Clinical trial NCT03713684
Conditions: Type 2 Diabetes Mellitus
Sponsor: Sanofi
Start date: 2018-11-09; Completion date: 2021-01-04
Enrollment: 370 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To demonstrate the superiority of once weekly injection of efpeglenatide in comparison to placebo in glycated hemoglobin (HbA1c) change in participants with type 2 diabetes mellitus (T2DM) inadequately controlled with basal insulin alone or in combination with oral antidiabetic drugs (OADs).

Secondary Objectives:

* To demonstrate the superiority of once weekly injection of efpeglenatide in comparison to placebo on glycemic control.
* To demonstrate the superiority of once weekly injection of efpeglenatide in comparison to placebo on body weight.
* To evaluate the safety of once weekly injection of efpeglenatide.

Detailed description:
Study duration per participant was approximately 64 weeks including an up to 2-week Screening Period, a 30-week Core Treatment Period, a 26-week Safety Extension Period, and a 6-week safety Follow-up Period.

Arms: arm 1: Participants received placebo (matched to efpeglenatide) subcutaneous (SC) injection once weekly up to Week 56 on top of basal insulin alone or in combination with oral antidiabetic drugs (OADs). arm 2: Participants received Efpeglenatide 2 milligrams (mg) SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. arm 3: Participants received Efpeglenatide 4 mg SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg and maintained at the 4 mg dose through-out the treatment duration up to Week 56. arm 4: Participants received Efpeglenatide 6 mg SC injection once weekly up to Week 56 on top of basal insulin alone or in combination with OADs. Participants initiated dosing at 2 mg once weekly up to Week 1; which was up titrated to 4 mg until Week 4 and later up-titrated to 6 mg and maintained at the 6 mg dose through-out the treatment duration up to Week 56.
Interventions: intervention 1: Efpeglenatide SAR439977 intervention 2: Placebo intervention 3: Background therapy
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: subcutaneous intervention 2: Pharmaceutical form: solution for injection Route of administration: subcutaneous intervention 3: Lantus (Insulin Glargine), SC, once daily; OADs, administered as per investigator prescription and in accordance with local labeling.

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, double-blind, 
placebo-controlled, randomized study to evaluate the 
efficacy and safety of efpeglenatide once weekly in 
patients with Type 2 diabetes mellitus inadequately 
controlled with basal insulin alone or in combination 
with oral antidiabetic drug(s) 
Protocol number: 
EFC14893 
Amendment number: 
01 
Compound number 
(Trademark/INN): 
SAR439977/efpeglenatide 
Short title: 
Efficacy and safety of efpeglenatide versus placebo in 
patients with Type 2 diabetes mellitus inadequately 
controlled with basal insulin alone or in combination 
with oral antidiabetic drug(s) (AMPLITUDE-L) 
Sponsor name: 
Legal registered 
address: 
Regulatory agency identifying number(s): 
EudraCT number: 
2017-002955-27 
IND number: 
112780 
UTN number: 
U1111-1189-5009 
Approval Date: 
30-Sep-2019
Total number of pages: 103 
NCT03713684


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Sponsor signatory: 
 
Please refer to the last page of this document for electronic signatures including date and time. 
Monitoring Team’s Representative 
Name and Contact Information: 
   


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 
30 September 2019, version 1 (electronic 1.0) 
Original Protocol 
 
20 June 2018, version 1 (electronic 2.0) 
 
 
AMENDED PROTOCOL 01 (30 September 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 
postdose sample collection 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. 


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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis and 
Section 2.1 Study rationale 
Specified the patient population and mentioned that 
patients with T2DM should be inadequately controlled 
with basal insulin alone or in combination with OAD(s) 
Clarification on the studied 
population. 
Section 1.1 Synopsis 
(Noninvestigational medicinal 
product) and Section 6.1.2.1 
Background medication 
The Lantus starting dose should be based on HbA1c at 
screening instead of at randomization 
Clarification 
Section 1.1 Synopsis 
(Statistical consideration-
Primary analysis) and Section 
9.4.1 Efficacy analysis 
Clarified that the primary efficacy endpoint will be 
analyzed in all participants randomized 
Clarification 
Section 1.3 Schedule of 
activities - ADA 
The following text was added in the notes section: “or as 
soon as possible after study database lock whichever 
comes later.” 
Clarification 
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 at selected 
clinical visits.  
For a subset of participants, 1 additional postdose 
sample will be taken either 4 days (±1 day) after 1st IMP 
dose, or 4 days (±1 day) after 4th dose, or 4 days (±1 
day) after 12th dose). A separate consent will be signed. 
See Section 8.5.” 
To:  
“All participants will have 1 blood sample collected just 
before their weekly injection (and at least 6 days after last 
IMP dose administration) for the predose serum 
concentration (Ctrough) of efpeglenatide at selected clinical 
visits. 
For participants who consent, at least 1 additional 
postdose sample will be taken 3 days (±1 day) after 
administration of IMP, preferably between Week 8 and 
Week 12. 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. 
The timeline of PK predose 
sample collection from the 
previous IMP dose administration 
has 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 
antidrug antibodies (ADA) 
formation. 
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). 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities - footnote “a” 
Footnote “a” has been updated from: 
“In case of premature permanent IMP discontinuation, the 
participant should have a visit as soon as possible after 
the last IMP administration with the assessments 
normally planned for EOT visit.” 
To 
“In case of premature permanent IMP discontinuation, the 
participant should have a visit as soon as possible after 
the last IMP administration with the assessments 
normally planned for EOT visit (including a PK sample if 
the visit can be scheduled 6-7 days after the permanent 
IMP discontinuation).” 
 
“For safety reasons, participant who wish to terminate 
participation in the study, should be assessed 6 weeks 
(±1 week) from the last IMP dose (at the minimum) using 
the procedure normally planned for the posttreatment 
follow-up visit at EOS.” 
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 posttreatment follow-
up visit (EOS).” 
The footnote has been reworded 
for clarity. 
Section 2.2 Background 
Under diabetic retinopathy bullet point, the text was 
updated from “No cases have been reported for 
efpeglenatide”  
To “No cases have been reported for efpeglenatide in 
completed Phase 1 and 2 studies”. 
Specified the section numbers of the IB (Section 5 
Nonclinical Studies and Section 6 Effects in humans) that 
contains nonclinical and clinical information of 
efpeglenatide, respectively. 
Clarification 
 
 
 
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 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 [Week 1], or 4 days 
[±1 day] after 4th dose [Week 4], or 4 days [±1 day] after 
12th dose [Week 12] in a subset of participants, at least 
10% of total: [N = 12 per group]).” 
To:  
“Postdose serum concentration 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 5.3.1 Meals and dietary 
restrictions 
Under fasting conditions, the following wording has been 
added to the first and second bullet, respectively: 
 
“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. 
Section 6.1 Study 
intervention(s) administered 
Table 2 Overview of Study 
Interventions Administered 
The following text was added under dosing instructions: 
“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).” 
To clarify the site of IMP 
administration before PK 
sampling. 
Section 6.1.1 Investigational 
medicinal products 
Specified the name of reference document “Pharmacy 
Manual”. 
The following text was added “In case of emergency only, 
for scheduled or unscheduled visits, the IMP and Lantus 
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 6.1.2.1 Background 
medication 
The following text added for Lantus: 
“Lantus is the only background therapy provided by the 
Sponsor. The appropriate number of kits will be 
dispensed for the period until the next dispensing visit 
(please refer to the SoA Section 1.3). Lantus will be 
provided until the end of study even in case of premature 
end of treatment for patients attending the safety 
follow-up visits. Storage conditions and use-by-end date 
(when required by country regulations) are part of the 
label text.” 
Clarification of Lantus allocation 
during treatment period and after 
premature treatment 
discontinuation 
Section 6.2 Preparation/ 
handling/storage/ accountability 
Specified the name of reference document “Pharmacy 
Manual”. 
The following text was added “except for IMP and Lantus 
in case of DTP shipment, for which a courier company 
has been approved by the Sponsor” 
Clarification.  
To include DTP, a new process 
regarding IMP dispensation in 
case of emergency. 
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. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.3.2 Randomization 
code breaking during the study 
The following text was changed from: 
Only the Project Manager and lead scientist at the 
Bioanalytical laboratory, as well as the popPK analyst, 
will have access to the randomization code to allow for 
the sorting of the efpeglenatide blood samples. 
To 
Only the predefined designated personnel from Sponsor 
and Bioanalytical laboratory will have access to the 
randomization code to allow for the sorting of the 
efpeglenatide blood samples.  
 
The following text was changed from:  
“Refer to Section 8.3.4 for suspected unexpected serious 
adverse reaction (SUSAR) unblinding by the Sponsor.” 
To 
“Randomization code breaking will be performed for 
reporting to the Health Authorities of any suspected 
unexpected serious adverse reaction (SUSAR). Refer to 
Section 8.3.4 for regulatory reporting requirements. The 
unblinding information will not be disclosed to patients, 
sites or any clinical team personnel prior to the database 
lock.” 
Clarification and simplification as 
process is detailed in the 
applicable standard procedure for 
PK analysis 
 
 
 
 
 
 
 
Clarification of the unblinding 
process for SUSARs 
 
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 
IMP and Lantus unless the Sponsor provides written 
authorization.” 
To: 
“The Investigator will not destroy the used and unused 
IMP and Lantus unless the Sponsor or delegate provides 
written authorization.” 
Clarification on who can provide 
authorization for destruction of 
IMP 
Section 7.1.1 Permanent 
discontinuation 
The following text was modified from: 
“As all data until the scheduled date of study completion 
will be used in statistical analyses, it is important to 
collect data for all participants, under treatment or not, 
during the 56 weeks of the study. A high rate of missing 
data could jeopardize efficacy results of the study. 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.” 
To: 
”As all randomly assigned 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. 
Collection of Week 30 data is of highest importance as 
they are needed for primary endpoint analysis. 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 
Clarification and reinforcing the 
importance of data collection for 
primary and main secondary 
endpoints after permanent IMP 
discontinuation.  
 
 
 
 
 
 
 
 
 
 
 


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Section # and Name 
Description of Change 
Brief Rationale 
time of intervention discontinuation and follow-up and for 
any further evaluations that need to be completed.” 
 
The following text was modified from: 
“If possible, the participants will be assessed using the 
procedure normally planned for the EOT Visit, including a 
PK sample when the permanent discontinuation occurred 
during the Core Treatment Period and the visit can be 
scheduled 7 days after the permanent discontinuation of 
intervention. For participants who discontinue IMP but 
remain in the study, the remaining visits should occur as 
scheduled where possible.” 
To: 
“If possible, the participants who discontinue IMP will be 
assessed using the procedure normally planned for the 
EOT Visit, including a PK sample when the permanent 
discontinuation occurred during the Core Treatment 
Period and the visit can be scheduled 6 to 7 days after 
the permanent discontinuation of IMP. For participants 
who discontinue IMP, but who remain in the study, the 
remaining visits should occur as scheduled, where 
possible, until Week 56 (Visit 13), and all planned 
procedures should be performed.” 
 
 
 
 
Clarification of the schedule of 
assessments after permanent IMP 
discontinuation  
Section 8.1.1 Hemoglobin A1c 
Reference to SoA Section 1.3 added 
Clarification 
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 on heart rate 
measurement.  
Section 8.2.3 12-lead 
electrocardiogram 
The text updated from: 
“Each ECG trace must be analyzed in comparison with 
the screening ECG results.” 
To 
“Each ECG trace must be analyzed in comparison with 
the baseline ECG results.” 
Text corrected for consistency 
with the SoA. 
Section 8.2.5 Hypoglycemia  
Added analysis of documented hypoglycemia with a 
measured plasma glucose concentration “≥3.0 and 
≤3.9 mmol/L (≥54 and ≤70 mg/dL)”. 
To align with new FDA 
recommendations regarding 
hypoglycemia definition.  
Section 8.3 Adverse Event and 
Serious Adverse Event 
The reference to Appendix 1 (Section 10.1.4.3) has been 
deleted from the diabetic retinopathy complications bullet. 
Maintaining consistency among 
the sections.  


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.3.1 Time period and 
frequency for collecting AE and 
SAE information 
The following text was added: 
“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 8.5 Pharmacokinetics 
The following text has been added pertaining to predose 
PK sampling: 
“Blood samples for measurement of serum 
concentrations of efpeglenatide will be collected for all 
participants in order to keep blinding and analyzed for 
participants in efpeglenatide arms only. 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).” 
 
The following text has been modified from: 
“For a subset of participants, 10% of total (N = 12 per 
group): 1 additional postdose sample will be taken either 
4 days (±1 day) after 1st IMP dose, or 4 days (±1 day) 
after 4th dose, or 4 days (±1 day) after 12th dose. To 
reach this number and due to the blind design of the 
study, PK postdose sample will be collected in the first 80 
randomly assigned participants who will accept this 
additional sampling, sign the separate consent form, and 
provide a valid postdose sample.” 
To: 
“For participants who consent for additional postdose PK 
sampling, at least 1 additional postdose sample will be 
taken 3 days (±1 day) after administration of 
efpeglenatide or placebo, preferably between Week 8 
and Week 12, but other weeks are also acceptable (eg, 
after 1st dose, 4th dose, or 12th dose). A minimum of 
120 evaluable postdose samples (in participants on 
efpeglenatide) are needed to contribute to popPK 
analysis. To reach this number and due to the blind 
design of the study, PK postdose samples will be 
collected in participants who will accept this additional 
sampling, sign the separate consent in the main ICF and 
provide a valid postdose sample until the above number 
of evaluable samples is confirmed.” 
Clarification on the general 
predose PK sampling process. 
 
 
 
 
 
 
 
 
To allow collection of more PK  
data in the drug absorption phase 
and to allow higher flexibility with 
regard to postdose sample 
collection window in order to 
facilitate additional postdose 
sampling. 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.8.1 Immunogenicity 
Assessments 
The following wording changed: 
From 
“Blood samples are taken to assess the ADA status 
(positive or negative) and level (titer).” 
To 
“Blood samples for assessment of ADA status (positive or 
negative) and level (titer) will be collected for all 
participants in order to keep blinding and analyzed for 
participants in efpeglenatide arms only.” 
 
And from 
“Participants positive for ADAs at the end of study, and 
who experienced severe injection site or hypersensitivity 
reaction at any time during the study, will be asked to 
provide sample for anti efpeglenatide antibodies 
assessments 4 and 6 months after the end of the 
treatment.” 
To 
 “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 additional samples for anti efpeglenatide 
antibodies assessments approximately 4 and 6 months 
after the end of the treatment or as soon as possible after 
study database lock whichever comes later.” 
 
 
Clarification provided for ADA 
sampling requirements. 
 
 
 
 
 
 
Clarification on the ADA follow-up 
sampling for patients who are 
ADA positive at the EOS and 
experienced predefined severe 
events while on treatment 
Section 9.4.3, Table 8 Other 
analyses 
Clarified text pertaining to postdose PK samplings, text 
changed from: 
“Efpeglenatide predose and postdose serum 
concentrations of participants in the efpeglenatide groups 
will be listed and summarized by visit in the PK 
population, using descriptive statistics by n geometric 
mean, coefficient of variation, median, minimum and 
maximum.” 
To 
“Efpeglenatide predose and postdose serum 
concentrations of participants in the efpeglenatide groups 
will be listed and summarized by visit in the PK 
population, using descriptive statistics by n geometric 
mean, coefficient of variation, median, minimum and 
maximum.” 
Clarification of  PK statistical 
analysis 


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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.1.3 Data protection 
The following text was added: 
“All personal data collected related to participants, 
Investigators, or any person involved in the study, which 
may be included in the Sponsor’s databases, shall be 
treated in compliance with all applicable laws and 
regulations including the GDPR (Global Data Protection 
Regulation).” 
“When archiving or processing personal data pertaining 
to the Investigator and/or to the participants, the Sponsor 
shall take all appropriate measures to safeguard and 
prevent access to this data by any unauthorized 
third party.” 
To update the section with 
reference to GDPR and archiving 
requirements. 
Section 10.1.6 Data quality 
assurance 
Text was updated for retaining records and documents 
from 15 years to 25 years after the signature of the final 
study report 
To update in accordance with new 
document retention requirements 
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; all efforts to be done to 
collect all medical documents from ophthalmologic 
examination(s) related to potential diabetic retinopathy 
events.”  
Adverse event of diabetic 
retinopathy complications will be 
reviewed as per current medical 
review process without an 
independent ophthalmologist 
expert review.  
Section 10.1.7 Source 
documents 
Specified the name of reference document “GCP training 
module” 
Clarification. 
Section 10.3 Appendix 3 
Specified the name of reference document “the site file 
(detailed Study Contact List)”. 
Clarification.  
Section 10.5 Appendix 5 
Flowchart for neutropenia was updated 
To update in accordance with new 
follow-up recommendations 
Section 10.5.2.1 Elevation of 
amylase and/or lipase >2 x 
ULN without clinical signs 
and/or symptoms 
The following bullet points were updated 
From 
“If value(s) is/are >2 to 3 × ULN: retest within 7 days. 
If value(s) is/are >3 × ULN: retest within 48 hours.” 
To 
“If value(s) is/are >2 to 3 × ULN in a participant with 
baseline amylase and/or lipase values <2 × ULN: retest 
within 7 days. 
If value(s) is/are >3 × ULN: retest within 48 hours, 
regardless of baseline amylase and/or lipase values.” 
Clarification on the 
recommendations for 
amylase/lipase retest according to 
baseline values 
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 ............................................................................... 3 
TABLE OF CONTENTS ................................................................................................................................ 12 
LIST OF TABLES ......................................................................................................................................... 16 
LIST OF FIGURES ........................................................................................................................................ 16 
1 
PROTOCOL SUMMARY ............................................................................................................... 17 
1.1 
SYNOPSIS ..................................................................................................................................... 17 
1.2 
SCHEMA ........................................................................................................................................ 23 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 24 
2 
INTRODUCTION............................................................................................................................ 30 
2.1 
STUDY RATIONALE ..................................................................................................................... 30 
2.2 
BACKGROUND ............................................................................................................................. 30 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 31 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 34 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 36 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 37 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 37 
5 
STUDY POPULATION .................................................................................................................. 38 
5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 39 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 41 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 41 


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5.4 
SCREEN FAILURES ..................................................................................................................... 42 
6 
STUDY INTERVENTION ............................................................................................................... 43 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 43 
6.1.1 
Investigational medicinal products ................................................................................................. 44 
6.1.2 
Noninvestigational medicinal products .......................................................................................... 45 
6.1.2.1 
Background medication ................................................................................................................. 45 
6.1.2.2 
Rescue therapy .............................................................................................................................. 47 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...................................................... 48 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 50 
6.3.1 
Methods of blinding ........................................................................................................................ 50 
6.3.2 
Randomization code breaking during the study ............................................................................. 50 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 51 
6.4.1 
Return and/or destruction of treatments ........................................................................................ 52 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 52 
6.6 
DOSE MODIFICATION .................................................................................................................. 53 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 53 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 54 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 54 
7.1.1 
Permanent discontinuation ............................................................................................................ 54 
7.1.2 
Temporary discontinuation ............................................................................................................. 55 
7.1.2.1 
Rechallenge ................................................................................................................................... 56 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 56 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 57 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 58 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 58 
8.1.1 
Hemoglobin A1c ............................................................................................................................. 58 
8.1.2 
Fasting plasma glucose ................................................................................................................. 58 
8.1.3 
Body weight .................................................................................................................................... 58 
8.1.4 
Waist circumference ...................................................................................................................... 59 
8.1.5 
7-point self-monitored plasma glucose profiles ............................................................................. 59 
8.1.6 
Use of rescue therapy .................................................................................................................... 59 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 60 


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8.2.1 
Physical examinations ................................................................................................................... 60 
8.2.2 
Vital signs ....................................................................................................................................... 60 
8.2.3 
12-lead electrocardiogram ............................................................................................................. 60 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 61 
8.2.5 
Hypoglycemia ................................................................................................................................. 61 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 63 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 64 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 65 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 65 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 65 
8.3.5 
Pregnancy ...................................................................................................................................... 65 
8.3.6 
Cardiovascular and death events .................................................................................................. 66 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 66 
8.3.8 
Guidelines for reporting product complaints/medical device incidents (including 
malfunctions) .................................................................................................................................. 66 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 66 
8.5 
PHARMACOKINETICS .................................................................................................................. 66 
8.6 
PHARMACODYNAMICS ............................................................................................................... 67 
8.7 
GENETICS ..................................................................................................................................... 67 
8.8 
BIOMARKERS ............................................................................................................................... 67 
8.8.1 
Immunogenicity assessments ........................................................................................................ 67 
8.9 
HEALTH ECONOMICS .................................................................................................................. 68 
9 
STATISTICAL CONSIDERATIONS  ............................................................................................. 69 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 69 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................ 69 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 70 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 70 
9.4.1 
Efficacy analyses ........................................................................................................................... 70 
9.4.2 
Safety analyses .............................................................................................................................. 74 
9.4.3 
Other analyses ............................................................................................................................... 76 
9.5 
INTERIM ANALYSES .................................................................................................................... 77 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 77 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 78 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 78 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 78 
10.1.2 
Informed Consent Process ............................................................................................................ 78 
10.1.3 
Data Protection .............................................................................................................................. 79 
10.1.4 
Committees Structure .................................................................................................................... 80 
10.1.4.1 Data Monitoring Committee ........................................................................................................... 80 
10.1.4.2 Clinical Endpoint Committee .......................................................................................................... 80 
10.1.5 
Dissemination of Clinical Study Data ............................................................................................. 80 
10.1.6 
Data Quality Assurance ................................................................................................................. 81 
10.1.7 
Source documents ......................................................................................................................... 81 
10.1.8 
Study and Site Closure .................................................................................................................. 81 
10.1.9 
Publication Policy ........................................................................................................................... 82 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 82 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 84 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 88 
10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 92 
10.5.1 
Laboratory abnormalities ............................................................................................................... 92 
10.5.2 
Monitoring of participants with increased lipase and/or amylase >2 × ULN .................................. 97 
10.5.2.1 Elevation of amylase and/or lipase >2 × ULN without clinical signs and/or symptoms ................. 97 
10.5.2.2 Elevation of amylase and/or lipase >2 × ULN with clinical signs and/or symptoms. ..................... 98 
10.5.3 
Management of participants with increased calcitonin values ....................................................... 98 
10.5.4 
Gastrointestinal events in relation to acute renal failure ................................................................ 99 
10.5.5 
Guidance for monitoring participants with diabetic retinopathy ..................................................... 99 
10.6 
APPENDIX 6: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  ............................................... 99 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 99 
10.8 
APPENDIX 8: HYPOGLYCEMIA CLASSIFICATION .................................................................. 100 
10.9 
APPENDIX 9: ABBREVIATIONS ................................................................................................. 101 
10.10 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY .............................................................. 102 
11 
REFERENCES............................................................................................................................. 103 
 


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LIST OF TABLES  
Table 1 - Objectives and endpoints ............................................................................................................... 33 
Table 2 - Overview of study interventions administered ............................................................................... 43 
Table 3 - Recommended Lantus dose adjustment algorithm ....................................................................... 46 
Table 4 - Rescue criteria ............................................................................................................................... 47 
Table 5 - Populations for analyses ................................................................................................................ 70 
Table 6 - Efficacy analyses ........................................................................................................................... 70 
Table 7 - Safety analyses .............................................................................................................................. 75 
Table 8 - Other analyses ............................................................................................................................... 76 
Table 9 - Protocol-required safety laboratory assessments .......................................................................... 83 
Table 10 - Highly effective contraceptive methods ....................................................................................... 90 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 23 
Figure 2 - Hypoglycemia classification ........................................................................................................ 100 
 


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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A 56-week, multicenter, double-blind, placebo-controlled, randomized study to 
evaluate the efficacy and safety of efpeglenatide once weekly in patients with 
Type 2 diabetes mellitus inadequately controlled with basal insulin alone or in 
combination with oral antidiabetic drug(s) 
Short title: 
Efficacy and safety of efpeglenatide versus placebo in patients with Type 2 
diabetes mellitus inadequately controlled with basal insulin alone or in 
combination with oral antidiabetic drug(s) (AMPLITUDE-L) 
Rationale: 
The aim for the present trial is to compare efpeglenatide once weekly versus placebo once weekly 
in addition to Lantus alone or with oral antidiabetic drug(s) OAD, in a population of patients with 
type 2 diabetes mellitus (T2DM) inadequately controlled with basal insulin alone or in 
combination with OAD(s), in terms of glycemic control, weight control, and other efficacy and 
safety parameters.  
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, or 6 mg in comparison to placebo in HbA1c 
change from baseline to Week 30 in participants with T2DM 
inadequately controlled with basal insulin alone or in 
combination with OAD(s) 
 
Change from baseline to Week 30 in HbA1c. 
Secondary 
 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4 and 6 mg in comparison to placebo on 
glycemic control. 
 
Number of participants with HbA1c <7% at Week 30. 
 
Change from baseline to Week 30 in fasting plasma 
glucose (FPG). 
 
 Change from baseline to Week 56 in HbA1c. 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4 and 6 mg in comparison to placebo on body 
weight. 
 
Change from baseline to Week 30 and Week 56 in 
body weight. 
To evaluate the safety of once-weekly injection of efpeglenatide 
2, 4 and 6 mg 
 
 
Number of participants with at least one 
hypoglycemic event during treatment period. 
 
Number of hypoglycemic events per participant-year 
during treatment period. 
 
Number of participants with AEs (see Section 8.3). 
AE: adverse event, FPG: fasting plasma glucose, HbA1c; hemoglobin A1c, OAD: oral antidiabetic drug, T2DM: type 2 diabetes 
mellitus 


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Overall design: 
This study is a Phase 3, multicenter, randomized, double-blind, placebo-controlled, 4-arm, 
parallel-group study in participants with T2DM inadequately controlled with basal insulin alone 
or in combination with OAD(s). 
The randomization (1:1:1:1) to efpeglenatide 2 mg, efpeglenatide 4 mg, efpeglenatide 6 mg, or 
placebo will be stratified by screening HbA1c (<8%, ≥8%) and sulfonylurea (SU) use at screening 
(Yes/No). 
An independent Data Monitoring Committee (DMC) will review accumulating clinical study 
safety data throughout the study and an independent Clinical Endpoint Committee [CEC] will 
review, assess, and/or adjudicate all events of death, selected cardiovascular adverse events (AEs), 
pancreatic events, and other selected AEs, see Appendix 1 (Section 10.1) for further details of 
study committees. 
Number of participants: 
Sufficient participants will be screened to achieve 400 randomly assigned participants assigned to 
study intervention for an estimated total of 100 participants per treatment group. All randomly 
assigned participants will be included in the population analyzed for efficacy endpoints. 
Section 9.2 gives details of the sample size determination. 
Intervention groups and duration: 
The study comprises 4 periods as follows: 
 A 2-week Screening Period. 
 A 30-week double-blind, placebo-controlled Core Treatment Period, for efficacy and 
safety assessment. 
 A 26-week double-blind, placebo-controlled Treatment Extension Period (participants will 
remain on the randomized investigational medicinal product [IMP] regimen). 
 A 6-week posttreatment Follow-up Period to collect safety information after last dose of 
IMP. 
The maximum study duration per participant will be 64 weeks. 
Study interventions 
Investigational medicinal product 
Efpeglenatide/Matching placebo 
 Formulation: 500 µL of a sterile, nonpyrogenic, clear, colorless solution in a 1 mL 
disposable prefilled syringe (PFS). 
 Route of administration: subcutaneous (SC). 
 Dose regimen: SC injection once weekly on the same week day (eg, each Monday) at any 
time of the day. 


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The dose will be titrated as shown in the table below. From Week 4 (Visit 4) through the rest of 
the double-blind treatment period, participants will remain on the randomized IMP until the end 
of treatment (EOT) at Week 56 (Visit 13). 
Investigational medicinal product dose schedule 
 
Dose 1 
Dose 2 
Dose 3 
Dose 4 
Dose 5 
 
Day 1 
Week 1 
Week 2 
Week 3 
Week 4 
 
Visit 2 
 
Visit 3 
 
Visit 4 
Dosing 
(on-site) 
(at home) 
(on-site) 
(at home) 
(on-site) 
Efpeglenatide 2 mg 
2 mg 
2 mg 
2 mg 
2 mg 
2 mg  
Efpeglenatide 4 mg 
2 mg 
2 mg  
4 mg  
4 mg  
4 mg  
Efpeglenatide 6 mg 
2 mg 
2 mg 
4 mg  
4 mg  
6 mg  
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
 
Noninvestigational medicinal product 
Lantus 
 Formulation: Lantus will be supplied as a sterile, nonpyrogenic, clear, colorless solution in 
the marketed Lantus SoloStar prefilled (disposable) pen (insulin glargine 100 U/mL 
solution for SC injection). Each Lantus SoloStar contains in total 300 units of insulin 
glargine (3.0 mL of 100 units/mL insulin glargine solution). The pen allows dose setting in 
the range of 1 to 80 units with minimum of 1 unit increment. Lantus must not be diluted or 
mixed with any other insulin or solution. 
 Route of administration: SC. 
 Dose regimen: Injections should be administered once daily at any time of the day, but at 
the same time every day SC to the abdomen, thigh, or upper arm. Within these regions, the 
sites of injection should be changed (rotated) at each administration to prevent skin 
reactions. 
Lantus starting dose at beginning of treatment period 
 At randomization, the prestudy dose of basal insulin (glargine 100 U/mL) should be 
converted to an equivalent dose of Lantus on a 1:1 unit basis. If HbA1c at screening is 
≤8.0%, the daily dose of Lantus should be reduced by 20% at randomization in order to 
avoid hypoglycemia when the participant starts the combination therapy with IMP.  
 The starting dose of Lantus can be further adjusted as per Investigator’s discretion based 
on most recent fasting self-monitored plasma glucose (SMPG) values and HbA1c value 
before randomization. 


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Lantus dose adjustment 
 After randomization, the Lantus dose should be kept stable within the first 8 weeks after 
addition of study treatment unless a dose adjustment is required in case of, eg, repeated 
hypoglycemia. After Week 8 (Visit 5), the Lantus dose should be adjusted according to 
the algorithm or local titration standards as needed based on the median of the 3 most 
recent fasting (prebreakfast) SMPG values measured by the participant using the glucose 
meter and accessories supplied by the Sponsor. The SMPG values and all Lantus dose 
adjustments must be documented in the patient diary. 
 Daily fasting (prebreakfast) SMPG measurements are required during first 8 weeks after 
randomization, when the study treatment is added and increasingly contributing to the 
glucose-lowering activity. After Week 8 (Visit 5), three fasting (prebreakfast) SMPG 
values per week are mandatory prior to each visit (these may include the day of the visit). 
During the other weeks, fasting SMPG values are to be measured at the discretion of the 
Investigator. 
Recommended Lantus dose adjustment algorithm 
Median of the 3 most recent fasting (prebreakfast) SMPG 
values 
Lantus dose adjustments (U/day)* 
≥10 mmol/L (≥180 mg/dL) 
+8 
≥7.8 mmol/L to <10.0 mmol/L (≥140 to <180 mg/dL) 
+6 
≥6.7 to <7.8 mmol/L (≥120 and <140 mg/dL) 
+4 
>5.6 to <6.7 mmol/L (>100 and <120 mg/dL) 
+2 
Glycemic target: ≥4.4 to 5.6 mmol/L (≥80 to 100 mg/dL), inclusive 
No change 
≥3.3 and <4.4 mmol/L (≥60 to <80 mg/dL) 
-2 
<3.3 mmol/L (<60 mg/dL) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or one severe hypoglycemic episode (requiring 
assistance) in the preceding week. 
- 3 to -4 or at the discretion of the Investigator or 
medically qualified designee** 
* Dose adjustment should not be done more often than every 3 to 4 days. 
** in case of SU background treatment, SU reduction or discontinuation might also be considered 
SMPG: self-monitored plasma glucose, SU: sulfonylurea 
In case of any concerns with the treatment, more visits (telephone contact or clinic visits) than 
those scheduled may be arranged as needed. 
Oral antidiabetic drug(s) (OAD[s]) 
 Route of administration: Oral. 
 Dose regimen: Administered as per Investigator prescription and in accordance with local 
labeling. If metformin is taken as the only OAD in addition to the basal insulin, it should 
be at a dose of ≥1500 mg/day (or maximum tolerated dose or as per country regulation if 
less). Dose(s) of background OAD(s) should be kept stable throughout the study unless 
dose reduction is needed for safety reasons. 


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Rescue therapy 
 Route of administration: Oral, injectable. 
 Dose regimen: Open-label rescue medication(s) to treat hyperglycemia will be prescribed 
at the discretion of the Investigator and in accordance with local standard of care and 
prescribing practice. Adjustments of the Lantus dose will not be considered as rescue 
therapy. If adjustment of the Lantus dose does not result in further improvement of 
glycemic control, the recommended approach is addition of prandial insulin. 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), including OADs or insulin, 
can be prescribed to treat the hyperglycemia. If a participant requires glycemic rescue, the 
IMP received during the randomized, double-blind treatment period should be continued 
and must remain blinded until the end of the study (unless the Investigator considers a 
change necessary for safety reasons). Refer to Section 6.1.2.2 for full details of rescue 
therapy. 
Statistical considerations: 
 Primary analysis:  
The primary efficacy endpoint (change from baseline to Week 30 in HbA1c) will be analyzed in 
all participants randomized, using HbA1c values measured at baseline and Week 30 (observed or 
imputed), regardless of treatment discontinuation or initiation of rescue therapy. 
The primary analysis method for the primary efficacy endpoint will be an analysis of covariance 
(ANCOVA) model with missing values imputed by multiple imputation (MI) analysis method in 
2 parts as follows: 
1. Missing endpoint data in participants who prematurely discontinue the IMP before the 
Week 30 visit will be imputed using a model estimated from participants in the same 
treatment arm who prematurely discontinue the IMP before the Week 30 visit but have the 
measurement for the endpoint (retrieved dropouts). Considering that the number of 
participants in each treatment arm who discontinue the IMP but have the measurement for 
the endpoint is expected to be small, a simple imputation model will be used, where only 
the baseline measurements are included as the predictor. Each treatment group will have 
their own imputation model. Missing data will be imputed using the regression method.  
2. Missing endpoint data in all participants, including those in the efpeglenatide arms, 
who stay on the IMP until the Week 30 visit, will be imputed separately, using a model 
estimated from participants in the placebo group who stay on the IMP until the endpoint 
visit and have the Week 30 data available. The imputation model will include the 
randomization strata and corresponding baseline values but without including any 
intermediate values. Missing data will be imputed using the regression method.  
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data sets 
with complete data. Each of the completed datasets after the imputation will be analyzed by the 
ANCOVA model with the treatment groups (efpeglenatide 2, 4, or 6 mg, or placebo), 
randomization stratum of screening HbA1c (<8%, ≥8%), randomization stratum of SU (yes/no) 
and geographical region as fixed effects, and baseline HbA1c value as a covariate. The baseline 


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value is defined as the last available value prior to the first dose administration of IMP or the last 
available value on or before the date of randomization if not treated with the double-blinded IMP.  
The results from the 10 000 analyses will be combined using Rubin’s formula to provide the 
adjusted mean change in HbA1c from baseline to Week 30 (regardless of treatment 
discontinuation or initiation of rescue therapy) for each treatment group, as well as the difference 
between each efpeglenatide dose and placebo and the 95% confidence interval (CI) for the 
difference. 
As noted, the number of retrieved dropouts is expected to be small, and there may not be 
sufficient data to support the imputation approach in item 1 described above. If there are fewer 
than 5 participants in any treatment arms who prematurely discontinue the IMP before the 
Week 30 visit but have the HbA1c measurements for the endpoint, a back-up imputation method 
for the primary efficacy analysis will be used. In particular, missing endpoint data in all 
participants in both efpeglenatide and placebo groups, regardless of staying on the IMP or not, 
will be imputed using a model estimated from participants in the placebo group with endpoint 
data, where randomization strata and baseline HbA1c value are included as the predictors. 
Missing data will be imputed using the regression method. 
A hierarchical procedure will be performed to adjust for the multiplicity of comparison. First, the 
highest dose of efpeglenatide (6 mg) will be compared to placebo. If the superiority is 
demonstrated for the 6 mg dose of efpeglenatide, then the superiority of the 4 mg dose of 
efpeglenatide versus placebo will be tested. If superiority is also demonstrated for the 4 mg dose 
of efpeglenatide, then the lowest dose (2 mg) versus placebo will be tested. When the superiority 
is not obtained in a step, then the sequential testing procedure will be stopped. 
Summary statistics (for screening value, baseline value, observed values, and observed changes 
from baseline) at scheduled visits will be provided for each treatment group over the whole 
treatment period including the 26-week Treatment Extension Period. The summary will include 
the number of observations, mean, standard deviation (SD), standard error (SE), minimum, 
median, and maximum. Graphical presentations will also be used to examine trends over time 
using mean values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits 
(using observed cases [OC]). 
 Analysis of secondary and other efficacy endpoints: 
Continuous secondary efficacy endpoints will be analyzed using the same ANCOVA model with 
missing values imputed by MI method as the method used for the primary efficacy endpoint 
analysis. Differences between treatment groups and CIs will be estimated by this method. 
Categorical efficacy endpoints will be analyzed by the Cochran Mantel-Haenszel method 
stratified by the randomization strata. For the HbA1c <7.0% analysis, participants with missing 
HbA1c data at Week 30 or Week 56 will be considered nonresponders in the intent-to-treat (ITT) 
population. 
Comparisons of time-to-event endpoints between treatment groups will be performed using the 
Cox proportional hazards regression model with the treatment groups (efpeglenatide 2, 4, or 6 mg, 
or placebo), randomization stratum of screening HbA1c (<8%, ≥8%), randomization stratum of 
SU use (yes/no), and geographical region as the factors. 


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Data Monitoring Committee: Yes 
See Appendix 1 (Section 10.1) for details. 
1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
1:1:1:1 randomization, stratified by HbA1c (<8.0% and ≥8.0%) at Week -2 and SU use (Yes/No) at screening.  
Visit schedule: From Visit 1 (Week -2) to Visit 14 (Week 56/EOT + 6 weeks) 
EOS, end of study; EOT, end of treatment; HbA1c, hemoglobin A1c; R, Randomization; SU, sulfonylurea. 
 


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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
 
Procedure 
Screening  
(2 weeks) 
Double-blind, placebo-controlled Core Treatment 
Period  
(30 weeks) 
Double-blind, placebo-
controlled Treatment 
Extension Period 
(26 weeks) 
Post-
treatment 
Follow-up 
Period 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
-2 
0 
Baseline 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP+ 
6 weeks 
 
Acceptable range 
(days) 
-14 to  
-11 
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) 
 
Injection of weekly dose 
on the day of visit 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
Participant will self-administer the 
injection only after blood samples have 
been drawn at the respective visit 
Injection of weekly dose 
may be on a different 
day than visit 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
See Table 2 for details of dosing windows 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent taken prior to any 
study-related procedures being 
performed 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Check eligibility before randomization 
Demography, 
medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes diabetes complications, 
cardiovascular (CV) and allergy history, 
alcohol and smoking habits 
Physical examination 
X 
X 
 
 
 
X 
 
 
X 
 
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 
 
VV-CLIN-0549777 1.0


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Procedure 
Screening  
(2 weeks) 
Double-blind, placebo-controlled Core Treatment 
Period  
(30 weeks) 
Double-blind, placebo-
controlled Treatment 
Extension Period 
(26 weeks) 
Post-
treatment 
Follow-up 
Period 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
-2 
0 
Baseline 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP+ 
6 weeks 
 
Acceptable range 
(days) 
-14 to  
-11 
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) 
 
Waist circumference 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Section 8.1.4 
12-lead ECG 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
The 12-lead ECG recording should be 
obtained in supine position prior to IMP 
dose administration (see Section 8.2.3). 
Transition from prestudy 
insulin glargine 100 U/mL 
to Lantus 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 6.1.2.1 of NIMPs. 
IMP injection 
training/retraining with 
prefilled syringe if needed 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
See Section 6.1.1. 
Review of injection sites 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Diary dispensation 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Diary collection 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Review of SMPG and 
Lantus dose adjustments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Glucose meter 
dispensation and training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Will include training for hypoglycemia 
awareness and management. 
Diet and lifestyle 
counselling 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
As per current practice, to be 
documented (Section 5.3.1). 
IRT contact 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Lantus dispensation 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
Lantus collection and 
accounting 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
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Procedure 
Screening  
(2 weeks) 
Double-blind, placebo-controlled Core Treatment 
Period  
(30 weeks) 
Double-blind, placebo-
controlled Treatment 
Extension Period 
(26 weeks) 
Post-
treatment 
Follow-up 
Period 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
-2 
0 
Baseline 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP+ 
6 weeks 
 
Acceptable range 
(days) 
-14 to  
-11 
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) 
 
IMP dispensation 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
IMP collection and 
accounting 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SMPG, IMP, Lantus, 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 conditions as described 
in Section 5.3.1 and Section 8.1.2. 
C-peptide (fasting) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
For these visits, participants need to 
come in fasting conditions as described 
in Section 5.3.1. 
7-point SMPG profiles (on 
at least 1 day in the week 
prior to the visit)  
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Performed on at least 1 day in the week 
prior to clinical visits indicated. See 
Section 8.1.5 for complete details. 
Fasting (prebreakfast) 
SMPG 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily within first 8 weeks after 
randomization and at least 3 days in the 
other weeks, prior to visits indicated. See 
Section 8.1.5. 
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) 
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Procedure 
Screening  
(2 weeks) 
Double-blind, placebo-controlled Core Treatment 
Period  
(30 weeks) 
Double-blind, placebo-
controlled Treatment 
Extension Period 
(26 weeks) 
Post-
treatment 
Follow-up 
Period 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
-2 
0 
Baseline 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP+ 
6 weeks 
 
Acceptable range 
(days) 
-14 to  
-11 
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) 
 
Lipid profile 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2) 
Urinalysis 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2) 
Pregnancy test (for 
women of childbearing 
potential) 
X 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
Serum pregnancy testing (β-HCG) at 
screening for WOCBP (Appendix 4 
[Section 10.4]), urine pregnancy testing 
subsequently (at on-site visits and 
monthly at home in between visits). If the 
urine test is positive, serum β-HCG 
should be tested for confirmation of the 
pregnancy. 
Serum FSH and estradiol 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
For women of nonchildbearing potential. 
In case the definition of postmenopausal 
or premenopausal cannot be satisfied. 
See Appendix 4 (Section 10.4). 
ADA  
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Participants positive for ADAs at the end 
of study, and who experienced severe 
injection site or hypersensitivity reaction 
at any time during the study will be asked 
to provide samples for anti-efpeglenatide 
antibodies assessments 4 and 6 months 
after the end of the treatment or as soon 
as possible after study database lock 
whichever comes later. 
IMP concentration (PK) 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
All participants will have 1 blood sample 
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Procedure 
Screening  
(2 weeks) 
Double-blind, placebo-controlled Core Treatment 
Period  
(30 weeks) 
Double-blind, placebo-
controlled Treatment 
Extension Period 
(26 weeks) 
Post-
treatment 
Follow-up 
Period 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
-2 
0 
Baseline 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP+ 
6 weeks 
 
Acceptable range 
(days) 
-14 to  
-11 
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) 
 
Sampling  
collected just before their weekly injection 
(and at least 6 days after last IMP dose 
administration) for the predose serum 
concentration (Ctrough) of efpeglenatide at 
selected clinical visits. 
For participants who consent, at least 
1 additional postdose sample will be 
taken 3 days (±1 day) after 
administration of IMP, preferably between 
Week 8 and Week 12. See Section 8.5. 
Rescue therapy 
assessment 
 
Continuous assessment and recording during treatment periods 
 
After randomization, the need of rescue 
therapy should be assessed by the 
Investigator via fasting SMPG performed 
by the participants and the central 
laboratory alerts received on FPG and on 
HbA1c (from Week 12 onwards). 
Participants must have an unscheduled 
in-person visit prior to rescue therapy 
initiation, with the assessments normally 
planned for EOT visit. 
See Section 6.1.2.2. 
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Procedure 
Screening  
(2 weeks) 
Double-blind, placebo-controlled Core Treatment 
Period  
(30 weeks) 
Double-blind, placebo-
controlled Treatment 
Extension Period 
(26 weeks) 
Post-
treatment 
Follow-up 
Period 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
 
Week 
-2 
0 
Baseline 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP+ 
6 weeks 
 
Acceptable range 
(days) 
-14 to  
-11 
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) 
 
Concomitant medication 
review 
Continuous assessment and recording throughout the study 
 
AE/SAE recording 
 
Reporting hypoglycemia 
(symptoms, SMPG) 
Hypoglycemia eCRF page must be filled 
in for all SMPG ≤70 mg/dL (3.9 mmol/L) 
and/or in case of symptoms suggesting 
hypoglycemia. 
a In case of premature permanent IMP discontinuation, the participant should have a visit as soon as possible after the last IMP administration with the assessments normally planned for EOT visit (including a 
PK sample if the visit can be scheduled 6-7 days after the permanent IMP discontinuation). Afterwards, the participant should continue in the study up to the scheduled date of study completion and be followed 
according to the study procedures as specified in the protocol. Every effort should be made to have the participant complete the Week 30 and Week 56 visits’ 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 posttreatment follow-up visit (EOS). At the time corresponding to their Week 56 visit, all attempts will be made to contact the participant to inquire about safety and/or vital status. 
 
Abbreviations: ADA: antidrug antibody, AE: adverse event, β-HCG: beta-human chorionic gonadotropin, BP: blood pressure, CV: cardiovascular, ECG: electrocardiogram, eCRF: electronic Case Report Form, EOS: 
end of study, EOT: end of treatment, FPG: fasting plasma glucose, FSH: follicle stimulating hormone, HbA1c: hemoglobin A1c, HR: heart rate, IMP: investigational medicinal product, IRT: interactive response 
technology, NIMP: noninvestigational medicinal product, PK: pharmacokinetic, 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 for the present trial is to compare efpeglenatide once weekly versus placebo once weekly 
in addition to Lantus alone or with OAD(s), in a population of patients with T2DM inadequately 
controlled with basal insulin alone or in combination with OAD(s), 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 therapy options are 
necessary. 
In recent years, the GLP-1 RA class of pharmacotherapy for T2DM has evolved as an effective 
treatment option, from multiple daily 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 GLP-1 RA, is a novel long-acting exendin-4 (exenatide) analogue 
that is being developed for the treatment of T2DM by once-weekly SC injection. In clinical 
Phase 2 studies, it has shown effects on body weight and may therefore provide potential for 
development for use in obesity. 
In total, 7 clinical studies (two Phase 1 studies and five Phase 2 studies) including approximately 
1000 participants (~720 exposed to efpeglenatide) have been completed. The Phase 2 studies have 
been conducted in participants with T2DM and in obese nondiabetic individuals. In participants 
with T2DM, weekly doses between 0.3 to 4 mg or monthly doses between 8 to 16 mg were used, 
whereas in nondiabetic obese 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 
tolerability profile consistent with currently available GLP-1 RAs. Based on Phase 1 and 2 study 
data, 3 weekly efpeglenatide doses (2, 4, or 6 mg) have been selected for use in Phase 3 studies. 
These doses are expected to demonstrate efficacy in the target population while mitigating 
potential safety concerns and the incidence of adverse events (AEs). 


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Details of nonclinical and clinical information on efpeglenatide can be found in Section 5 
Nonclinical studies and Section 6 Effects in humans, respectively, of the Investigator’s Brochure 
(IB) (1). 
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 EFC14893: 
 Gastrointestinal (GI) disorders such as nausea/vomiting and rarely pancreatitis are the 
most common AEs to the GLP-1 RAs class. Thus far, no case of pancreatitis has been 
identified with efpeglenatide. The trend over time for nausea and vomiting events 
appeared dose related, with an increase after the first injection and generally decreasing 
thereafter within a period of approximately 2 to 4 weeks. It is anticipated that the planned, 
gradual dose escalation scheme employed in study EFC14893 will reduce intensity and 
frequency of GI events, mainly nausea and vomiting.  
 Increase in heart rate is a known side-effect of GLP-1 RAs. In study EFC14893, periodic 
monitoring of vital signs including heart rate and blood pressure 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, GLP1-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 EFC14893, patients with history of MTC or MEN-2 or with elevated calcitonin 
levels (≥5.9 pmol/L [20 pg/mL]) at screening will not be randomized. Calcitonin will be 
monitored throughout the study and guidelines for follow-up are provided if this threshold 
will be reached after randomization.  
 Diabetic retinopathy complications have been reported for one of GLP-1 RAs (as of 
05 December 2017). No cases have been reported for efpeglenatide in completed Phase 1 
and 2 studies. Patients with a recent or planned retinal treatment for retinopathy or 
maculopathy will be excluded in the current study. Diabetic retinopathy complications will 
be monitored throughout the study. 
 Additional safety monitoring in study EFC14893 includes the collection of AEs, antidrug 
antibodies (ADA, immunogenicity, [2, 3]), as well as safety laboratory and 12-lead 
electrocardiogram (ECG).  
 In 3 large Phase 2 clinical studies with efpeglenatide (HM EXC-203, HM-EXC-204, and 
HM-EXC-205), overall a total of 12 out of 571 participants on efpeglenatide and 3 out of 
183 participants on comparators had postbaseline alanine aminotransferase (ALT) 
elevation ≥3 × ULN; most had confounding factors (1). In this study, patients with 
elevated liver enzymes >3 × upper limit of the normal (ULN) or total bilirubin 
>1.5 × ULN (except in cases of Gilbert’s syndrome) will be excluded from participation. 
Liver function tests will be done regularly throughout the study. 


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Efpeglenatide concentrations will also be sampled in study EFC14893. These sparse PK samples 
will be used for population PK (popPK) analyses to determine the PK characteristics of 
efpeglenatide in the target T2DM population.  
The risks to the study participants will be minimized by careful patient selection according to 
appropriate inclusion and exclusion criteria based on existing nonclinical and clinical data. During 
the study, participants will be closely monitored at the regular visits, including physical 
examinations and laboratory tests to monitor the glucose-lowering effects and to early detect 
eventual adverse reactions. Suggested actions and follow-up measurements for laboratory 
abnormalities and other safety findings are provided in Appendix 5 (Section 10.5) of the protocol. 
Placebo injections will not contribute to lower the plasma glucose but the participation in the 
study may increase patient motivation and result in an improvement of glycemic control. In any 
case, the close monitoring will detect early deterioration of glycemic control and allow initiation 
of “rescue therapy” as deemed necessary. The HbA1c and fasting plasma glucose (FPG) tests will 
be performed approximately every 3 to 4 months. Participants will be provided with a glucose 
meter and test strips to regularly self-measure their plasma glucose. Central laboratory alerts on 
FPG and on HbA1c (from Week 12 and onwards) will be set up to ensure that glycemic 
parameters remain under predefined rescue thresholds. 
More detailed information about the known and expected benefits and risks and reasonably 
expected 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 (1). 


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3 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, or 6 mg in comparison to placebo in HbA1c 
change from baseline to Week 30 in participants with T2DM 
inadequately controlled with basal insulin alone or in 
combination with OAD(s). 
 
Change from baseline to Week 30 in HbA1c. 
Secondary 
 
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4 and 6 mg in comparison to placebo on 
glycemic control. 
 
Number of participants with HbA1c <7% at Week 30. 
 
Change from baseline to Week 30 in fasting plasma 
glucose (FPG). 
 
Change from baseline to Week 56 in HbA1c.  
To demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4 and 6 mg in comparison to placebo on body 
weight.  
 
Change from baseline to Week 30 and Week 56 in 
body weight.  
To evaluate the safety of once-weekly injection of efpeglenatide 
2, 4 and 6 mg. 
 
 
Number of participants with at least one 
hypoglycemic event during treatment period. 
 
Number of hypoglycemic events per participant-year 
during treatment period. 
 
Number of participants with AEs (see Section 8.3). 
Tertiary/exploratory 
 
To characterize the pharmacokinetics (PK) of efpeglenatide in 
dose regimen of once weekly injection of 2, 4, and 6 mg. 
 
Serum concentration (Ctrough) of efpeglenatide at 
predose (Weeks 4, 12, 24, and 30). 
 
Postdose serum concentration of efpeglenatide in 
participants who consent. 
To evaluate the immunogenicity of once weekly injection of 
efpeglenatide 2, 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 with 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 
polyethylene glycol (PEG) linker of efpeglenatide at 
scheduled visits. 


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Objectives 
Endpoints 
To compare the effects on once weekly injection of 
efpeglenatide 2, 4 and 6 mg with placebo on additional 
parameters of glycemic control 
 
Change from baseline to Week 30 and Week 56 in 
mean 24-hour SMPG (7-point SMPG 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 HbA1c <7.0% at 
Week 30 and Week 56 without weight gain. 
 
Time to initiation of rescue therapy. 
 
Number of participants with rescue therapy used until 
Week 30 and Week 56. 
 
Change from baseline to Week 56 in FPG. 
 
Number of participants with HbA1c <7.0% at 
Week 56. 
To compare the effects on once weekly injection of 
efpeglenatide 2, 3 and 6 mg with placebo on waist 
circumference 
 
Change from baseline to Week 30 and Week 56 in 
waist circumference. 
To compare the effect of once weekly injection of efpeglenatide 
2, 4, and 6 mg with placebo on insulin dose 
 
Change from baseline to Week 30 and 56 in daily 
basal insulin dose. 
ADA: antidrug antibody, AE: adverse event, FPG: fasting plasma glucose, GLP-1: glucagon-like peptide-1,  
HbA1c: hemoglobin A1c, OAD: oral antidiabetic drug, PK: pharmacokinetic, PEG: polyethylene glycol, PPG: post prandial glucose,  
SMPG: self-monitored plasma glucose, T2DM: type 2 diabetes mellitus 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Efpeglenatide added to basal insulin alone or in combination with OAD(s) in participants with 
T2DM who have inadequate glycemic control on their previous antidiabetic therapy is expected to 
lower HbA1c over 30 weeks of treatment (primary efficacy analysis). 
The concentration of HbA1c reflects the glycemic history of the previous 120 days and is thus an 
index of mean glycemia, documenting glycemic control over the past 2 to 3 months. 
Hemoglobin A1c has also been shown to correlate with the development of long-term 
complications of diabetes, and reduction of HbA1c is known to reduce the risk of long-term 
microvascular complications. Therefore, HbA1c is considered an appropriate measurement for 
assessing the efficacy of a novel treatment for Type 2 diabetes.  
The problem of weight gain in T2DM is widely recognized. More than 80% of individuals with 
T2DM are overweight, many at the time of diagnosis. Consequently, iatrogenic weight gain is not 
only unwelcome, but represents an important clinical issue that can become a barrier to the 
successful management of glycemic control. Therefore, in this study assessing change in body 
weight from baseline to Week 30 and Week 56 is a secondary endpoint. 
Improvements in preprandial and postprandial plasma glucose (PPG) have been observed with 
efpeglenatide in previous studies. Therefore, assessment of both preprandial plasma glucose and 


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PPG (by 7-point SMPG profile) is relevant in this study. These 2 parameters are also considered 
by regulatory agencies to be supportive of efficacy of an antidiabetic agent. 
The other efficacy and safety assessments in this study are standard, well established 
measurements for a Phase 3 study evaluating the treatment of T2DM in adult participants.  
The duration of study is considered appropriate, for enabling an adequate assessment of time 
dependent changes in HbA1c, and to evaluate the safety profile during the Treatment Extension 
Period. 


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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
The current protocol EFC14893, is a multicenter, 30-week, double-blind, randomized, 
placebo-controlled Phase 3 study with an additional 26-week Treatment Extension Period 
evaluating the efficacy and safety of efpeglenatide addition in participants with T2DM 
inadequately controlled with basal insulin alone or in combination with OAD(s). 
Eligible participants will be randomly assigned to 1 of 3 dose levels of efpeglenatide (2, 4, or 
6 mg) or to placebo, to be administered SC once weekly. Randomization will be stratified by 
HbA1c at screening (<8%, ≥8%) and SU use at screening (Yes/No). Masked weekly dose 
escalation over the course of 4 weeks will be used to reach the assigned 4 and 6 mg efpeglenatide 
weekly doses. Escalation will start from 2 mg once weekly to the maximum of 4 or 6 mg once 
weekly, as assigned at Randomization. Participants randomly assigned to the efpeglenatide 2 mg 
dose arm will also initiate dosing at 2 mg once weekly and remain on this dose for the treatment 
duration. In order to blind the treatments, both efpeglenatide and placebo will be provided in 
volume matched PFSs. 
The study will be comprised of 4 periods as follows:  
 A 2-week screening period. 
 A 30-week double-blind, placebo-controlled Core Treatment Period, for efficacy and 
safety assessment. 
 A 26-week double-blind, placebo-controlled Treatment Extension Period; participants will 
remain on the randomized IMP regimen. 
 A 6-week posttreatment Follow-up Period to collect safety information after last dose of 
IMP. 
The maximum study duration per participant will be 64 weeks. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This study is designed to demonstrate the efficacy and safety of efpeglenatide when used as added 
antidiabetic treatment in participants with T2DM inadequately controlled with basal insulin alone 
or in combination with OAD(s). Efpeglenatide will be compared to placebo. Based on the study 
design, the protocol stipulates that participants can receive antidiabetic rescue therapy according 
to a predefined algorithm.  
A placebo control will be used to allow for an unbiased assessment of treatment effects and safety 
data. Bias will be minimized by randomizing the participants to treatment groups, blinding the 
participants, the Investigators, and the Sponsor to the treatment allocations, and by adjudicating 
the selected AEs in a blinded fashion. 


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A parallel-group, randomized, placebo-controlled design was selected because trial participants 
are exposed to a single treatment and dose and assignment to that treatment is based solely on 
chance. This design is free of the limitations of competing designs such as crossover in which 
there may be a carryover of effect from the first to the second treatment. Although this carryover 
effect can be minimized with a washout period, it is possible that some longer-term effects may 
persist. While the sample size of the parallel group design is larger to account for more variability 
when participants cannot serve as their own control, the above-mentioned limitations of the 
crossover design have led the randomized controlled trial design to be the standard for therapeutic 
confirmatory trials for regulatory approval such as this trial.  
4.3 
JUSTIFICATION FOR DOSE  
The selection of efpeglenatide 2, 4, and 6 mg once weekly doses is based on the results of early 
phase studies.  
Efpeglenatide has shown increasing efficacy up to the highest dose tested. Both once-weekly 
2 mg and 4 mg doses have shown clinically relevant efficacy in study HM-EXC-203. The 
achieved Hb1Ac reduction indicates that the dose-response plateau has not been reached with the 
4 mg dose so most likely, higher efficacy of the 6 mg dose compared to the 4 mg dose can also be 
expected for glycemic control in diabetic patients. The once-weekly 6 mg dose tested in 
non-diabetic subjects in the Phase 2 study (HM-EXC-205) has shown higher efficacy in the 
decrease of body weight than the once-weekly 4 mg dose in this population. 
Nausea and vomiting events appeared to be dose related and the trend over time showed an 
increase in incidence after the first injection with a general decrease thereafter for all tested doses. 
Based on the observed general decrease of GI event incidence after the first week of treatment 
with efpeglenatide, dose increases to achieve the higher doses of 4 and 6 mg (in the corresponding 
arm) will be in 2 mg step intervals every 2 weeks in order to minimize the GI adverse effects. 
The escalation step of 2 mg is small enough to contribute to improvement of GI tolerability at 
dose increase. With this dose escalation schedule, the dose of 4 mg once-weekly will be achieved 
2 weeks and the maximal dose of 6 mg once-weekly will be achieved only 4 weeks after the first 
dose of efpeglenatide. 
Please refer to the IB for more details (1).  
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant in the study 
(as scheduled per protocol or if trial is stopped prematurely based on the advice of the 
independent DMC or other unforeseen development). 


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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be ≥18 years of age at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Participants with T2DM. 
I 03. Diabetes diagnosed at least 1 year before screening. 
I 04. Participants on a background antidiabetic treatment for which all of the below apply: 
a) Participants on basal insulin regimen alone or in combination with OAD(s) for at least 
6 months prior to screening, 
b) Participants on insulin glargine 100 U/mL as only basal insulin for at least 3 months prior 
to screening, 
c) Participants on stable daily dose of insulin glargine 100 U/mL (±20% total dose) for at 
least 2 months prior to screening. 
I 05. HbA1c between 7.0% and 10.0% (inclusive) measured by the central laboratory at 
screening. 
 
Informed consent 
I 06. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 


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5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. History of severe hypoglycemia requiring emergency room admission or hospitalization 
within 3 months prior to screening. 
E 02. Retinopathy or maculopathy with one of the following treatments, either recent 
(within 3 months prior to screening) or planned: intravitreal injections or laser or 
vitrectomy surgery. 
E 03. Clinically relevant history of GI disease associated with prolonged nausea and vomiting, 
including (but not limited to) gastroparesis, unstable and not controlled gastroesophageal 
reflux disease requiring medical treatment within 6 months prior to screening or history of 
surgery affecting gastric emptying. 
E 04. History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy 
has been performed), pancreatitis during previous treatment with incretin therapies, 
chronic pancreatitis, pancreatectomy. 
E 05. Personal or family history of MTC or genetic conditions that predisposes to MTC 
(eg, multiple endocrine neoplasia syndromes). 
E 06. Body weight change of ≥5 kg within the last 3 months prior to screening. 
E 07. Systolic blood pressure >180 mmHg and/or diastolic blood pressure >100 mmHg at 
randomization. 
E 08. End-stage renal disease as defined by estimated glomerular filtration rate (eGFR, by 
Modification of Diet in Renal Disease [MDRD]) of <15 mL/min/1.73 m2. 
E 09. Laboratory findings at the Screening Visit: 
- 
ALT or aspartate aminotransferase (AST) >3 × ULN or total bilirubin >1.5 × ULN 
(except in case of documented Gilbert’s syndrome). 
- 
Amylase and/or lipase: >3 × ULN. 
- 
Calcitonin ≥5.9 pmol/L (20 pg/mL). 
E 10. Known presence of factors that interfere with the HbA1c measurement (eg, specific 
hemoglobin variants, hemolytic anemia) compromising the reliability of HbA1c 
assessment or medical conditions that affect interpretation of HbA1c results (eg, blood 
transfusion or severe blood loss in the last 3 months prior to randomization, any condition 
that shortens erythrocyte survival). 


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E 11. Any clinically significant abnormality identified either in medical history or during 
screening evaluation (eg, physical examination, laboratory tests, ECG, vital signs) or any 
AE during screening period which, in the judgment of the Investigator, would preclude 
safe participation in the study or constrains efficacy assessment. 
Prior/concomitant therapy 
E 12. Participants not on stable daily dose of OAD(s) (any change in total dose) within 3 months 
prior to screening. 
E 13. Participants on a GLP-1 RA and/or DPP-4 inhibitor in the last 3 months prior to screening. 
E 14. If treatment with metformin as the only OAD: not at a stable dose of at least 1500 mg/day 
(except for South Korea/Taiwan: at least 1000 mg/day) or individually tolerated maximum 
dose for at least 3 months prior to screening. 
E 15. 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 16. 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 17. Participation in any previous clinical trial of efpeglenatide/HM11260C. 
E 18. Exposure to any investigational drugs in the last 4 weeks or 5 half-lives, whichever is 
longer, prior to screening. 
E 19. Concomitant enrollment in any other clinical study involving an investigational study 
treatment or any other type of medical research. 
Other exclusions 
E 20. Any contraindication to use Lantus and OAD (if taken) as defined in the national product 
label(s). 
E 21. Participants not willing to switch to once daily injections of Lantus. 
E 22. Hypersensitivity to any of the study treatments, or components thereof, or to any 
GLP-1-RAs. 
E 23. History of drug or alcohol abuse within 6 months prior to the time of screening. 
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E 25. 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 26. 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 27. Any country-related specific regulation that would prevent the participant from entering 
the study. 
E 28. 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 29. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol. 
E 30. Participants who withdraw consent during the screening period (starting from signed ICF). 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
Diet and exercise  
Lifestyle and diet therapy provided before the time of screening is to be continued during the 
study. Individualized dietary and lifestyle counseling will be given by a healthcare professional as 
per Schedule of Activities (SoA; Section 1.3) and should be consistent with international or local 
guidelines for participants with T2DM (for example, see [4]). 
Fasting conditions 
 For Visits 2 (Day 1), 5 (Week 8), 6 (Week 12), 9 (Week 30), 11 (Week 43), and 
13 (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 (prebreakfast and before administration of antidiabetic medication) SMPG must be 
performed per the SoA (Section 1.3). 
 


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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized (randomly assigned to study 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 events (SAEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once in cases where the original screen failure was due to reasons expected to change 
at rescreening (based upon the Investigator’s clinical judgment). A participant should not be 
randomly assigned more than once (ie, entering the randomized period twice). 


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6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
The IMP includes efpeglenatide in 3 doses (2, 4, and 6 mg) and placebo for SC injection during 
the 56 weeks of treatment. 
Non-IMP (NIMP) includes Lantus for SC injections, OAD(s) 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. Except for GLP-1 RAs and DPP-4 inhibitors, any approved 
medication(s) can be prescribed at the Investigator’s discretion to treat the hyperglycemia. The 
regimen of the rescue medication(s) will be in accordance with local standard of care and 
prescribing practice. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 2 - Overview of study interventions administered  
Study 
intervention 
name 
Efpeglenatide 
Placebo 
  
Dosage formulation 
Sterile, nonpyrogenic, clear, colorless solution in a 
1 mL disposable PFS in the formulation buffer 
(containing citric acid monohydrate, L-methionine, 
polysorbate 20, D-mannitol, sodium hydroxide 
and water for injection). 
Sterile, nonpyrogenic, clear, colorless solution in 
a 1 mL disposable PFS in the formulation buffer 
(containing citric acid monohydrate, 
L-methionine, polysorbate 20, D-mannitol, 
sodium hydroxide and water for injection). 
  
Unit dose 
strength(s)/Dosage 
level(s) 
2 mg/500 µL, 4 mg/500 µL, and 6 mg/500 µL 
(at 4, 8, and 12 mg/mL concentrations, 
respectively). 
NA 
  
Route of 
administration 
SC injection 
SC injection 
  
Dosing instructions 
The injection interval of the IMP is once-weekly, 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. For each injection, the date, time, and region of administration should 
be recorded. Within any selected region, the site of injection should be changed (rotated) at each time 
to prevent skin reactions.  
For selected visits during the Core 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 should then 
 


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Study 
intervention 
name 
Efpeglenatide 
Placebo 
  
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. 
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 the last dose of IMP. The 
corresponding study visits (Visit 4, Visit 6, Visit 8, and Visit 9) 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 2 
 
Visit 3 
 
Visit 4 
Dosing 
(on-site) 
(at home) 
(on-site) 
(at home) 
(on-site) 
Efpeglenatide 2 mg 
2 mg 
2 mg 
2 mg 
2 mg 
2 mg 
Efpeglenatide 4 mg 
2 mg 
2 mg 
4 mg 
4 mg 
4 mg 
Efpeglenatide 6 mg 
2 mg 
2 mg 
4 mg 
4 mg 
6 mg 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
Placebo 
From Week 4 (Visit 4) through the rest of the double-blind treatment period, participants will remain on 
the randomized IMP dose or placebo until the EOT at Week 56 (Visit 13). 
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. 
EOT: end of treatment, IMP: investigational medicinal product, NA: not applicable, PK: pharmacokinetic, PFS: prefilled syringe, 
SC: subcutaneous, SoA: Schedule of Activities. 
6.1.1 Investigational medicinal products  
The appropriate number of kits will be dispensed for the period until the next dispensing visit 
(please refer to the SoA Section 1.3). Storage conditions and use-by-end date (when required by 
country regulations) are part of the label text. 
Participants will be trained on the use of the PFS by the study staff at Visit 1 (Screening) and 
provided with an “instructions for use” leaflet, which will describe the handling procedures for the 
PFS and administration technique. The injection training pads can be used, if needed. Initial 
injection technique training at Visit 1 (Screening) may include self-injection with a training PFS 
and assessment of participant’s skills and understanding by observing teach-back (if needed). 
Also, if needed, an additional training PFS can be used for self-injection technique training any 
time prior to the day of randomization. 


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Review of injection technique can be done at any other visit as needed (self-injection with IMP at 
site during selected visits until Week 43, under close supervision).  
Review of injection sites will be performed at all on-site visits. 
Prefilled syringe-related issues (malfunctions) should be reported by the sites 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 and Lantus 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  
Lantus 
Lantus is the only background therapy provided by the Sponsor. The appropriate number of kits 
will be dispensed for the period until the next dispensing visit (please refer to the SoA 
Section 1.3). Lantus will be provided until the end of study even in case of premature end of 
treatment for patients attending the safety follow-up visits. Storage conditions and use-by-end 
date (when required by country regulations) are part of the label text. 
 Formulation: Lantus will be supplied as a sterile, nonpyrogenic, clear, colorless solution in 
the marketed Lantus SoloStar prefilled (disposable) pen (insulin glargine 100 U/mL 
solution for SC injection). Each Lantus SoloStar contains in total 300 units of insulin 
glargine (3.0 mL of 100 units/mL insulin glargine solution). The pen allows dose setting in 
the range of 1 to 80 units with minimum of 1 unit increment. Lantus must not be diluted or 
mixed with any other insulin or solution. 
 Route of administration: SC. 
 Dose regimen: Injections should be administered once daily at any time of the day, but at 
the same time every day SC to the abdomen, thigh, or upper arm. Within these regions, the 
sites of injection should be changed (rotated) at each administration to prevent skin 
reactions. 
Lantus starting dose at beginning of Treatment Period 
 At randomization, the prestudy dose of basal insulin (glargine 100 U/mL) should be 
converted to an equivalent dose of Lantus on a 1:1 unit basis. If HbA1c at screening is 
≤8.0%, the daily dose of Lantus should be reduced by 20% at randomization in order to 
avoid hypoglycemia when the participant starts the combination therapy with IMP.  
 The starting dose of Lantus can be further adjusted as per Investigator’s discretion based 
on most recent fasting SMPG values and HbA1c value before randomization. 


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Lantus dose adjustment 
 After randomization, the Lantus dose should be kept stable within the first 8 weeks after 
addition of study treatment unless a dose adjustment is required in case of, eg, repeated 
hypoglycemia. After Week 8 (Visit 5), the Lantus dose should be adjusted according to the 
algorithm (Table 3) or local titration standards as needed based on the median of the 
3 most recent fasting (prebreakfast) SMPG values measured by the participant using 
glucose meter and accessories supplied by the Sponsor. The SMPG values and all Lantus 
dose adjustments are to be documented in the patient diary. 
 Daily fasting (prebreakfast) SMPG measurements are required during first 8 weeks after 
randomization, when the study treatment is added and increasingly contributing to the 
glycemic control. After Week 8 (Visit 5), three fasting (prebreakfast) SMPG values per 
week are mandatory prior to each visit (these may include the day of the visit). During the 
other weeks fasting SMPG values are to be measured at the discretion of the Investigator. 
Table 3 - Recommended Lantus dose adjustment algorithm  
Median of the 3 most recent fasting (prebreakfast) 
SMPG values 
Lantus dose adjustments (U/day)* 
≥10 mmol/L (≥180 mg/dL) 
+8 
≥7.8 mmol/L to <10.0 mmol/L (≥140 to <180 mg/dL) 
+6 
≥6.7 to <7.8 mmol/L (≥120 and <140 mg/dL) 
+4 
>5.6 to <6.7 mmol/L (>100 and <120 mg/dL) 
+2 
Glycemic target: ≥4.4 to 5.6 mmol/L (≥80 to 100 mg/dL), inclusive 
No change 
≥3.3 and <4.4 mmol/L (≥60 to <80 mg/dL) 
-2 
<3.3 mmol/L (<60 mg/dL) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or one severe hypoglycemic episode (requiring 
assistance) in the preceding week. 
- 3 to -4 or at the discretion of the Investigator or 
medically qualified designee** 
* Dose adjustment should not be done more often than every 3 to 4 days. 
** in case of SU background treatment, SU reduction or discontinuation might also be considered 
SMPG: self- monitored plasma glucose, SU: sulfonylurea 
In case of any concerns with the treatment, additional unscheduled visits (telephone contact or 
clinic visits) may be arranged as needed. 
Oral antidiabetic drug(s) (OAD[s]) 
 Route of administration: Oral. 
 Dose regimen: Administered as per Investigator prescription and in accordance with local 
labeling. If metformin is taken as the only OAD in addition to the basal insulin, it should 
be at a dose of ≥1500 mg/day (or maximum tolerated dose or as per country regulation if 
less). Dose(s) of background OAD(s) should be kept stable throughout the study unless 
dose reduction is needed for safety reasons. 


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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 4 and are dependent on study period. 
Table 4 - Rescue criteria  
Time in study 
Threshold 
From randomization up through the scheduled Week 8 visit (Visit 5). 
FPG >15.0 mmol/L (>270 mg/dL) 
After the Week 8 visit up through the scheduled Week 12 visit (Visit 6). 
FPG >13.3 mmol/L (>240 mg/dL) 
After the Week 12 visit (Visit 6) through the end of the 30-week Core 
Treatment Period. 
FPG >11.1 mmol/L (>200 mg/dL) or HbA1c ≥8.5% 
After the Week 30 Visit (Visit 9) through the end of the Treatment 
Extension Period. 
FPG >8.9 mmol/L (>160 mg/dL) or HbA1c ≥8.0% 
FPG: fasting plasma glucose, HbA1c: hemoglobin A1c 
Routine fasting SMPG and central laboratory alerts on FPG (and HbA1c from Week 12 [Visit 6] 
onwards) will be set up to ensure that glycemic parameter results remain below the predefined 
thresholds. 
If a fasting SMPG value exceeds the specific glycemic limit on 1 day, the participant must check 
it again during the following 2 days. If all the SMPG values in 3 consecutive days exceed the 
specific limit, the participant should contact the Investigator and a central laboratory 
FPG measurement (and HbA1c from Week 12 onwards) be performed as soon as possible for 
confirmation. 
Upon receipt of a central laboratory alert for either FPG or HbA1c, a central laboratory retest 
must be completed and confirmed as exceeding the threshold for rescue before rescue therapy is 
initiated. The retest confirmation should be performed as soon as possible during an unscheduled 
visit.  
In the event that a confirmatory FPG and/or HbA1c value exceeds the threshold, the Investigator 
should ensure that no reasonable explanation exists for insufficient glucose control and in 
particular that: 
 The increased FPG has been tested at a fasting status (ie, no food or liquid intake [except 
water] for ≥8 hours). 
 IMP was given at the planned dose and was appropriately injected (as per weekly 
schedule). 
 Lantus dose was appropriately adjusted. 
 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. 


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If any of the above-mentioned explanations can reasonably explain the insufficient glycemic 
control, the Investigator should consider not initiating rescue medication(s) and should undertake 
appropriate action as follows, ie: 
 Assess FPG (ie, after the participant has fasted for ≥8 hours). 
 Initiate an evaluation and treatment of intercurrent disease (to be reported in the 
AE/concomitant medication parts of the electronic Case Report Form (eCRF) and the 
medical record). 
 Stress the absolute need for the participant to be compliant with treatment. 
 Organize a specific interview with the participant and a Registered Dietician or other 
qualified nutrition professional to reinforce the absolute need to be compliant with diet and 
lifestyle recommendations, and schedule a FPG/HbA1c assessment at the next visit. 
If none of the above-mentioned reasons can be found, or if an appropriate action fails to decrease 
FPG/HbA1c 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 prerescue assessments (which are the same as those specified for EOT, Week 56, 
Visit 13), prior to starting the rescue medication(s). 
If adjustment of the Lantus dose does not result in further improvement of glycemic control, the 
recommended approach is addition of prandial insulin.  
Prescription of open-label rescue medication(s) to treat hyperglycemia will be at the discretion of 
the Investigator and in accordance with local standard of care and prescribing practice. 
Adjustment in the Lantus dose will not be considered as rescue therapy. 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, double-blind 
treatment period should be continued and must remain blinded until the end of the study (unless 
the Investigator considers a change necessary for safety reasons). 
All concomitant antidiabetic medications (background OAD[s] and/or rescue therapy) will be 
documented in the eCRF.  
The cost of background OADs and/or rescue therapy not covered by health insurance will be 
reimbursed by the study Sponsor where permitted by local regulations. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
The Investigators or other authorized persons (eg, pharmacists) are responsible for storing the 
IMP and Lantus in a secure and safe place in accordance with local regulations, labeling 
specifications, policies, and procedures. 


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Control of IMP and Lantus 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 IMP and Lantus labels (when required by country regulation), 
and storage conditions are written on the IMP and Lantus 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 intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual.  
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP and Lantus will be responsible for ensuring that the IMP and Lantus used in the clinical trial 
is securely maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. All IMPs and Lantus will be dispensed in accordance with the Investigator's 
prescription and it is the Investigator's responsibility to ensure that an accurate record of IMP and 
Lantus 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 by 
the sites 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 and Lantus in case of DTP shipment, for which a courier company has been approved by the 
Sponsor), allow the IMP/NIMP/device to be used other than as directed by this clinical trial 
protocol, or dispose of IMP/NIMP/device in any other manner. 


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6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study intervention using 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 randomly assigned 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 
randomly assigned more than once in the study. 
Previously allocated IMP should not be redispensed to the participants. 
6.3.1 Methods of blinding  
During the entire double-blind treatment period, Investigators and participants will be blinded to 
the allocation of active doses of efpeglenatide or placebo treatment arms. Efpeglenatide and 
placebo will be provided in indistinguishable PFSs in identical kits. Each titration and treatment 
kit (and the corresponding syringes) will be labeled with a unique number. The list of kit numbers 
will be generated by Sanofi. 
In accordance with the double-blind design, Investigators will remain blinded to IMP and will not 
have access to the randomization (treatment) codes except under exceptional medical 
circumstances.  
Members of the CEC will review and adjudicate events in a blinded manner (please also refer to 
Appendix 1 [Section 10.1]). 
The Investigator will not have access to the data of the primary efficacy endpoint (ie, HbA1c) or 
FPG obtained after the baseline/randomization visit (Visit 2) as those data will be masked. If the 
central laboratory detects FPG greater than the rescue thresholds, the Investigator will receive an 
alert from the central laboratory (see Section 6.1.2.2). The HbA1c alerts will also be sent if a 
value is greater than the threshold from the Week 12 visit (Visit 6) onwards. 
6.3.2 Randomization code breaking during the study  
The blind may be broken if, in the opinion of the Investigator, it is in the participant’s best interest 
for the Investigator to know the IMP assignment. The Sponsor must be notified before the blind is 
broken unless identification of the IMP is required for a medical emergency in which the 
knowledge of the specific blinded IMP will affect the immediate management of the participant’s 
condition (eg, antidote available). In this case, the Sponsor must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the source 
documentation and 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. 


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When documenting the reason for unblinding, the Investigator must not provide any detail 
regarding the nature of the IMP. The Investigator should not divulge IMP detail to the Sponsor’s 
representative or to any staff members until database closure. Furthermore, when completing 
forms (eg, AE, SAE, adjudication information), the IMP should not be disclosed on the forms. 
Randomization code breaking will also be performed during the analysis of the PK serum 
concentration samples and ADA samples in order to enable the laboratory to sort the samples 
(verum [dose group], placebo) and start analyzing the samples (verum group only) while the study 
is still ongoing. Only the predefined designated personnel from Sponsor and Bioanalytical 
laboratory will have access to the randomization code to allow for the sorting of the efpeglenatide 
blood samples. The Bioanalytical laboratory and responsible personnel will follow the standard 
procedures to ensure the protection of the blind within the Sponsor’s clinical team. The 
randomization code or the individual analytical results will not be disclosed to any clinical team 
personnel prior to the 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]). 
Randomization code breaking will be performed for reporting to the Health Authorities of any 
suspected unexpected serious adverse reaction (SUSAR). Refer to Section 8.3.4 for regulatory 
reporting requirements. The unblinding information will not be disclosed to patients, sites or any 
clinical team personnel prior to the database lock. 
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 treatment dispensing is planned. 
 The Investigator or his/her delegate will track treatment accountability/compliance by 
comparing the treatment kit number recorded on the patient diary with the treatment kit 
number of returned treatment kits (whether empty or unused) and completes 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 
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6.4.1 Return and/or destruction of treatments  
A detailed treatment log of the destroyed IMP (and Lantus, as provided by the Sponsor) will be 
established with the Investigator (or the pharmacist) and countersigned by the Investigator and the 
monitoring team. The Investigator will not destroy the used and unused IMP and Lantus 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. 
Sharp containers containing all used PFSs will be brought back to the site by the study participant 
for the purpose of destruction. 
Destruction is strongly encouraged at site level, nevertheless, if the site is not able to destroy or 
destruction is not allowed in the country, all treatment kits will be retrieved by the Sponsor. 
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 (short-term use [<10 consecutive days] of short-acting 
insulin for treatment of acute illness or surgery is allowed) other than the IMP and Lantus 
or change in dose or preexisting OAD(s) before prerescue assessments and initiation of 
rescue therapy. 
 Initiation of any GLP-1 RAs (eg, exenatide, lira-, dula-, or semaglutide) and 
DPP-4 inhibitors (eg, sita-, saxa-, vilda-, or linagliptin). 
 Initiation of any prescription weight-loss drugs (eg, phentermine, lorcaserin, or orlistat). 
 Gastric surgery or other gastric procedures for weight loss. 
 Systemic use of glucocorticoids for more than 10 consecutive days (topical, nasal spray, 
inhaled, or intra-articular applications are allowed). 
 Any investigational drug other than IMP for this study. 
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 4) 
through the rest of the double-blind treatment period, participants will remain on the randomized 
IMP (efpeglenatide assigned dose or placebo) until the EOT at Week 56 (Visit 13). 
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 nonparticipant contact follow-up 
(eg, medical record checks). The site should document any case of withdrawal of consent. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
The IMP should be continued whenever possible. 
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
permanent IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. In any case, the participant should remain in the study as long as 
possible to collect endpoint data at Week 30 and Week 56 and vital safety status at the scheduled 
end of study. 
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]), 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. 
 At the specific request of the Sponsor. 


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As all randomly assigned 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. Collection of Week 30 data is of highest importance as they are needed for 
primary endpoint analysis. 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 within 24 hours) before making a decision of 
permanent discontinuation of the IMP for the concerned participant. 
Handling of participants after permanent intervention discontinuation 
Every effort should be made to maintain participants in the study. Participants will be followed 
according to the study procedures specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed as specified in this 
protocol, whichever comes last. 
If possible, the participants who discontinue IMP will be assessed using the procedure normally 
planned for the EOT Visit, including a PK sample when the permanent discontinuation occurred 
during the Core Treatment Period and the visit can be scheduled 6 to 7 days after the permanent 
discontinuation of IMP. For participants who discontinue IMP, but who remain in the study, the 
remaining visits should occur as scheduled, where possible, until Week 56 (Visit 13), and all 
planned procedures should be performed. 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 (one) dose not administered to 
the participants. 
All IMP discontinuation should initially be considered as temporary unless permanent 
discontinuation is mandated by the protocol (see Section 7.1), and the Investigator should make 
best effort to resume IMP treatment as early as practically possible. There is no defined limit to 
the duration of temporary discontinuation. 


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Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs (including intolerance to IMP planned dose). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF. 
7.1.2.1 Rechallenge  
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 rechallenge is recommended following temporary discontinuation before deciding to 
permanently discontinue the IMP. If a maximum of 2 consecutive doses are missed, the IMP can 
be restarted with the last dose given. In cases where 3 or more consecutive doses are missed, the 
titration should be re-initiated. 
Participants who temporarily discontinue IMP should be reassessed at every visit to determine 
whether it is possible to safely resume IMP. If a decision has been made that the discontinuation is 
permanent, then the participant should be considered as permanently discontinued and the 
corresponding eCRF page should be completed. Please note that permanent discontinuation 
should be a last resort. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
Refer to the SoA (Section 1.3) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
Participants who have withdrawn from the study cannot be rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 


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7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 Before a participant is deemed as lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


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8 
STUDY ASSESSMENTS AND PROCEDURES  
 Study procedures and their timing are summarized in the SoA (Section 1.3). 
Protocol waivers or exemptions are not allowed. 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed before confirming Visit 2 
(randomization) in IRT, 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 (see SoA Section 1.3).  
If a participant needs to receive rescue therapy (see Section 6.1.2.2), then HbA1c assessment 
should be performed before the introduction of rescue medication(s). 
8.1.2 Fasting plasma glucose  
Plasma glucose will be assessed in a fasted state (as defined in Section 5.3.1) according to the 
schedule detailed in the SoA (Section 1.3). If participant is not fasting at the time of the visit, a 
retest should be scheduled in 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 Week 30 and 
Week 56 in body weight. 
Body weight is measured at every on-site study visit (see SoA, Section 1.3), with the participant 
wearing only undergarments or very light clothing and no shoes, and with an empty bladder. 
The same scale should be used throughout the study and calibrated on a regular basis as 
recommended by the manufacturer. Calibration should be documented in source documents. 


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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). 
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, on at least 1 day within 
the weeks prior to selected study visits (see SoA, Section 1.3), and must be recorded in the patient 
diary. Participants should repeat the 7-point SMPG profile if any time point is missed. 
The 7-point SMPG profile should be measured at the following 7 points: prebreakfast and 
2 hours postbreakfast, prelunch and 2-hour postlunch, predinner and 2-hour postdinner, and at 
bedtime. Two hours postprandial (breakfast, lunch, and dinner) is defined as 2 hours after the start 
of the meal. 
On days when 7-point SMPG profiles are measured, the fasting prebreakfast SMPG profile will 
be considered as the first point of measurement (ie, “prebreakfast” time point). 
8.1.6 Use of rescue therapy  
The use of rescue medication(s) for hyperglycemia will be assessed and reported throughout the 
treatment period to allow determination of the start of rescue therapy and the percentage of 
participants using rescue therapy at Weeks 30 and 56. Routine fasting SMPG will be measured by 
the participants, and alerts on FPG and/or HbA1c from the central laboratory will be 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 values greater than the 
predefined thresholds, refer to Section 6.1.2.2. 


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8.2 
SAFETY ASSESSMENTS   
The planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
 A complete physical examination will be performed as per clinical practice in order to 
assess the health status of the participant at screening and evaluate the inclusion/exclusion 
criteria. 
 At the other selected on-site visits, a limited physical examination focused on any affected 
body area or organ system and other symptomatic or related organ system(s) will be 
performed. 
 Height will be measured at screening only. If for any reason it was not measured at this 
visit, it can be measured at any other visit in the study. 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs  
 Blood pressure measurements will be assessed while participant is 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 
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 12-lead electrocardiogram  
A 12-lead ECG recording will be performed locally as scheduled in the SoA (see Section 1.3). 
The 12-lead ECG should be performed after the participants 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. 


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Note: Any new ECG abnormality should be rechecked for confirmation and reported as an AE if 
considered clinically significant by the Investigator. 
8.2.4 Clinical safety laboratory assessments  
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA (Section 1.3) for the timing and frequency of sample collection.  
 The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. 
The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, unless judged by the Investigator to be more severe than expected for the 
participant’s condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline 
or are no longer considered clinically significant by the Investigator or Medical Monitor. 
- 
If such values do not return to normal or baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA (Section 1.3).  
 If local laboratory results are used to make study treatment decision, for response 
evaluation, or to diagnose/follow-up 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 (5, 6, 7) as follows 
(also see Appendix 8 [Section 10.8]): 
 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 


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episodes in which neurological impairment was severe enough to prevent self-treatment 
and which were thus thought to place participants at risk for injury to themselves or others.  
Note that “requiring assistance of another person” means that the participant could not 
help himself or herself. Assisting a participant out of kindness, when assistance is not 
required, should not be considered a “requiring assistance” incident. 
Severe hypoglycemia will be reported as an SAE only if it fulfills SAE criteria 
(see Appendix 3 [Section 10.3]). For example, events of seizure, unconsciousness or coma 
must be reported as SAEs. 
 Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia is an 
event during which typical symptoms of hypoglycemia are accompanied by a measured 
plasma glucose concentration less than or equal to 3.9 mmol/L (70 mg/dL). Clinical 
symptoms that are considered to result from a hypoglycemic episode are, eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, 
palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
 Asymptomatic hypoglycemia: Asymptomatic hypoglycemia is an event not accompanied 
by typical symptoms of hypoglycemia but with a measured plasma glucose concentration 
less than or equal to 3.9 mmol/L (70 mg/dL).  
 Probable symptomatic hypoglycemia: Probable symptomatic hypoglycemia is an event 
during which symptoms of hypoglycemia are not accompanied by a plasma glucose 
determination, but was presumably caused by a plasma glucose concentration less than or 
equal to 3.9 mmol/L (70 mg/dL); symptoms are treated with oral carbohydrate.  
 Relative hypoglycemia: (recently termed “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 ≥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 (5). 
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. 


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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. The classification of AESI may 
be changed during the study by protocol amendment (eg, further AE classified as AESI, or AE 
losing their AESI status). 
 Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP (see Section 8.3.5): 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
 Symptomatic overdose (serious or nonserious) with IMP/NIMP: 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the planned dose (eg, two or more injections) if given within 3 days (72 hours), 
- 
An overdose (accidental or intentional) with the NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as at least twice 
the recommended dose during the planned interval(s), 
- 
Of note, asymptomatic overdose has to be reported as a standard AE. 
 Increase in ALT >3 × ULN (see Appendix 5 [Section 10.5]). 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention and/or study (see Section 7).  
Adverse events requiring specific monitoring 
An AE requiring specific monitoring is a serious or nonserious AE of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring may be 
appropriate. Such events may require further investigation to characterize and understand them. 
These events should be reported on the AE page and additional information required on the 
specific eCRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria). 


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The AEs requiring specific monitoring for this study are as follows:  
 Severe GI events. 
 Severe hypoglycemia (see Section 8.2.5). 
 Pancreatic events (including abnormal values of pancreatic enzymes [see Appendix 5, 
Section 10.5.2]) will be adjudicated by CEC. 
 Major adverse cardiovascular events (MACE; CV death, myocardial infarction, 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] 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. 
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). 


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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 (IECs), and Investigators. 
 Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
 An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file the report along with 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 14). 
 If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in 
Appendix 4 (Section 10.4). 
 In the event of pregnancy in a female participant, IMP should be discontinued. 
 A pregnancy will be qualified as an SAE only if it fulfills 1 of the seriousness criteria 
(see Appendix 3 [Section 10.3]). 


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 Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Cardiovascular and death events  
For CV events, see details of the AEs requiring specific monitoring above. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.8 Guidelines for reporting product complaints/medical device incidents (including 
malfunctions)  
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within the required timelines. 
Appropriate information (eg, samples, labels, or documents like pictures or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered. The 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
8.4 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should do the following: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
3. Document the quantity of the excess dose as well as the duration of the overdose in the 
CRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
Blood samples for measurement of serum concentrations of efpeglenatide will be collected for all 
participants in order to keep blinding and analyzed for participants in efpeglenatide arms only. 
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). 


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Blood samples will be collected for measurement of serum concentrations of efpeglenatide as 
specified in the SoA (see Section 1.3). Instructions for the collection and handling of biological 
samples will be provided by the Sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded along with the dates, times, and body regions (abdomen, thigh, or arm) of 
drug administration. Samples not collected, missed or lost, for any reason should be recorded.  
 For participants who consent for additional postdose PK sampling, at least 1 additional 
postdose sample will be taken 3 days (±1 day) after administration of efpeglenatide or 
placebo, preferably between Week 8 and Week 12, but other weeks are also acceptable 
(eg, after 1st dose, 4th dose, or 12th dose). A minimum of 120 evaluable postdose samples 
(in participants on efpeglenatide) are needed to contribute to popPK analysis. To reach this 
number and due to the blind design of the study, PK postdose samples will be collected in 
participants who will accept this additional sampling, sign the separate consent in the main 
ICF and provide a valid postdose sample until the above number of evaluable samples is 
confirmed. 
 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 popPK analysis by nonlinear 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.  
8.8.1 Immunogenicity assessments  
Blood samples for assessment of ADA status (positive or negative) and level (titer) will be 
collected for all participants in order to keep blinding and analyzed for participants in 
efpeglenatide arms only. Cross-reactivity of confirmed positive samples to endogenous GLP-1 
(positive or negative), endogenous glucagon (positive or negative), neutralizing capacity of 


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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 additional samples 
for anti-efpeglenatide antibodies assessments approximately 4 and 6 months after the end of the 
treatment or as soon as possible after study database lock whichever comes later. 
8.9 
HEALTH ECONOMICS  
Health Economics and Health Economics parameters are not evaluated in this study. 


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9 
STATISTICAL CONSIDERATIONS   
9.1 
STATISTICAL HYPOTHESES  
For the primary efficacy variable of change from baseline to Week 30 in HbA1c, the following 
statistical null hypothesis and alternative will be tested for each efpeglenatide dose: 
 H0: No treatment difference. 
 H1: Efpeglenatide has a higher reduction in HbA1c from baseline than placebo. 
Based on data from previous Phase 1 and 2 studies and modeling, a minimum treatment effect 
difference of -0.6% in HbA1c change from baseline to Week 30 was considered as reasonable for 
this study. 
9.2 
SAMPLE SIZE DETERMINATION   
The sample size calculations were performed based on the primary endpoint, change in 
HbA1c (%) from baseline to Week 30. 
A sample size of approximately 100 participants per arm (ie, 100 participants for each of the 
efpeglenatide doses and 100 for the placebo group) has 89% power to detect a treatment 
difference of -0.5% (and 96% power to detect a treatment difference of -0.6%) between each dose 
of efpeglenatide and placebo in HbA1c change from baseline to Week 30, assuming a common 
SD of 1.1% (2-sided, α = 0.05) for each comparison.  
Hence, there are 4 parallel dosing arms as follows: 
 Efpeglenatide 2 mg, N=100. 
 Efpeglenatide 4 mg, N=100. 
 Efpeglenatide 6 mg, N=100. 
 Efpeglenatide placebo, N=100. 
A hierarchical procedure will be performed to adjust the multiplicity of comparison. 


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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 5): 
Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF. 
Randomized 
All screened participants who have a treatment kit number allocated and recorded in 
the IRT database, regardless of whether the treatment kit was used or not. 
ITT 
All participants randomized irrespective of rescue therapy use and compliance with 
the study protocol and procedures. Participants will be analyzed in the treatment 
group to which they are randomly assigned. 
Safety 
All participants randomly assigned to IMP and who take at least 1 dose of IMP. 
Participants will be analyzed according to the treatment they actually received. 
ADA 
All participants from the safety population with at least 1 postbaseline valid 
ADA sample after drug administration. 
PK 
All participants from the safety population with at least 1 valid PK sample available for 
analysis. 
ADA: antidrug antibody, ICF: informed consent form, IRT: interactive response technology, ITT: intent to treat, PK: pharmacokinetic. 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
9.4.1 Efficacy analyses  
Table 6 - Efficacy analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
Change from baseline to Week 
30 in HbA1c. 
Primary analysis: 
The primary efficacy endpoint will be analyzed in all participants randomized, using all HbA1c 
values measured at baseline and Week 30 (observed or imputed), regardless of treatment 
discontinuation or initiation of rescue therapy. 
The primary analysis method for the primary efficacy endpoint will be an ANCOVA model with 
missing values imputed by MI analysis method in 2 parts as follows: 
1. 
Missing endpoint data in participants who prematurely discontinue the IMP before 
the Week 30 visit will be imputed using a model estimated from participants in the 
same treatment arm who prematurely discontinue the IMP before the Week 30 visit 
but have the measurement for the endpoint (retrieved dropouts). Considering that 
the number of participants in each treatment arm who discontinue the IMP but have 
the measurement for the endpoint is expected to be small, a simple imputation 
model will be used, where only the baseline measurements are included as the 
predictor. Each treatment group will have their own imputation model. Missing data 
will be imputed using the regression method.  


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2. 
Missing endpoint data in all participants, including those in the efpeglenatide arms, 
who stay on the IMP until the Week 30 visit, will be imputed separately, using a 
model estimated from participants in the placebo group who stay on the IMP until the 
Week 30 visit and have the endpoint data available. The imputation model will 
include the randomization strata and corresponding baseline values without 
including any intermediate. Missing data will be imputed using the regression 
method.  
In this analysis, missing endpoint values will be imputed 10 000 times to generate 10 000 data 
sets with complete data. Each of the completed datasets after the imputation will be analyzed 
by the ANCOVA model with treatment groups, randomization strata, and geographical regions 
as fixed effects and the corresponding baseline HbA1c values as a covariate.  
The baseline value is defined as the last available value prior to the first dose administration of 
IMP or the last available value on or before the date of randomization if not treated with the 
double-blinded IMP.  
The results from the 10 000 analyses will be combined using Rubin’s formula and provide the 
adjusted mean change in HbA1c from baseline to Week 30 (regardless of treatment 
discontinuation or initiation of rescue therapy) for each treatment group, as well as the 
difference between each efpeglenatide dose and placebo and the 95% CI for the difference.  
A hierarchical procedure will be applied to adjust for the multiplicity of comparison on the 
primary endpoint as follows: 
 
First, the highest dose of efpeglenatide (6 mg) will be compared to placebo to 
demonstrate superiority of this dose versus placebo. 
 
If superiority is demonstrated for efpeglenatide 6 mg, the superiority of 4 mg dose of 
efpeglenatide versus placebo will be tested. 
 
If superiority is also demonstrated for 4 mg dose, the lowest dose (2 mg) will be 
tested for superiority over placebo. 
When the superiority is not obtained in a step, the sequential testing procedure will be 
stopped. 
As noted, the number of retrieved dropouts is expected to be small, and there may not be 
sufficient data to support the imputation approach in item 1 described above. If there are fewer 
than 5 participants in any treatment arms who prematurely discontinue the IMP before the 
Week 30 visit but have the HbA1c measurements for the endpoint, a back-up imputation 
method for the primary efficacy analysis will be used. In particular, missing endpoint data in all 
participants in both efpeglenatide and placebo groups, regardless of staying on the IMP or not, 
will be imputed using a model estimated from participants in the placebo group with endpoint 
data, where randomization strata and corresponding baseline values are included as the 
predictors. Missing data will be imputed using the regression method.  
Summary statistics (for screening value, baseline value, observed values, and observed 
changes from baseline) at scheduled visits will be provided by treatment group for HbA1c 
value over the whole treatment period including the 26-week Treatment Extension Period. 
The summary will include the number of observations, mean, SD, SE, minimum, median, and 
maximum. Graphical presentations will also be used to examine trends over time using mean 
values (±SE) and mean changes from baseline (±SE) at each of the scheduled visits 
(using OCs). 
Sensitivity analysis: 
Tipping-point analysis based on the same MI method as described above will be performed to 
examine the robustness of the results from the primary analysis. A penalty δ will be added to 
participants in efpeglenatide groups (2, 4, or 6 mg) who have no HbA1c data at Week 30. 
The penalty will be gradually increased to evaluate at which level the conclusion of the 
analyses in terms of statistical significance is changed for each efpeglenatide dose group. The 
tipping point is the penalty level, at which the magnitude of efficacy reduction in participants 


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without HbA1c data at Week 30 creates a shift in the treatment effect of efpeglenatide from 
being statistically significantly better than placebo to a nonstatistically significant effect. Least 
squares mean difference between each efpeglenatide dose and placebo and its associated 
p-value will be provided for each penalty level.  
The primary endpoint will be assessed too by an ANCOVA model with missing values imputed 
by control-based MI method (copy to reference) under the MNAR framework in the 
ITT population. Data will be imputed 10 000 times: 
 
For participants in the placebo group, missing data will be imputed based on the 
placebo group data. 
 
For participants in the efpeglenatide groups, missing data will be imputed as if the 
participants were on placebo throughout the study.  
In particular, a 2-step approach will be used as follows: 
 
Step 1: Use the Markov Chain Monte Carlo method conjunction with the 
IMPUTE=MONOTONE option in PROC MI to create an imputed data set with a 
monotone missing pattern. 
 
Step 2: Based on the MONOTONE data sets obtained from Step 1, build the 
imputation model using the regression method on data from the placebo group, and 
use the built model conditional on participant’s previous observed data to impute the 
missing data in both placebo and efpeglenatide groups. The imputation model will 
include the randomization stratum of HbA1c value at screening (<8%, ≥8%), and the 
randomization stratum of SU use (Yes, No). This will be implemented using MNAR 
statement in PROC MI. 
Each of the complete datasets after the imputation will be analyzed using the same ANCOVA 
model as used for the primary analysis. Results from each complete dataset will be combined 
using Rubin’s formula. 
Descriptive analyses will be conducted to explore missing data patterns for HbA1c in the 
primary efficacy analysis, with number and percentage of participants in each of the following 
categories presented by treatment group. 
 
Pattern 1: participants without baseline values, if any. 
 
Pattern 2: participants with baseline values but without postbaseline values during 
the 30-week Core Treatment Period. 
 
Pattern 3: participants with baseline values and at least 1 postbaseline value during 
the 30-week Core Treatment Period but not at Week 30. 
 
Pattern 4: participants with baseline values and a Week 30 value during the 30-week 
Core Treatment Period. 
HbA1c values by visit will be presented by missing data pattern for each treatment group, 
using descriptive statistics and/or graphs 
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%). 


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 
Baseline BMI (<30 kg/m2, ≥30 kg/m²). 
 
Diabetes duration (<10 years, ≥10 years). 
 
Country. 
 
United States/non-United States. 
 
Antidiabetic drugs at the time of screening (Lantus, Lantus + OAD). 
 
SU use at screening (Yes, No). 
The treatment effects (efpeglenatide 2, 4, or 6 mg versus placebo) across the subgroups 
defined for each of these factors will be estimated for the change from baseline to Week 30 in 
HbA1c in the ITT population and using a similar approach as applied to the analysis for the 
primary efficacy endpoint. The ANCOVA model will include treatment groups (efpeglenatide 2, 
4, or 6 mg, placebo) and randomization stratum of screening HbA1c (<8%, ≥8%), 
randomization stratum of SU use (Yes, No), 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 placebo) with SE 
and 95% CIs will be provided across the subgroups, as appropriate. A graphical presentation 
of the results (ie, forest plot) will also be provided. 
In the case that the subgroup factor is identical or similar to a randomization strata factor 
(eg, baseline HbA1c, SU use), 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 colinearity 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 HbA1c 
Change from baseline to 
Week 30 in FPG 
Change from baseline to 
Weeks 30 and 56 in body weight  
Number of participants with 
HbA1c <7.0% at Week 30 
(yes/no) 
 
 
Continuous secondary efficacy endpoints will be analyzed using the same ANCOVA model 
with missing values imputed by MI method as the method used for the primary efficacy 
endpoint analysis. Differences between treatment groups and CIs will be estimated by this 
method.  
Categorical efficacy endpoints will be analyzed by the Cochran Mantel-Haenszel method 
stratified by the randomization strata. For the HbA1c <7.0% analysis, participants with missing 
HbA1c data at Week 30 or Week 56 will be considered nonresponders in the ITT population. 
Summary statistics (for screening value, baseline value, observed values, and observed 
changes from baseline) at scheduled visits will be provided for each treatment group over the 
whole treatment period including the 26-week Treatment Extension Period. The summary will 
include the number of observations, mean, SD, SE, minimum, median, and maximum. 
Graphical presentations will also be used to examine trends over time using mean values 
(±SE) and mean changes from baseline (±SE) at each of the scheduled visits (using OCs). 
Multiplicity considerations 
To control the family-wise Type I error, a step-down testing procedure will be applied. For the 
primary efficacy endpoint (change from baseline to Week 30 in HbA1c), the 3 efpeglenatide 
doses will be tested in the order of 6 mg, 4 mg, and 2 mg. once the primary endpoint is 
statistically significant at α = 0.05 (2-sided) for all 3 efpeglenatide doses, a hierarchical testing 
procedure will be performed to test the following study secondary efficacy endpoints by the 
following prioritized order: 
1. 
HbA1c <7% at Week 30 for efpeglenatide 6 mg versus placebo (yes/no). 
2. 
Change from baseline to Week 30 in body weight (kg) for efpeglenatide 6 mg versus 
placebo. 
3. 
HbA1c <7% at Week 30 for efpeglenatide 4 mg versus placebo (yes/no). 
4. 
Change from baseline to Week 30 in body weight (kg) for efpeglenatide 4 mg versus 
placebo. 
5. 
HbA1c <7% at Week 30 for efpeglenatide 2 mg versus placebo (yes/no). 


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Endpoint 
Statistical Analysis Methods 
6. 
Change from baseline to Week 30 in FPG (mmol/L, mg/dL) for efpeglenatide 6 mg 
versus placebo. 
7. 
Change from baseline to Week 30 in FPG (mmol/L, mg/dL) for efpeglenatide 4 mg 
versus placebo. 
8. 
Change from baseline to Week 56 in body weight (kg) for efpeglenatide 6 mg versus 
placebo. 
9. 
Change from baseline to Week 56 in body weight (kg) for efpeglenatide 4 mg versus 
placebo. 
10. Change from baseline to Week 56 in HbA1c (%) for efpeglenatide 6 mg versus 
placebo. 
11. Change from baseline to Week 56 in HbA1c (%) for efpeglenatide 4 mg versus 
placebo. 
12. Change from baseline to Week 56 in HbA1c (%) for efpeglenatide 2 mg versus 
placebo. 
13. Change from baseline to Week 56 in body weight (kg) for efpeglenatide 2 mg versus 
placebo. 
14. Change from baseline to Week 30 in body weight (kg) for efpeglenatide 2 mg versus 
placebo. 
The testing will stop as soon as an endpoint for an efpeglenatide dose is found to be not 
statistically significant at α = 0.05 (2-sided) for 1 efpeglenatide dose. No multiplicity adjustment 
will be made on other secondary efficacy variables or the comparison of other efpeglenatide 
dose versus placebo than mentioned above. 
Exploratory endpoints 
See Section 3 
 
Comparisons of time-to-event endpoints between treatment groups will be performed using the 
Cox proportional hazards regression model with the treatment groups (efpeglenatide 2, 4, or 
6 mg, placebo), randomization stratum of screening HbA1c (<8%, ≥8%), randomization 
stratum of SU use (yes/no) and geographical region as the factors. The curve of the 
cumulative incidence of participants with rescue therapy initiation will be estimated using 
Kaplan-Meier method by treatment group. 
Summary statistics (for screening value, baseline value, observed values, and observed 
changes from baseline) at scheduled visits will be provided for each treatment group over the 
whole treatment period including the 26-week Treatment Extension Period. The summary will 
include the number of observations, mean, SD, SE, minimum, median, and maximum. 
Graphical presentations will also be used to examine trends over time using mean values 
(±SE) and mean changes from baseline (±SE) at each of the scheduled visits (using OCs). 
ANCOVA: analysis of covariance, BMI: body mass index, CI: confidence interval, FPG: fasting plasma glucose, HbA1c: hemoglobin A1c,  
ITT: intent to treat, MI: multiple imputation, MNAR: missing not at random, OC: observed cases, SD: standard deviation, SE: standard error, 
SMPG: self-monitored plasma glucose, SU: sulfonylurea. 
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. 


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 The whole on-treatment period is defined as the time from the first injection of IMP up to 
30 days (7 days for hypoglycemia) after the last injection of IMP: 
- 
The 30-week core on-treatment period is defined as the time from the first injection of 
IMP up to Visit 9 (Week 30) (or Day 210 if Visit 9 [Week 30] visit is missing) or up to 
30 days (7 days for hypoglycemia) after the last injection of IMP, whichever comes 
earlier. 
 The 30-week on-study period is defined from the first injection of IMP up to Week 30, 
irrespectively if IMP was still used or already discontinued at Week 30. 
 The posttreatment 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: 
 Pretreatment AEs are AEs that developed or worsened or became serious during the 
pretreatment period. 
 Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became 
serious during the on-treatment period. 
 Posttreatment AEs are AEs that developed or worsened or became serious during the 
posttreatment period. 
Table 7 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
AEs 
All AEs will be coded to a “LLT”, “PT”, “HLT”, and “HLGT” and associated “SOC” using the 
version of MedDRA currently in use by the Sponsor at the time of database lock. 
Adverse event incidence tables will be presented by primary SOC (sorted by internationally 
agreed order), HLGT, HLT and PT (sorted in alphabetical order) for each treatment group, 
showing the number (n) and percentage (%) of participants who experienced an AE. 
The primary focus of AE reporting will be on TEAEs. Pretreatment and posttreatment AEs will 
be described separately. 
Adverse event incidence tables will be provided by treatment group for all types of TEAEs: 
all TEAEs, all treatment-emergent SAEs, all TEAEs leading to permanent treatment 
discontinuation, and all TEAEs leading to death. 
Tables will be presented for the “30-week core on-treatment period” and for the “whole on-
treatment period including the 26-week controlled Treatment Extension Period”. 
AE, SAE, and AEs leading to death tables will be presented for the 30-week on-study 
period too. 
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 [06:00 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. 
Similar summaries will be also provided for the 30-week core on-treatment period. 


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Endpoint 
Statistical Analysis Methods 
Vital signs and laboratory data 
ECG data 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and changes from baseline values by 
visit and treatment group.  
The incidence of potentially clinically significant abnormalities (PCSA), defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review, will be summarized at any time during the 
on-treatment period. 
Results will be presented both in standard international and conventional US units. 
The incidence of normal and abnormal ECG status at any time during the on-treatment period 
will be summarized by treatment group whatever the baseline level and according to baseline 
status. 
 
Tables will be presented on the “30-week core on-treatment period” and on the “whole 
on-treatment period including the 26-week controlled Treatment Extension Period”. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock 
AE: adverse event, ECG: electrocardiogram, HLGT: higher-level grouped term, HLT: higher-level term, LLT: lower-level term, MedDRA: Medical 
Dictionary for Regulatory Activities, PCSA: potentially clinically significant abnormalities, PT: preferred term, SAE: serious adverse event, 
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 8. 
Table 8 - 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 ADA (among the 
participants with ADA negative or missing at baseline) during the study period. 
 
Number and percentage of participants with treatment-boosted ADA (among the 
participants with ADA positive at baseline) during the study period. 
 
ADA titer at scheduled time points will be summarized by visit using descriptive 
statistics by number (N), median, quartiles, minimum, and maximum.  
 
Number and percentage of participants with ADA cross-reactivity to endogenous GLP-1 
at scheduled visits. 
 
Number and percentage of participants with ADA cross-reactivity to endogenous 
glucagon at scheduled visits. 
 
Number and percentage of participants with ADAs directed against PEG linker of 
efpeglenatide at schedule visits. 
Correlation, scatterplots, and/or subgroup analyses will be conducted as appropriate to assess 
the relationship between immunogenicity endpoints and efficacy/safety assessments. 


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Endpoint 
Statistical Analysis Methods 
PK endpoints: serum 
concentration of 
efpeglenatide at predose and 
postdose 
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. 
ADA: antidrug antibody, GLP-1: glucagon-like peptide 1, PEG: polyethylene glycol, PK: pharmacokinetic. 
 
9.5 
INTERIM ANALYSES  
Not applicable. 
9.5.1 Data Monitoring Committee (DMC)  
See Appendix 1 (Section 10.1) for details. 


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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines, 
- 
Applicable laws and regulations. 
 The protocol, protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
 The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC, 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
10.1.2 Informed Consent Process  
 The Investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study.  
 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 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  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
 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) will 
be collected in this study because these data are required by several regulatory authorities 
(eg, on African American population for US Food and Drug Administration [FDA]).  
 The data collected in this study will only be used for the purpose(s) of the study and to 
document the evaluation of the benefit/risk ratio, efficacy, and safety of the product(s). 
They may be further processed if they have been anonymized. 
 When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 


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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. 
 Making a recommendation to the Sponsor regarding the study following each meeting. 
The DMC will review and analyze, on a regular basis, unblinded safety data throughout the study, 
as well as safety data from the other ongoing clinical studies conducted with efpeglenatide 
(a single DMC for the whole efpeglenatide program). Details describing the DMC processes and 
procedures are outlined in the DMC Charter. To maintain continuous blinding and study integrity, 
the analysis will be conducted by an independent statistician who will directly transfer data to 
DMC members, and measures will be taken to ensure the validity of the data. 
10.1.4.2 Clinical Endpoint Committee  
Independent CEC(s) will be composed of experts in the field of cardiology, neurology and 
gastroenterology (and other appropriate medical specialties as needed). This committee will be 
independent from the Sponsor, the CRO and the Investigators, and will be implemented to review, 
assess, and/or adjudicate all events of death, selected CV events (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 publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, European Union clinical trial register (eu.ctr), 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 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 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.7 Source documents  
 Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
 Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
 Definition of what constitutes source data can be found in 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 9 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. 


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Table 9 - Protocol-required safety laboratory assessments  
Laboratory 
assessmentsa 
Parameters 
Hematology 
Platelet count  
RBC count 
Hemoglobin 
Hematocrit 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistry 
Creatinine 
Potassium 
AST 
Total bilirubin (in case of values above 
the normal range, differentiation in 
conjugated and nonconjugated bilirubin). 
 
Sodium 
ALP 
ALT 
eGFR (MDRD formula). 
 
Amylase 
Lipase 
 
 
Routine urinalysis 
pH, glucose, protein, blood/hemoglobin, ketones, leucocyte, by dipstick 
Lipid profile 
Triglyceride 
Cholesterol: 
Total cholesterol 
Low-density lipoprotein cholesterol 
High-density lipoprotein cholesterol 
Antidrug antibodies 
Serum antidrug antibody 
Calcitonin 
Calcitonin 
Other screening 
tests 
 
Follicle-stimulating hormone and estradiol (as needed in unconfirmed postmenopausal 
women). 
 
NOTE: For women not of childbearing potential (Appendix 4, Section 10.4), follicle stimulating 
hormone and estradiol levels should be tested in case the definition of postmenopausal or 
premenopausal cannot be satisfied, eg, no medical document of hysterectomy or cessation of 
menses <12 months without an alternative medical cause. 
 
Serum human β-HCG pregnancy test (as needed for women of childbearing potential)b. 
 
C-peptide. 
NOTES: 
a All study-required laboratory assessments will be performed by a central laboratory except urine pregnancy tests and urinalysis by dipstick, 
which will be performed locally; the results of each test must be entered into the 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, ALP: alkaline phosphatase, AST: aspartate aminotransferase, β-HCG: human beta-chorionic gonadotropin, 
eGFR: estimated glomerular filtration rate, MDRD: Modification of Diet in Renal Disease, RBC: red blood cells, 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 2 (Day 1), until the study has been unblinded. Details of the 
conditions in which unblinding can occur, and the procedure, are detailed in Section 6.3.2. 


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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
 An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
Events NOT meeting the AE definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 


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 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 


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f) Other situations: 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information in the eCRF. 
 It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor representative in lieu of completion of the SAE 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 the Sponsor representative. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
 The Investigator will submit any initial SAE/AESI data to the Sponsor representative 
within 24 hours of its acknowledgement. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 


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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. 
 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 make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor 
representative. 
 The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor representative with a copy of any 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 within 24 hours 
of receipt of the information. 


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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. 
 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 
(see next section) 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 1 of the following: 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 


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3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or 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 non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10. 
In addition WOCBP must refrain from donating ova for the duration of the study and at least 
5 weeks after last dose of IMP. 


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Table 10 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation  
 
Oralb.  
 
Intravaginal.  
 
Transdermal. 
Progestogen only hormonal contraception associated with inhibition of ovulation 
 
Oralb. 
 
Injectable. 
Highly effective methods that are user independenta 
 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation. 
 
Intrauterine device (IUD). 
 
Intrauterine hormone-releasing system (IUS). 
 
Bilateral tubal occlusion. 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be 
used. 
Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the study and the preferred and usual lifestyle of the participant. 
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies.  
b Pharmacokinetic drug-interaction potential of oral hormonal contraception with the study treatment is low, but still unknown. Therefore, if the 
oral contraceptive cannot be replaced by 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 poststudy pregnancy-related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he/she may learn of an SAE through spontaneous reporting.  
 Any female participant who becomes pregnant while participating in the study will 
discontinue study 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. 


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


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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the 
baseline visit. The algorithm does not apply to the instances of increase in ALT during screening. 
 
See Section 8.3 for guidance on safety reporting. 
 
Normalization is defined as ≤ ULN or baseline value, if baseline value is >ULN. 


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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
Rapid increase in serum creatinine over 150 µmol/L 
or rapid decrease in creatinine clearance below
50 mL/mn
INCREASE IN SERUM CREATININE
Can be rapidly reversed:
• By volume repletion
• Or relief of urinary tract 
obstruction (according to etiology)
Cannot be rapidly reversed: 
• Occurrence/aggravation of life 
threatening symptoms of ARF: anemia, 
hyperkalemia, hyperuricemia, metabolic 
acidosis, cardiac insufficiency, 
pulmonary edema, arrhythmia, DIC, etc.
• And/or predominant elimination of 
investigational medicinal product by 
renal route
1.
Investigational medicinal 
product may be continued
2.
MONITOR serum creatinine 
until return to baseline level
1.
INFORM the local monitor
2.
DISCONTINUE
investigational medicinal product 
administration
3.
HOSPITALIZATION should be 
considered and seek for nephrologic
advice
4.
PERFORM the following 
examinations: 
•
BP, HR, hydration status, ECG
•
Blood count
•
Liver function tests + CPK
•
Biochemistry, including urea
•
Urinalysis
5.
COLLECT/STORE one sample 
following handling procedures 
described in PK sections (for studies 
with PK sampling) and freeze one 
serum sample (5 mL) on Day 1 
(cessation of investigational 
medicinal product)
6.
MONITOR renal function until 
return to baseline level (every day at 
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Increase in creatine phosphokinase is to be recorded as an AE only if at least 1 of the criteria in 
the general guidelines for reporting AEs in Appendix 3 (Section 10.3) is met. 
If Increase in CPK (expressed in ULN)
> 3 ULN
Repeat immediately the count.
If confirmed, inform the local monitor and
INVESTIGATE for the origin:
- PERFORM:
•
ECG
•
CPK-MB -MM 
•
Troponin
•
Creatinine
•
Iono (k+, Ca2+)
•
Transaminases + Total and conjugated bilirubin
•
Myoglobin (serum and urines)
- COLLECT/STORE one sample following handling procedures described in PK sections (for 
studies with PK sampling) and freeze one serum sample (5 mL) on Day 1 (cessation of 
investigational medicinal product). 
- INTERVIEW the patient about a recent intensive muscular effort, trauma, convulsions, electrical 
injury, injury or stress to the skeletal muscle, multiple intramuscular injections, recent surgery, 
concomitant medications, consumption of alcohol, morphine, cocaine.
- SEARCH for alternative causes to cardiac or muscular toxicity, ie, stroke, pulmonary infarction, 
dermatomyositis or polymyositis, convulsions, hypothyroidism, delirium tremens, muscular 
dystrophies.
If either the cardiac origin or the 
rhabdomyolysis is confirmed or if CPK 
> 10 ULN:
1. DISCONTINUE investigational 
medicinal product administration
2. MONITOR CPK every 3 days for the 
first week then once weekly until return 
to normal or for at least 3 months
3. HOSPITALIZATION should be 
considered
If the cardiac origin or the rhabdomyolysis is 
ruled out and if CPK 10 ULN:
MONITOR CPK every 3 days for the first week 
then once weekly until return to normal or for 
at least 3 months
Muscular symptoms (myalgia, pain, weakness, 
dark urines)
Systematic CPK assessment as per 
protocol
Perform CPK
INCREASE IN CPK SUSPECTED TO BE OF NON-CARDIAC ORIGIN 
AND NOT RELATED TO INTENSIVE PHYSICAL ACTIVITY


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10.5.2 Monitoring of participants with increased lipase and/or amylase >2 × ULN  
GLP-1 RAs stimulate pancreatic beta-cell and suppress alpha-cell function. Some cases of acute 
pancreatitis have been reported with marketed GLP-1 RAs. Therefore, participants enrolled in this 
study should be closely monitored for any suspected pancreatitis, eg, with symptoms and/or signs 
of acute abdominal distress or abnormal levels of pancreatic enzymes. Serum amylase and lipase 
concentrations are monitored routinely at screening, baseline, and periodically during the study 
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. 
Refer to Section 10.5.2.1 and Section 10.5.2.2 below for actions to take in case of elevation of 
amylase and/or lipase with or without clinical signs and/or symptoms evocative of pancreatitis, 
respectively. 
In any situation as described below, 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. 
10.5.2.1 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 in a participant with baseline amylase and/or lipase values 
<2 × ULN: retest within 7 days. 
 If value(s) is/are >3 × ULN: retest within 48 hours, regardless of baseline amylase and/or 
lipase values. 
 If the value(s) remain(s) >2 × ULN upon retesting: amylase and/or lipase levels should be 
retested weekly until values are <2 × ULN. 
In case a retest is >2 × ULN a gastroenterological evaluation and imaging (ultrasound and/or 
computed tomography [CT] or magnetic resonance imaging [MRI] with contrast, as appropriate) 
is highly recommended. The absence of clinical signs and/or symptoms should be documented in 
the source documents (if clinical signs and/or symptoms develop, please see Section 10.5.2.2 
below). 


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Best clinical judgment is to be used when interpreting elevated serum amylase and lipase levels in 
asymptomatic participants. Temporary discontinuation of the IMP may be considered in these 
cases if deemed necessary by the Investigator. 
10.5.2.2 Elevation of amylase and/or lipase >2 × ULN with clinical signs and/or symptoms.  
In the presence of clinical signs and/or symptoms evocative of pancreatitis (as previously 
described) associated with elevated amylase and/or lipase, treatment with the IMP should be 
promptly and at least temporarily discontinued pending further clinical evaluation and diagnosis 
confirmation. Clinical signs and/or symptoms are to be documented in the source data. 
A laboratory determination of amylase and lipase must be obtained at the time of the event and 
again within 48 hours or earlier as clinically indicated. If the value(s) remain(s) >2 × ULN, then 
amylase and/or lipase levels should be retested as described in Section 10.5.2.1, or more often if 
clinically indicated. 
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. 
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). 


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 The participant should continue to be followed according to protocol schedule (including 
planned calcitonin measurements). The AE form and all other related eCRF pages should 
be updated with any new information collected during the follow-up. 
 If calcitonin value ≥50 pg/mL (14.75 pmol/L) is found at any time during follow-up, the 
participant should be permanently discontinued from IMP and referred to a specialist. 
As far as possible, blood should be collected 1 to 2 weeks after IMP discontinuation and 
sent to the central laboratory for calcitonin measurement. As per protocol, the participant 
should be followed according to study procedures up to the scheduled end of the study. 
If at any time during follow-up calcitonin value ≥20 pg/mL increases by 20% or more between 
2 assessments (while remaining below 50 pg/mL), a repeated measurement should be performed 
earlier than scheduled in the protocol, ie, 1 month later. Once results are available, discussion with 
Sponsor representative should be initiated without delay for further guidance. 
10.5.4 Gastrointestinal events in relation to acute renal failure  
Acute renal impairment caused by dehydration is a potential risk described for other GLP-1 RAs. 
Acute renal impairment is not thought to be caused directly by GLP-1 RAs (including 
efpeglenatide) without dehydration. 
In case of prolonged or severe nausea and vomiting, if clinically indicated, serum creatinine 
measurement should be performed at the central laboratory. If there is an acute increase of serum 
creatinine, metformin must be discontinued (if concomitantly taken) until resolution of renal 
dysfunction. Please also refer to Appendix 5 (Section 10.5), Increase in serum creatinine 
flowchart for further recommendations. 
10.5.5 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; all efforts to be done to collect all 
medical documents from ophthalmologic examination(s) related to potential diabetic retinopathy 
events. 
10.6 
APPENDIX 6: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING   
Not applicable. 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 


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10.8 
APPENDIX 8: HYPOGLYCEMIA CLASSIFICATION  
Figure 2 - Hypoglycemia classification  
 
PG: plasma glucose, SAE: serious adverse event 
   


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10.9 
APPENDIX 9: ABBREVIATIONS  
 
ADA: 
antidrug antibody 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase 
CEC: 
Clinical Endpoint Committee 
CFR: 
Code of Federal Regulations 
CI: 
confidence interval 
CT: 
computed tomography 
CV: 
cardiovascular 
DMC: 
Data Monitoring Committee 
DPP-4: 
dipeptidyl peptidase 4 
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 RA: 
glucagon-like peptide 1 receptor agonists 
HbA1c: 
hemoglobin A1c 
HRT: 
hormone replacement therapy 
IB: 
Investigator's Brochure 
ICF: 
informed consent form 
IEC: 
Independent Ethics Committees 
IMP: 
Investigational Medicinal Product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
MACE: 
major adverse cardiovascular events 
MDRD: 
modification of diet in renal disease 
MEN-2: 
multiple endocrine neoplasia syndrome type 2 
MI: 
multiple imputation 
MRI: 
magnetic resonance imaging 
MTC: 
medullary thyroid cancer 
NIMP: 
noninvestigational medicinal product 
OAD: 
oral antidiabetic drug 


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OC: 
observed cases 
PEG: 
polyethylene glycol 
PFS: 
prefilled syringe 
PK: 
pharmacokinetic 
popPK: 
population pharmacokinetic 
PPG: 
postprandial plasma glucose 
SAE: 
serious adverse event 
SC: 
subcutaneous 
SD: 
standard deviation 
SE: 
standard error 
SMPG: 
self-monitored plasma glucose 
SoA: 
schedule of activities 
SU: 
sulfonylurea 
SUSAR: 
suspected unexpected serious adverse reaction 
T2DM: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WOCBP: 
women of childbearing potential 
 
10.10 APPENDIX 10: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 


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EFC14893 - efpeglenatide 
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11 
REFERENCES  
1. Investigator´s Brochure for SAR439977, latest edition. 
2. Food and Drug Administration. FDA draft Guidance for Industry: assay development and 
validation for immunogenicity testing of therapeutic protein products. 2016 Apr 25. 
3. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP): 
Guideline on immunogenicity assessment of biotechnology-derived therapeutic proteins. 2017 
May 18. EMEA/CHMP/BMWP/14327/2006 Rev 1. 
4. Evert AB, Boucher JL, Cypress M, Dunbar SA, Franz MJ, Mayer-Davis EJ, et al. Nutrition 
therapy recommendations for the management of adults with diabetes. Diabetes Care. 
2014;37(Suppl. 1):S120-43. 
5. International Hypoglycaemia Study Group. Glucose concentrations of less than 3.0 mmol/L 
(54 mg/dL) should be reported in clinical trials: a joint position statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 
2017;40:155-7. 
6. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36:1384-95. 
7. Workgroup on Hypoglycemia, American Diabetes Association. Defining and reporting 
hypoglycemia in diabetes: a report from the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2005;28(5):1245-9. 
 
 
 
 


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Page 1 
STATISTICAL ANALYSIS PLAN 
A 56-week, Multicenter, Double-blind, Placebo-controlled, Randomized Study to 
Evaluate the Efficacy and Safety of Efpeglenatide Once Weekly in Patients with 
Type 2 Diabetes Mellitus Inadequately Controlled with Basal Insulin Alone or in 
Combination with Oral Antidiabetic Drug(s) 
SAR439977-EFC14893 
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 11-Nov-2020 
Total number of pages: 
46 
NCT03713684


Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 4 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 5 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 5 
1.2 
OBJECTIVES ................................................................................................................................... 5 
1.2.1 
Primary objectives ............................................................................................................................ 5 
1.2.2 
Secondary objectives ....................................................................................................................... 5 
1.2.3 
Tertiary/exploratory .......................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 6 
1.4 
STUDY PLAN ................................................................................................................................... 6 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 7 
1.6 
STATISTICIAL MODIFICATIONS MADE IN STATISTICAL ANALYSIS PLAN .............................. 8 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ...................................................................... 9 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................. 9 
2.1.1 
Demographic and baseline characteristics ...................................................................................... 9 
2.1.2 
Prior or concomitant medications ................................................................................................... 10 
2.1.3 
Efficacy endpoints .......................................................................................................................... 11 
2.1.3.1 
Primary efficacy endpoint ............................................................................................................... 12 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................ 12 
2.1.3.3 
Exploratory efficacy endpoint(s) ..................................................................................................... 12 
2.1.4 
Safety endpoints ............................................................................................................................ 12 
2.1.4.1 
Adverse event observation period ................................................................................................. 13 
2.1.4.2 
Deaths ............................................................................................................................................ 14 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 14 
2.1.4.4 
Vital signs variables ....................................................................................................................... 15 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 15 
2.1.4.6 
Hypoglycemia ................................................................................................................................. 15 
2.1.5 
Immunogenicity endpoints ............................................................................................................. 16 
2.1.5.1 
Anti-drug (efpeglenatide) antibody ................................................................................................. 16 
2.1.6 
Pharmacokinetic endpoints ............................................................................................................ 16 


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2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 17 
2.2 
DISPOSITION OF PARTICIPANTS ............................................................................................... 17 
2.2.1 
Protocol Deviations ........................................................................................................................ 18 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 18 
2.3.1 
Efficacy populations ....................................................................................................................... 18 
2.3.1.1 
Intent-to-treat population ................................................................................................................ 18 
2.3.2 
Safety population ........................................................................................................................... 18 
2.4 
STATISTICAL METHODS ............................................................................................................. 19 
2.4.1 
Demographics and baseline characteristics .................................................................................. 19 
2.4.2 
Extent of investigational medicinal product exposure .................................................................... 19 
2.4.2.1 
Extent of investigational medicinal product exposure .................................................................... 19 
2.4.3 
Analyses of efficacy endpoints ....................................................................................................... 20 
2.4.4 
Analyses of safety data .................................................................................................................. 20 
2.4.4.1 
Analyses of adverse events ........................................................................................................... 21 
2.4.4.2 
Analysis of Hypoglycemia .............................................................................................................. 25 
2.4.4.3 
Deaths ............................................................................................................................................ 25 
2.4.4.4 
Analyses of vital sign variables ...................................................................................................... 26 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 26 
2.5.1 
General conventions ...................................................................................................................... 26 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 26 
2.5.3 
Missing data ................................................................................................................................... 26 
2.5.4 
Windows for time points ................................................................................................................. 28 
2.5.5 
Unscheduled visits ......................................................................................................................... 28 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 28 
2.5.7 
Statistical technical issues ............................................................................................................. 28 
3 
INTERIM ANALYSIS ..................................................................................................................... 29 
4 
DATABASE LOCK ........................................................................................................................ 30 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 31 
6 
REFERENCES ............................................................................................................................... 32 
7 
LIST OF APPENDICES ................................................................................................................. 33 
APPENDIX A 
CRITERIA FOR POTENTIALLY SIGNIFICANT ABNORMALITIES – FOR PHASE 
2/3 STUDIES (ONCOLOGY EXCEPTED) ..................................................................................... 34 
APPENDIX B 
SCHEDULE OF ACTIVITIES (SOA) ................................................................................... 41 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE: 
adverse event 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
CV: 
cardiovascular 
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 
MI: 
myocardial infarction 
NIMP: 
noninvestigational medicinal product 
OAD: 
oral antidiabetic drug 
OC: 
observed cases, standard deviation 
PCSA: 
potentially clinically significant abnormality 
PT: 
preferred term 
R: 
randomization 
SC: 
subcutaneous 
SOC: 
system organ class 
SU: 
sulfonylurea 
T2DM: 
Type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
TIA: 
transient ischemic attack 
WHO-DD: 
World Health Organization-Drug Dictionary 


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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
1.1 
STUDY DESIGN AND RANDOMIZATION 
Protocol EFC14893, is a multicenter, 30-week, double-blind, randomized, placebo-controlled 
Phase 3 study with an additional 26-week Treatment Extension Period evaluating the efficacy and 
safety of efpeglenatide addition in participants with type 2 diabetes mellitus (T2DM) inadequately 
controlled with basal insulin alone or in combination with Oral Antidiabetic Drug (OAD)(s). 
After a Screening phase of 2 weeks, participants will be centrally randomized (using permuted 
block randomization schedule) via Interactive Response Technology (IRT) in a 1:1:1:1 ratio to 1 
of the following 4 treatment groups: 
• 
efpeglenatide 2 mg  
• efpeglenatide 4 mg  
• efpeglenatide 6 mg  
• efpeglenatide placebo 
Randomization will be stratified by Screening hemoglobin A1c (HbA1c) (<8.0, ≥8.0%) and 
sulfonylurea (SU) use at Screening (Yes/No). Participants will receive double-blinded treatment 
for 56 weeks. Additional details on the study design and plan are located in Section 1.4. 
Approximately 400 participants (100 participants per treatment group) [details in Section 1.3] will 
be randomized. 
The study was early terminated by the Sponsor on 09 September 2020 (hereinafter referred to as 
“early termination”). 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate the superiority of once-weekly injection of 
efpeglenatide 2, 4, or 6 mg in comparison to placebo in HbA1c change from Baseline to Week 30 
in participants with T2DM inadequately controlled with basal insulin alone or in combination 
with OAD(s). 
1.2.2 Secondary objectives 
Secondary objectives of this study include: 
• To demonstrate the superiority of once-weekly injection of efpeglenatide 2, 4, and 6 mg in 
comparison to placebo on additional glycemic control  


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• To demonstrate the superiority of once-weekly injection of efpeglenatide 2, 4, and 6 mg in 
comparison to placebo on body weight 
• To evaluate the safety of once-weekly injection of efpeglenatide 2, 4, and 6 mg. 
1.2.3 Tertiary/exploratory  
• To characterize the pharmacokinetics (PK) of efpeglenatide in dose regimen of once 
weekly injection of 2, 4, and 6 mg 
• To evaluate the immunogenicity of once weekly injection of efpeglenatide 2, 4, and 6 mg 
• To compare the effects on once weekly injection of efpeglenatide 2, 4 and 6 mg with 
placebo on additional parameters of glycemic control 
• To compare the effects on once weekly injection of efpeglenatide 2, 3 and 6 mg with 
placebo on waist circumference 
• To compare the effect of once weekly injection of efpeglenatide 2, 4, and 6 mg with 
placebo on insulin dose 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculations are performed based on the primary endpoint, change in HbA1c (%) 
from Baseline to Week 30. 
A sample size of approximately 100 participants per arm (ie, 100 participants for each of the 
efpeglenatide doses and 100 for the placebo group) has 89% (96%) power to detect a treatment 
difference of -0.5% (-0.6%) between each dose of efpeglenatide and placebo in HbA1c change 
from Baseline to Week 30, assuming a common standard deviation of 1.1% (2-sided, alpha=0.05) 
for each comparison. 
Hence, there are 4 parallel dosing arms: 
• 
Efpeglenatide 2 mg, N=100 
• 
Efpeglenatide 4 mg, N=100 
• 
Efpeglenatide 6 mg, N=100 
• 
Efpeglenatide placebo, N=100 
Hierarchical procedure will be done to adjust the multiplicity of comparison. 
1.4 
STUDY PLAN 
This is a multicenter, 56-week, randomized, double-blind, placebo-controlled Phase 3 study 
consisting of 4 study periods: 
• 
A 2-week Screening Period (11 to 14 days) 


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• 
A 30-week double-blind, placebo-controlled Core Treatment Period, for efficacy and 
safety assessment 
• 
A 26-week double-blind, placebo-controlled Treatment Extension Period; participants will 
remain on the randomized investigational medicinal product (IMP) regimen 
• 
A 6-week Follow-up Period to collect posttreatment safety information for all participants 
after last dose of IMP 
The maximum study duration per participant will be 64 weeks with treatment lasting for 56 weeks 
(a 30-week core treatment period and a 26-week extension period). The graphical study design is 
shown in Figure 1. 
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  
Not applicable. 


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1.6 
STATISTICIAL MODIFICATIONS MADE IN STATISTICAL ANALYSIS PLAN 
Due to study early termination, the efficacy evaluations originally planned in the protocol were no 
longer considered to be relevant and were not performed. PK and ADA samples were not 
analyzed thus no analyses were planned. This is a simplified statistical analysis plan (SAP) for the 
purpose of synopsized clinical study report (CSR).  


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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The Baseline value (with the exception of serum creatinine and eGFR) 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 study treatment. Note: any assessment undertaken 
on the day of first dose administration of 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 double-blind IMP for those randomized and exposed to IMP or before randomization for 
those randomized but not exposed to IMP. 
All Baseline safety parameters (apart from those listed below) are presented along with the 
on-treatment summary statistics in the safety sections (Section 2.4.4).  
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), country (US, China and Korea), HbA1c (%) at screening, 
randomization strata HbA1c (%) at screening (<8%, ≥8%), randomization strata SU use at 
screening (Yes, No), baseline weight (kg), baseline body mass index (BMI) (quantitative and 
qualitative variable: <30, ≥30 and <40, ≥40 kg/m2), and baseline waist circumference. 
Participants counted as multiple races will not be counted in other race categories. 
Medical history 
Medical history includes medical or surgical history. 
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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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; 
• Antidiabetic drugs at the time of screening (basal insulin, basal insulin + SU, basal insulin 
+ OAD other than SU); 
• Basal insulin dose at Screening (U, U/kg); 
• Basal insulin dose at Baseline (U, U/kg); 
• Duration of treatment with (any) basal insulin; 
• Estimated Glomerular Filtration Rate (eGFR) at baseline (ml/min/1.73m2); 
• Estimated glomerular filtration rate (eGFR) categories at baseline (<15 ml/min/1.73 m2 
[End stage renal Disease], ≥15 to <30 ml/min/1.73 m2 [Severe decrease in glomerular 
filtration rate (GFR)], ≥30 to <60 ml/min/1.73 m2 [Moderate decrease in GFR], ≥60 to 
<90 ml/min/1.73 m2 [Mild decrease in GFR], and ≥90 ml/min/1.73 m2 [Normal]) 
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 IMP administration. Prior 
medications can be discontinued before first 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 


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drugs). A given medication can be classified both as a prior medication and as a 
concomitant medication. Concomitant medications do not include medications started 
during the posttreatment period (as defined in the observation period in Section 2.1.4).  
• 
Posttreatment medications are those the 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 includes Lantus for SC injections, and OAD(s) administered as per 
Investigator prescription and in accordance with local labeling.  
Rescue medication(s) is considered Non-IMP (NIMP) treatment. Except for GLP-1 RA and 
DPP-4 inhibitors, any approved medication(s) including oral antidiabetic drugs or prandial insulin 
can be prescribed at the Investigator’s discretion to treat the hyperglycemia. 
Prohibited medication(s) 
All prohibited medications are based on sponsor-defined Customized Drug Grouping (CDG). 
The following treatments are prohibited during the Screening Period and the 56 weeks of 
treatment period. 
• Initiation of any GLP-1 RAs (eg, exenatide, liraglutide, dulaglutide, or semaglutide) and 
DPP-4 inhibitors (eg, sitagliptin, saxagliptin, vildagliptin, or linagliptin) 
The following treatments are prohibited during the on-treatment treatment period from 1st intake 
up to the last intake of investigational product. 
• Initiation of any antidiabetic agents including oral or injectable antihyperglycemic agents 
other than IMP and Lantus or a change in dose or preexisting OAD(s) before pre-rescue 
assessments and initiation of rescue therapy. 
 
Note: Short-term use (<10 consecutive days) of short-acting insulin for treatment of acute 
illness or surgery is allowed 
• Initiation of any 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. 


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Efficacy variables HbA1c (%) and weight (kg) will be summarized in conventional units and FPG 
(mmol/L) will be summarized in SI units. 
2.1.3.1 Primary efficacy endpoint 
• Change in HbA1c (%) from Baseline at Week 30  
2.1.3.2 Secondary efficacy endpoints 
• Number of participants with HbA1c <7.0% at Weeks 30 and 56 (yes/no) 
• Change in FPG from Baseline at Weeks 30 and 56  
• Change in HbA1c (%) from Baseline at Week 56 
• Changes in body weight from Baseline at Weeks 30 and 56 
2.1.3.3 Exploratory efficacy endpoint(s) 
• HbA1c <7.0% at Week 30 and Week 56 without weight gain  
• Change in waist circumference from Baseline to Week 30 and 56 
• Changes in mean 24-hour SMPG (7-point SMPG profile) 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 
• Change in daily basal insulin dose from Baseline to Week 30 and 56 
• Time to initiation of rescue therapy (weeks) 
• Number of participants with rescue therapy used during the treatment period until 
Weeks 30 and 56 
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.  


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Observation period  
The observation 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 IMP 
• 
The whole on-treatment period is defined as the time from the first injection of the IMP 
up to 30 days (7 days for hypoglycemia) after the last injection of the IMP 
- 
The 30-week core on-treatment period is defined as the time from the first injection of 
IMP up to Visit 9 (Week 30) (or Day 210 if Visit 9 [Week 30] visit is missing) or up to 
30 days (7 days for hypoglycemia) after the last injection of IMP, whichever comes 
earlier 
• 
The post-treatment period is defined as the period from the end of the whole on-treatment 
period.  
The on-study observation period is defined as the time from first injection of IMP up to either 
the last protocol-planned visit or the date of last available information if participants discontinue 
the study prematurely (ie, the date collected on e-CRF page “Completion of End of Study/Follow-
up”), whichever is later. 
2.1.4.1 Adverse event observation period  
• 
Pretreatment 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 
• 
Posttreatment 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 


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• 
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 
• 
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 
Deaths will be categorized according to the following observation periods: 
• 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 (end of on-study observation 
period)  
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 B). 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 


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- 
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 
participants will be analyzed) 
- 
Calcitonin 
Technical formulas are described in Section 2.5. 
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 include 12-lead ECG interpretation (normal/abnormal) provided by the 
investigator. 12-lead ECG recording will be performed locally at Randomization, Week 12, 
Week 30 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. 


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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. 
• 
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 - <3.9 mmol/L (≥54 - <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. 
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) at Visit 2/Week 0, Visit 4/Week 4, Visit 6/Week 12, Visit 9/Week 30, at the end of 
treatment visit, and 6 weeks post-treatment follow up visit.  
2.1.6 Pharmacokinetic endpoints 
Pharmacokinetic variables include the concentration of efpeglenatide in the efpeglenatide groups: 
• 
Serum Ctrough of efpeglenatide at pre-dose (Weeks 4, 12, 24, 30); 
• 
Serum concentration of efpeglenatide at post-dose (either 4 days [±1 day] after first IMP 
dose, 4 days [±1 day] after 4th dose, or 4 days [±1 day] after 12th dose in a subset of 


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participants). All valid 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 a treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used. 
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  
• 
Nonrandomized but treated participants  
• 
Randomized participants  
• 
Randomized but not treated participants  
• 
Randomized and treated participants  
• 
Participants who have completed the 30-week core treatment period as per protocol 
• 
Participants who did not complete the 30-week core treatment period, and main reasons 
for permanently treatment discontinuation.  
• 
Participants who have completed the whole study treatment period including the 26-week 
extension period as per protocol 
• 
Participants who did not complete the whole study treatment period, and main reason for 
permanent treatment discontinuation 
• 
Participants who completed the study as per protocol 
• 
Participants who discontinued the study by main reason for permanent study 
discontinuation 
• 
Status at last study contact  
For all categories of participants (except for the screened, 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.  


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Summary of participants who discontinued treatment and/or study will be provided with reasons 
for discontinuation, including reasons related to COVID-19. 
2.2.1 Protocol Deviations 
All significant deviations, potentially impacting efficacy analyses, randomization, and drug 
dispensing irregularities, and other selected significant deviations will be recorded.  
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. 
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.  
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 intent-to-treat (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.  
2.3.2 Safety population 
The safety population is defined as:  
• 
Randomized population who actually 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 
included in the safety population as randomized according to their planned treatment. 


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• 
For participants receiving 1 or more injections of efpeglenatide during the trial, regardless 
of being assigned to the efpeglenatide groups or not, the treatment group allocation for 
as-treated analysis will be included in the efpeglenatide dose group that they are exposed 
for longer duration. In case of a tie, the highest dose group will be used. 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 participants is dispensed double-blind IMP and is 
lost to follow-up without any documented evidence, the participants will be considered 
exposed. 
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. 
Due to study early termination, the analyses specified in this document focus on demographics, 
disease characteristics at baseline, exposure, participants disposition, and safety. Primary and 
secondary efficacy data will be descriptively summarized. 
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. 
Technical formulas are described in Section 2.5. 
P-values on demographic and baseline characteristic data will not be calculated.  
2.4.2 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed and summarized by actual treatment within the 
safety population (Section 2.3.2).  
2.4.2.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by cumulative exposure (participants years), duration 
(days), and category (weeks). 


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Duration of 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). 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum). In addition, duration of treatment exposure will 
also be summarized 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; cumulative duration of treatment by category (weeks) will also be 
summarized. The duration of treatment exposure in weeks will be the duration (in days)/7 rounded 
to the nearest integer. 
2.4.3 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 or introduction of rescue 
therapy, unless otherwise specified (see Section 2.5.4). 
Descriptive summary will be provided at screening, baseline, Week 30 and Week 56 displaying 
observed value and change from baseline for efficacy endpoints (HbA1c, FPG, body weight and 
% participants achieving 7%).  
In summary by visits, Week 56 data will be presented respectively:  
1. Including all Week 56 visits performed per protocol as well as premature end of 
treatment/study visit recorded as Week 56 due to early termination.  
2. Including Week 56 visits for participants who completed treatment and/or study.  
2.4.4 Analyses of safety data 
The summary of safety results will be presented by treatment group on the “whole 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 following common rules: 
• 
Safety data in participants who do not belong to the safety population (eg, treated but not 
randomized) will be listed separately 


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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 A])  
- 
PCSA criteria will determine which participants had at least 1 PCSA during the whole 
on-treatment period, taking into account all evaluations performed during the whole 
on-treatment period, including nonscheduled or repeated evaluations. The number of 
all such participants will be the numerator for the whole 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 whole on-
treatment period by treatment group on the safety population. 
• 
The analysis of the safety variables will be descriptive, and no systematic testing is 
planned.  
2.4.4.1 Analyses of adverse events 
Generalities 
The primary focus of AE reporting will be on TEAEs.  
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. 
Sorting within tables ensures the same presentation for the set of all AEs within the observation 
period. 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. 


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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 
25. Surgical and medical procedures 
26. Social circumstances 
27. Product issues 


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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 
• 
Discontinued per investigator decision 
• 
Discontinued per participant decision 
- 
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.  
• 
Summary of common TEAEs (eg, PTs with incidence ≥2% in any treatment group) will be 
presented by primary SOC and PT 
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.  
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation per investigator decision, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of participants 
• 
All TEAEs leading to treatment discontinuation per investigator and/or participant 
decision, by primary SOC, HLGT, HLT, and PT, showing the number (%) of participants 
Analysis of adverse events of special interest and requiring specific monitoring  
Adverse events of special interest (AESI) and adverse events requiring specific monitoring 
(AERSM) include AE defined in Section 2.1.4 and the criteria of AESI and AERSM are in 
Table 1. 


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Table 1 - 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 CMQ 
Severe hypoglycemia 
Any hypoglycemia event which required assistance (from hypoglycemia page) 
Pancreatic event 
Cases reported in pancreatic specific eCRF 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 following TEAE summaries will be generated for the safety population: 
• All AESI by prespecified grouping and PT, showing number (%) of participants with at 
least 1 AESI, with PTs sorted by decreasing order in Efpeglenatide 6 mg group. 
• All AERSM by prespecified grouping and PT, showing number (%) of participants with at 
least 1 AERSM, with PTs sorted by decreasing order in Efpeglenatide 6 mg group. 


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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 events sent for adjudication, will be presented in the listings, which include at least the 
following information, sorted by treatment, participant identification, and onset date: treatment, 
participant identification, country, age, gender, race, 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/study procedures, 
outcome, date of death (if any), seriousness, seriousness criteria. 
2.4.4.2 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 2.1.4.5 (ie, 
severe, documented symptomatic, asymptomatic, probable symptomatic, relative). Documented 
hypoglycemia (symptomatic or asymptomatic) will be also evaluated for the more stringent 
plasma glucose threshold of <3.0 mmol/L (<54 mg/dL), as well as for ≥3.0 and <3.9 mmol/L (≥54 
and <70 mg/dL), and <3.9 mmol/L (<70 mg/dL). Frequency and percentage of participants with at 
least 1 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 count. Event rates of 
hypoglycemia per participant year [all reported hypoglycemia, severe, documented symptomatic, 
asymptomatic, probable symptomatic, relative hypoglycemia, and documented hypoglycemia 
with plasma glucose <3.0 mmol/L (<54 mg/dL) as well as for ≥3.0 and <3.9 mmol/L (≥54 and 
<70 mg/dL), and <3.9 mmol/L (<70 mg/dL)] will be presented by treatment group for the whole 
on-treatment period.  
A listing of participants for all severe hypoglycemia events reported on the specific eCRF 
“Hypoglycemic Event Information” page will be provided.  
2.4.4.3 Deaths 
Listing of all Deaths (Screened participants) will be generated. 


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2.4.4.4 Analyses of vital sign variables 
The incidence of PCSAs at any time during the whole on-treatment period will be summarized 
only for heart rate 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 
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 is imputed to 
January and the day = 01. 
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 x 
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. 


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Derived variables will be considered missing if any of the original variables required to calculate 
them are missing. For example, if either a baseline assessment or an endpoint assessment is 
missing for a particular 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 whole 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 2/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 posttreatment medication. 
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 whole 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 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 potentially clinically significant abnormalities  
If baseline is missing, the participant will be grouped in the category “normal/missing at 
Baseline.” 


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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. 
Handling of missing screening value to derive randomization strata 
In case of missing data at screening visit for HbA1c, 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. 
Participants who do not have a documented stable daily dose of SU for at least 3 months prior to 
screening will be considered non-SU users. 
Linked adverse events that worsened or became serious 
An AE that worsened or became serious will have a separate record in the data from the original 
event record with a reference identification number that links the new record to the original 
record. An AE that worsened or became serious will be considered a new recurring AE in the 
summary of recurrent events or in the summary of events by time intervals. 
2.5.4 Windows for time points 
Nominal post-baseline visits will be used for descriptive statistics and time course plots. 
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) of the date of the endpoint 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 measurement for a given parameter at an endpoint visit, the data is considered missing for efficacy 
analyses. 
2.5.5 Unscheduled visits 
Unscheduled visit measurements will be used for computation of Baseline and PCSA.  
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 4-6 weeks after last participant last visit.  


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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using SAS version 9.3 or higher. 


Statistical Analysis Plan  
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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. 
March 2010 (revision 1). 
 
 


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7 
LIST OF APPENDICES 
Appendix A 
Appendix B 
Criteria for Potentially Significant Abnormalities  
Schedule of Activities 
 
 


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Appendix A 
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. 
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Parameter 
PCSA 
Comments 
ALT and Total 
Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever the interval between 
measurements. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero can be deleted. 
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. 
 
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Parameter 
PCSA 
Comments 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 17th Ed., 2008. 
Blood Urea Nitrogen ≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
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Statistical Analysis Plan  
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Parameter 
PCSA 
Comments 
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) 
 
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. 
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Parameter 
PCSA 
Comments 
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) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 bpm 
Categories are cumulative 
 
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Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
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Parameter 
PCSA 
Comments 
<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 
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 
VV-CLIN-0591286 1.0


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
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Parameter 
PCSA 
Comments 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA categories to be identified in 
individual subjects/patients listings. 
 
VV-CLIN-0591286 1.0


Statistical Analysis Plan  
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Property of the Sanofi Group - strictly confidential 
Page 41 
Appendix B 
Schedule of Activities (SoA) 
Procedure 
Screening
(2 weeks) 
Double-blind placebo-controlled Core 
Treatment Period (30 weeks) 
Double-blind, 
placebo-controlled 
Extension Period (26 
weeks) 
Post-
treatment
Follow-up 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
Week 
-2 
 
0 
BL 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP 
+6 wks 
 
Acceptable range 
(days) 
-14 to -11 
 
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) 
 
Injection of weekly dose at 
day of visit 
 
X 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
Participant will self-administer the injection only after blood 
samples have been drawn at the respective visit. 
Injection of weekly dose 
may be on a different day 
than visit 
X 
 
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
See Table 2 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 
 
 
 
 
 
 
 
 
 
 
 
 
Check eligibility before Randomization. 
Demography, 
medical/surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Includes diabetes complications, cardiovascular (CV) and 
allergy history. Includes alcohol and smoking habits. 
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 
 
Waist circumference 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
See Section 8.1.4 in the protocol 
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Statistical Analysis Plan  
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Procedure 
Screening
(2 weeks) 
Double-blind placebo-controlled Core 
Treatment Period (30 weeks) 
Double-blind, 
placebo-controlled 
Extension Period (26 
weeks) 
Post-
treatment
Follow-up 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
Week 
-2 
 
0 
BL 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP 
+6 wks 
 
Acceptable range 
(days) 
-14 to -11 
 
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) 
 
12-lead ECG 
 
X 
 
 
 
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) 
Transition from prestudy 
insulin glargine 100 U/mL 
to Lantus 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
See Section 6.1.2.1 in the protocol of NIMPs 
IMP injection 
training/retaining with 
prefilled syringe if needed  
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
See Section 6.1.1 in the protocol 
Review of injection sites 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Diary dispensation 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Diary collection 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Review of SMPG and 
Lantus dose adjustments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Glucose meter 
dispensation and training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Will include training for hypoglycemia awareness and 
management 
Diet and lifestyle 
counseling 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
As per current practice, to be documented (Section 5.3.1 in 
the protocol) 
IRT contact 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
X 
 
Lantus dispensation 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
VV-CLIN-0591286 1.0


Statistical Analysis Plan  
11-Nov-2020 
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Property of the Sanofi Group - strictly confidential 
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Procedure 
Screening
(2 weeks) 
Double-blind placebo-controlled Core 
Treatment Period (30 weeks) 
Double-blind, 
placebo-controlled 
Extension Period (26 
weeks) 
Post-
treatment
Follow-up 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
Week 
-2 
 
0 
BL 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP 
+6 wks 
 
Acceptable range 
(days) 
-14 to -11 
 
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) 
 
Lantus collection and 
accounting 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
IMP dispensed 
 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
 
 
 
 
IMP collection and 
accounting 
 
 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
 
Compliance 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SMPG, IMP, Lantus, 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 
conditions as described in Section 5.3.1 and Section 8.1.2 in 
the protocol 
C-peptide (fasting) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
For these visits, participants need to come in fasting 
conditions as described in Section 5.3.1 in protocol 
7-point SMPG profiles (on 
at least 1 day in the week 
prior to the visit) 
 
 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
Performed on at least 1 day in the week prior to clinical 
visits indicated. See Section 8.1.5 in protocol for complete 
details. 
Fasting (prebreakfast) 
SMPG 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Daily within first 8 weeks after randomization and at least 3 
days in the other weeks, prior to visits indicated. See 
Section 8.1.5 in protocol 
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Procedure 
Screening
(2 weeks) 
Double-blind placebo-controlled Core 
Treatment Period (30 weeks) 
Double-blind, 
placebo-controlled 
Extension Period (26 
weeks) 
Post-
treatment
Follow-up 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
Week 
-2 
 
0 
BL 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP 
+6 wks 
 
Acceptable range 
(days) 
-14 to -11 
 
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) 
 
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 
Pregnancy test (for 
women of childbearing 
potential) 
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 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 
ADA 
 
X 
 
X 
 
X 
 
 
X 
 
 
 
X 
X 
Participants with positive ADA at the end of study, and who 
experienced severe injection site or hypersensitivity reaction 
at 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 or as soon as 
possible after study database lock whichever comes later 
VV-CLIN-0591286 1.0


Statistical Analysis Plan  
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Page 45 
Procedure 
Screening
(2 weeks) 
Double-blind placebo-controlled Core 
Treatment Period (30 weeks) 
Double-blind, 
placebo-controlled 
Extension Period (26 
weeks) 
Post-
treatment
Follow-up 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
Week 
-2 
 
0 
BL 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP 
+6 wks 
 
Acceptable range 
(days) 
-14 to -11 
 
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) 
 
IMP concentration (PK) 
sampling 
 
 
 
X 
 
X 
 
X 
X 
 
 
 
 
 
All participants will have 1 blood sample collected just 
before their weekly injection of the IMP (and at least 6 days 
after last IMP dose administration) for the predose serum 
concentration (Ctrough) of efpeglenatide at selected clinical 
visits. For participants who consent, at least 1 additional 
postdose sample will be taken 3 days (±1 day) after 
administration of IMP, preferably between Week 8 and 
Week 12. See Section 8.5 in the protocol 
Rescue therapy 
assessment 
 
Continuous assessment and recording during treatment periods 
 
After randomization, the need of rescue therapy should be 
assessed by the Investigator via fasting SMPG performed by 
the participants and the central laboratory alerts received on 
FPG and on 
HbA1c (from Week 12 onwards). Participants must have an 
unscheduled in-person visit prior to rescue therapy initiation, 
with the assessments normally planned for EOT visit. See 
Section 6.1.2.2. in protocol 
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Statistical Analysis Plan  
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Page 46 
Procedure 
Screening
(2 weeks) 
Double-blind placebo-controlled Core 
Treatment Period (30 weeks) 
Double-blind, 
placebo-controlled 
Extension Period (26 
weeks) 
Post-
treatment
Follow-up 
(6 weeks) 
Notes 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
 
 
R 
 
 
 
 
 
 
 
 
 
 
EOT 
EOS 
Week 
-2 
 
0 
BL 
2 
4 
8 
12 
18 
24 
30a 
36 
43 
50 
56 
Last IMP 
+6 wks 
 
Acceptable range 
(days) 
-14 to -11 
 
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) 
 
Concomitant medication 
review  
Continuous assessment and recording throughout the study 
 
AE/SAE recording 
 
Reporting hypoglycemia 
(symptoms, SMPG) 
Hypoglycemia eCRF page must be filled in for all SMPG 
≤70 mg/dL (3.9 mmol/L) and/or in case of symptoms 
suggesting hypoglycemia  
a In case of premature permanent IMP discontinuation, the participant should have a visit as soon as possible after the last IMP administration with the assessments normally planned for EOT visit. 
Afterwards, the participant should continue in the study up to the scheduled date of study completion and be followed according to the study procedures as specified in the protocol. Every effort should be 
made to have the participant complete the Week 30 and Week 56 visits’ assessments (primary and main secondary endpoints) as the minimum. For safety reasons, participant who wish to terminate 
participation in the study, should be assessed 6 weeks (±1 week) from the last IMP dose (at the minimum) using the procedure normally planned for the posttreatment follow-up visit at EOS. At the time 
corresponding to their Week 56 visit, all attempts will be made to contact the participant to inquire about safety and/or vital status. 
Abbreviations: ADA: antidrug antibody, AE: adverse event, β-HCG: beta-human chorionic gonadotropin, BP: blood pressure, CV: cardiovascular, ECG: electrocardiogram, eCRF: electronic Case Report Form, 
EOS: end of study, EOT: end of treatment, FPG: fasting plasma glucose, FSH: follicle stimulating hormone, HbA1c: hemoglobin A1c, HR: heart rate, IMP: investigational medicinal product, IRT: interactive 
response technology, NIMP: noninvestigational medicinal product, PK: pharmacokinetic, R: Randomization, SAE: serious adverse event, SMPG: self-monitored plasma glucose, WOCBP: women of 
childbearing potential. 
 
VV-CLIN-0591286 1.0


Signature Page for VV-CLIN-0591286 v1.0
efc14893-16-1-9-sap
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