020 
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Property of the Sanofi Group - strictly confidential 
Page 72 
Appendix C 
Diagram for Identifying Missing Data due to COVID-19 
 
Note: the diagram could be adapted to secondary efficacy endpoints as appropriate. 
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Statistical Analysis Plan 
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Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 73 
Appendix D 
Schedule of Activities (SOA) 
 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 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 
 
 
 
 
 
Participants 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 
X 
X 
X 
 
See Table 2 in the protocol 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 V2 and before 
randomization 
Demography, medical/surgical 
history  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes diabetes complications, CV 
and allergy history, alcohol and 
smoking habits. 
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Statistical Analysis Plan 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Physical examination  
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Vital signs  
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
BP and HR in sitting position after at 
least 5 minutes of rest. 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Waist circumference  
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Section 8.1.4 in the protocol 
12-lead ECG 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
X 
 
The 12-lead ECG recording should 
be obtained in supine position prior 
to IMP dose administration. See 
Section 8.2.3 in the protocol. 
IMP injection training/retraining 
as needed 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
See Section 6.1.1 in the protocol. 
Inspection of injections sites 
 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
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Statistical Analysis Plan 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Diary dispensation 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Diary review and collection 
 
 
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 counseling 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
As per current practice, to be 
documented. See Section 5.3.1 in 
the protocol 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
IMP dispensation 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
At V2, training kit(s) will be allocated; 
self-injection will be done at site. 
IMP collection and accounting 
 
X 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
Training kit(s) will be collected and 
accounted at V2. 
Compliance  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SMPG, IMP, diary 
Efficacy: 
HbA1c 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
FPG  
 
 
X 
 
 
X 
X 
 
 
X 
 
X 
 
X 
 
For these visits, participants need to 
come in fasting condition as 
described in Section 5.3.1 in the 
protocol 
C-peptide (fasting) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
For these visits, participants need to 
come in fasting condition as 
described Section 5.3.1 in the 
protocol 
7-point SMPG 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
Performed on at least 1 day in the 
week prior to visits indicated. See 
Section 8.1.5 in the protocol for 
details. 
Fasting (prebreakfast) SMPG 
 
 
X 
X 
X 
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 weeks prior to other visits 
indicated. See Section 8.1.2 in the 
protocol for details. 
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Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Safety: 
Hematology 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
See Appendix 2 (Section 10.2) in the 
protocol. 
Clinical chemistry 
X 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
See Appendix 2 (Section 10.2) in the 
protocol. 
Calcitonin 
X 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
See Appendix 2 (Section 10.2) in the 
protocol. 
Lipid profile 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2) in the 
protocol. 
Urinalysis 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2) in the 
protocol. 
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 78 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Pregnancy test (WOCBP) 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Serum pregnancy testing (β-HCG) at 
screening for WOCBP (Appendix 4 
[Section 10.4] in the protocol), 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] in the protocol). 
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 79 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Antidrug antibody (ADA) 
sampling 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Participants positive for ADA at EOS, 
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 end of the treatment. Blood 
samples are to be collected to 
assess the efpeglenatide ADA status 
(positive or negative) and level (titer) 
applicable for the participants 
assigned to efpeglenatide.  
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 80 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
IMP concentration (PK) 
sampling 
 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
All participants assigned to 
efpeglenatide will have 1 blood sample 
collected just before their weekly 
injection (and at least 6 days after last 
dose administration) for the predose 
serum concentration (Ctrough) of 
efpeglenatide at selected clinical visits. 
See Section 8.5 in the protocol. 
For efpeglenatide participants who 
consent, at least 1 additional postdose 
sample will be taken 3 days (±1 day) 
after administration of efpeglenatide, 
preferably between Week 8 and 
Week 12, but other weeks are also 
acceptable (eg, after the 1st dose, 4th 
dose, or 12th dose). Participant will 
need to provide separate consent. See 
Section 8.5 in the protocol. 
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 81 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Patient-reported Outcomes 
PQATv2  
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
PQATv2 should be completed by 
participants as far as possible at 
home before on-site visits. See 
Section 8.1.7 in the protocol. 
PROMIS GI symptoms scale, 
version 1 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
This questionnaire will have to be 
completed by participants as far as 
possible at home before on-site visits 
after randomization and additionally 
at Weeks 1, 3, 5, 6, 7, and 18. 
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 82 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Rescue therapy assessment 
 
 
Continuous assessment and recording during treatment periods 
After randomization, the need of 
rescue treatment should be 
assessed by the Investigators via 
fasting SMPG performed by the 
participants and/or the central 
laboratory alerts received on FPG 
and on HbA1c (from Week 12 
[Visit 7] onwards). Participants must 
have an unscheduled in-person visit 
prior to rescue therapy initiation, with 
the assessments normally planned 
for the EOT visit. See Section 6.1.2.2 
in the protocol 
VV-CLIN-0365236 2.0


Statistical Analysis Plan 
02-Oct-2020 
SAR439977-EFC14829 - efpeglenatide 
Version number: 2 
 
Property of the Sanofi Group - strictly confidential 
Page 83 
Procedure 
Screening  
(up to 3 
weeks) 
Treatment Period  
(56 Weeks) 
Post 
treatment 
Follow-
up  
(6 wks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
–3 
–1 
0 
base-
line 
2 
4 
8 
12 
18 
24 
30 
36 
43 
50 
56 a 
Last 
IMP+6 
weeks 
 
Acceptable range (days) 
-21 
to -11 
-7 
(±3) 
1 
14 
(±3) 
28 
(±3)  
56 
(±3) 
84 
(±3) 
126 
(±3) 
168 
(±3) 
210 
(±3) 
252 
(±5) 
301 
(±5) 
350 
(±5) 
392 
(±5) 
434 
(±7) 
V2 can be done as soon as the 
screening eligibility is confirmed 
V3 can be done 4 to 10 days after V2 
V3 should be done at least 11 days 
after V1 (to allow IMP to be sent to 
the site) and no later than 21 days 
after V1 
Concomitant medication recording 
Continuous assessment and recording throughout the study 
 
AE/SAE recording 
 
Reporting hypoglycemia 
(symptoms, SMPG) 
Hypoglycemia eCRF page must be 
filled in for all SMPG values 
≤3.9 mmol/L (≤70 mg/dL) and/or in 
case of symptoms suggesting 
hypoglycemia (between V1 and V2, 
SMPG values measured with non-
study glucometer can be used) 
a In case of premature permanent IMP discontinuation, participants should have a visit as soon as possible after last IMP administration with the assessments normally planned for EOT visit 
(including a PK sample if the visit can be scheduled 7 days after the permanent IMP discontinuation). Afterwards, the participants should continue in the study up to the scheduled date of study 
completion and be followed up according to the study procedures as specified in the protocol. Every effort should be made to have the participant complete the Week 56 Visit assessments 
(primary and main secondary endpoints) as the minimum.  
For safety reasons, participants who do not want to continue to be followed in the study after IMP discontinuation, should be assessed 6 weeks (±1 week) from the last IMP dose (at the 
minimum) using the procedure normally planned for the post-treatment follow-up visit at EOS. At the time corresponding to their Week 56 Visit, all attempts will be made to contact the 
participants to inquire about safety/vital status. 
Abbreviations: ADA: antidrug antibody, AE: adverse event, β-HCG: beta-human chorionic gonadotropin, BP: blood pressure, CV: cardiovascular, ECG: electrocardiogram, EOS: end of study, EOT: 
end of treatment, FPG: fasting plasma glucose, FSH: follicle-stimulating hormone, HbA1c: hemoglobin A1c, GI: gastrointestinal, HR: heart rate, IMP: investigational medicinal product, IRT: 
interactive response technology, PK: pharmacokinetics, PQATv2: Patient´s Qualitative Assessment of Treatment version 2; PROMIS: Patient-Reported Outcomes Measurement Information System; 
R: Randomization; SAE: serious adverse event, SMPG: self-monitored plasma glucose, WOCBP: women of childbearing potential 
VV-CLIN-0365236 2.0


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