Conditions: Type 1 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 210
Healthy volunteers: no

Brief summary:
Primary Objective:

To demonstrate similarity in pharmacokinetics (PK) of SAR341402 and NovoLog after 4x4-week periods of alternating administration of SAR341402 and NovoLog compared to 16-week continuous use of NovoLog in participants with Type 1 diabetes mellitus (T1DM) also using insulin glargine.

Secondary Objectives:

* To compare the effects of alternating administration of SAR341402 and NovoLog with continuous use of NovoLog on immunogenicity.
* To evaluate the safety of alternating administration of SAR341402 and NovoLog versus continuous use of NovoLog.
* To compare other PK parameters between the two treatment arms (alternating administration of SAR341402 and NovoLog and continuous use of NovoLog).

Detailed description:
The study duration per participant was less than 19 weeks (for participants who did not require the run-in period) and less than 31 weeks (for participants who require the run-in period).

Arms:
arm 1: Participants self-administered subcutaneous (SC) injection daily prior to the start of a meal during the 16-week treatment period, starting with NovoLog (100 units per milliliters \[U/mL\]) for the first 4 weeks, then SAR341402 (100 U/mL) for 4 weeks, followed by NovoLog (at same dose) for 4 weeks and then SAR341402 (at same dose) for the last 4 weeks on top of mandatory background therapy with Lantus (Insulin glargine, 100 U/mL) as basal insulin. arm 2: Participants self-administered SC injection of NovoLog (100 U/mL) daily prior to the start of a meal during the 16-week treatment period on top of mandatory background therapy with Lantus (Insulin glargine, 100 U/mL) as basal insulin.

Interventions: intervention 1: Insulin Aspart SAR341402 intervention 2: Insulin Aspart intervention 3: Insulin glargine U100
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: Pharmaceutical form: Solution for injection Route of administration: Subcutaneous

Protocol document:
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 4.1 Sanofi dated 29-MAR-2018 based on TransCelerate CPT version 4 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 02  
Protocol title: 
Randomized, Open label, Parallel-group Study 
Comparing the Pharmacokinetics and Immunogenicity 
of Alternating Use of SAR341402 and NovoLog® versus 
Continuous Use of NovoLog in Participants with Type 1 
Diabetes Mellitus also Using Insulin Glargine 
Protocol number: 
EFC15178 
Amendment number: 
02 
Compound number 
(INN/Trademark): 
SAR341402 
(insulin aspart) 
Short title: 
Comparison of SAR341402 to NovoLog in Adult 
Patients with Type 1 Diabetes Mellitus also Using 
Insulin Glargine (Gemelli X) 
Sponsor name: 
 
Legal registered 
address: 
 
Monitoring Team’s 
Representative Name 
and Contact Information 
 
Regulatory agency identifying number(s): 
EudraCT number: 
Not applicable 
IND number: 
136342 
WHO number: 
U1111-1197-7811 
NCT number: 
NCT03874715 
Approval Date: 
13-Aug-2019 
Total number of pages: 81 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 02  
All 
13 August 2019, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01  
All 
27 February 2019, version 1 (electronic 1.0) 
Original Protocol 
 
5 November 2018, version 1 (electronic 2.0) 
Amendment 02 (13-Aug-2019) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
Based on current treatment practices in Type 1 diabetes mellitus patients in the US and to open up 
the pool of potentially eligible patients for the study, a run-in period has been added to allow for 
switching of patients who have not been using NovoLog and insulin glargine (100 U/mL) for at 
least 12 weeks prior to screening to ensure a sufficient amount of time on this background therapy 
prior to randomization.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 1.2 Schema; 
1.3 Schedule of Activities (SoA); 
2.1 Study Rationale; 3 Objectives 
and Enpoints; 4.1 Overall Design; 
4.2 Scientific Rationale for Study 
Design; 5.1 Inclusion Criteria, 
5.2 Exclusion Criteria; 5.3 Lifestyle 
Considerations; 5.4 Screen Failures; 
6 Study Intervention; 6.1 Study 
Intervention(s) Administered; 
6.3 Measures to Minimize Bias: 
Randomization and Blinding; 
6.4 Study Intervention Compliance; 
6.4.1 Return and/or Destruction of 
Treatment; 6.5 Concomitant Therapy; 
8.1.2 Self-monitored plasma glucose 
An up-to-12-week run-in period has been 
added for study participants who have not 
been on NovoLog and insulin glargine 
(100 U/mL) for at least 12 weeks prior to 
the screening visit. During this period, such 
patients will take NovoLog and insulin 
glargine (100 U/mL), ie, Lantus, so that 
they will have been on this background 
therapy for at least 12 weeks and would 
subsequently become eligible for study 
randomization (provided that all other 
eligibility criteria are met). 
A run-in period has been added to 
accommodate change in patients’ 
eligibility. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis; 2.1 Study Rationale; 
3 Objectives and Endpoints; 
9.4.2 Immunogenicity analyses 
To compare the treatment effect on 
immunogenicity (secondary objective), the 
number of participants with 
treatment-emergent insulin aspart 
antibodies (AIA) will be used as endpoint 
rather than the AIA status 
(positive/negative) by visit (this endpoint 
has been moved to tertiary/exploratory).  
According to the Sponsor internal technical 
recommendations, the AIA incidence 
seems to be a more relevant indicator than 
the AIA status by visit. 
1.1 Synopsis; 4.1 Overall Design; 
4.3 Justification for Dose; 
6.5 Concomitant Therapy 
In case of hypoglycemia, any 
countermeasure may be administered, 
instead of carbohydrates only. 
To allow Investigator to select the most 
suitable countermeasure in case of 
hypoglycemia. 
1.1 Synopsis; 4.1 Overall Design 
The breakfast content on the day of PK visit 
will be determined per the Investigator’s 
judgement, with focus on prevention of 
hypoglycemia or significant hyperglycemia 
during this period. 
Clarification on breakfast content. 
1.1 Synopsis; 1.3 Schedule of 
Activities (SoA) 
For participants not requiring run-in, the 
screening period may be extended by up to 
a maximum of 3 days after the 
2-week period. 
For participants requiring run-in, to ensure 
that the minimum of 12-week duration on 
NovoLog and insulin glargine (100 U/mL) is 
achieved and to facilitate participant’s 
scheduling, the run-in period may be 
extended by up to a maximum of 3 days 
after the 12-week period. 
To allow centers to adequately organize all 
screening and/or run-in activities prior to 
participant’s randomization. 
10.4 Appendix 4 Contraceptive 
Guidance and Collection of 
Pregnancy Information 
Injectable combined hormonal 
contraception and barrier contraception 
have been added as permitted 
contraception. 
Injectable combined hormonal 
contraception and barrier contraception 
are deemed sufficiently effective to 
mitigate the risk of pregnancy in this trial. 
1.1 Synopsis; 9.2 Sample Size 
Determination 
If the planned number of study participants 
with evaluable PK data can be assumed to 
be reached before all planned 
184 participants are randomized, then the 
study randomization may be stopped 
sooner. 
To prevent unnecessary enrolment. 
6.4 Study Intervention Compliance 
“Additionally, the use of any other insulin 
during the period after the last visit will be 
questioned” has been removed. 
Sentence removed as this activity is not 
necessary. 
7.1.1 Definitive Discontinuation 
Only clinically-significant abnormal 
laboratory values will be rechecked for 
confirmation as soon as possible.  
To ensure consistency with the current 
process, where participant's 
discontinuation is not triggered by 
non-clinically-significant abnormal 
laboratory findings and to facilitate a 
reasonable timeframe for follow-up 
activities. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.1.2 Self-monitored plasma glucose 
Occasional use of the participant’s personal 
glucometer or continuous glucose 
monitoring device allowed if deemed 
necessary for the safety of the participant  
To guarantee safety of the participants. 
8.1.2 Self-monitored plasma glucose 
Nocturnal measurement plasma glucose 
has been added. 
To be consistent with 
Section 1.3 Schedule of Activities. 
8.3 Adverse Events and Serious 
Adverse Events 
Immediate notification of adverse events of 
special interest has to be done within 
24 hours. 
To clarify the meaning of immediate 
notification. 
9.4.3 Safety Analyses 
MedDRA coding level has been removed. 
This level of detail is not necessary in the 
protocol and it will be provided in the 
Statistical Analysis Plan. 
10.1.5 Committees Structure 
Events of potential loss of efficacy will be 
adjudicated by the Allergic Reaction 
Adjudication Committee (ARAC). 
Updated information to ensure consistency 
with the ARAC charter. 
1.1 Synopsis; 9.4.1 Pharmacokinetic 
analyses 
The Hodges-Lehmann estimate for Tmax for 
the shift in location between treatment 
groups has been removed.  
This analysis will not be performed as 
descriptive statistics were deemed to be 
sufficient for this parameter. 
1.3 Schedule of Activities (SoA) 
The Visit 1 window has been changed (to 
minimum 7 days before Visit 3) for study 
participants who do not require run-in. 
To have at least 7 days of insulin data 
before randomization. 
6.1 Study Intervention(s) 
Administered 
Specific conditions for Lantus dose 
increase have been removed. 
To ensure consistency with the rest of the 
protocol, which requires that Lantus 
titration is done according to the 
Investigator’s best judgment based on the 
local label requirements. 
3 Objectives and Endpoints 
A tertiary endpoint has been added to 
compare the clinical effects of anti-insulin 
aspart neutralizing antibodies on glycemic 
control and insulin dose.  
Neutralizing antibodies can increase or 
decrease the investigational medicinal 
product (IMP) activity and it might have an 
impact on the efficacy and the insulin 
dose. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 02 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 15 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 16 
1.3.1 
SoA for participants without run-in ................................................................................................. 16 
1.3.2 
SoA for participants with run-in ...................................................................................................... 20 
1.3.3 
Pharmacokinetic flow-chart ............................................................................................................ 24 
2 
INTRODUCTION............................................................................................................................ 25 
2.1 
STUDY RATIONALE ..................................................................................................................... 25 
2.2 
BACKGROUND ............................................................................................................................. 26 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 26 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 27 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 28 
4 
STUDY DESIGN ............................................................................................................................ 30 
4.1 
OVERALL DESIGN ........................................................................................................................ 30 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 31 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 32 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 32 
5 
STUDY POPULATION .................................................................................................................. 33 
5.1 
INCLUSION CRITERIA .................................................................................................................. 33 
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5.2 
EXCLUSION CRITERIA ................................................................................................................ 34 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 36 
5.4 
SCREEN FAILURES ..................................................................................................................... 36 
6 
STUDY INTERVENTION ............................................................................................................... 37 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 37 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...................................................... 39 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 40 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 41 
6.4.1 
Return and/or destruction of treatment .......................................................................................... 41 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 42 
6.5.1 
Evaluation of participants not meeting glycemic goals .................................................................. 43 
6.6 
DOSE MODIFICATION .................................................................................................................. 43 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 43 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 44 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 44 
7.1.1 
Definitive discontinuation ............................................................................................................... 44 
7.1.2 
Temporary discontinuation ............................................................................................................. 45 
7.1.2.1 
Rechallenge ................................................................................................................................... 46 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 46 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 47 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 48 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 48 
8.1.1 
Glycated hemoglobin A1c .............................................................................................................. 48 
8.1.2 
Self-monitored plasma glucose ...................................................................................................... 48 
8.1.3 
Fasting plasma glucose ................................................................................................................. 49 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 49 
8.2.1 
Physical examinations ................................................................................................................... 49 
8.2.2 
Vital signs ....................................................................................................................................... 49 
8.2.3 
Clinical safety laboratory assessments .......................................................................................... 50 
8.2.4 
Hypoglycemia ................................................................................................................................. 50 
8.2.4.1 
Documentation and Classification of Hypoglycemia ...................................................................... 50 
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8.2.4.2 
Self-measured plasma glucose during symptomatic hypoglycemia .............................................. 51 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 52 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 53 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 54 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 54 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 54 
8.3.5 
Pregnancy ...................................................................................................................................... 55 
8.3.6 
Guidelines for reporting product complaints .................................................................................. 55 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 55 
8.5 
PHARMACOKINETICS .................................................................................................................. 55 
8.6 
PHARMACODYNAMICS ............................................................................................................... 56 
8.7 
GENETICS ..................................................................................................................................... 56 
8.8 
BIOMARKERS ............................................................................................................................... 56 
8.8.1 
Immunogenicity assessments ........................................................................................................ 56 
8.9 
HEALTH ECONOMICS .................................................................................................................. 56 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 57 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 57 
9.2 
SAMPLE SIZE DETERMINATION................................................................................................. 57 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 58 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 58 
9.4.1 
Pharmacokinetic analyses ............................................................................................................. 59 
9.4.2 
Immunogenicity analyses ............................................................................................................... 59 
9.4.3 
Safety analyses .............................................................................................................................. 59 
9.4.4 
Other analyses ............................................................................................................................... 61 
9.5 
INTERIM ANALYSES .................................................................................................................... 61 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 61 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 62 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 62 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 62 
10.1.2 
Financial disclosure ....................................................................................................................... 62 
10.1.3 
Informed Consent Process ............................................................................................................ 63 
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10.1.4 
Data Protection .............................................................................................................................. 63 
10.1.5 
Committees Structure .................................................................................................................... 64 
10.1.6 
Dissemination of Clinical Study Data ............................................................................................. 64 
10.1.7 
Data Quality Assurance ................................................................................................................. 64 
10.1.8 
Source documents ......................................................................................................................... 65 
10.1.9 
Study and site closure .................................................................................................................... 65 
10.1.10 Publication Policy ........................................................................................................................... 66 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 66 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 67 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 72 
10.5 
APPENDIX 5: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 75 
10.6 
APPENDIX 6: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 76 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 76 
10.8 
APPENDIX 8: ABBREVIATIONS ................................................................................................... 76 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY .................................................................. 78 
11 
REFERENCES............................................................................................................................... 80 
 
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LIST OF TABLES  
Table 1 - Pharmacokinetic flow chart ............................................................................................................ 24 
Table 2 - Objectives and endpoints ............................................................................................................... 27 
Table 3 - Overview of study interventions administered ............................................................................... 37 
Table 4 - Populations for analyses ................................................................................................................ 58 
Table 5 - Pharmacokinetic analyses ............................................................................................................. 59 
Table 6 - Immunogenicity analyses ............................................................................................................... 59 
Table 7 - Safety analyses .............................................................................................................................. 60 
Table 8 - Protocol-required laboratory assessments .................................................................................... 66 
Table 9 - Contraceptives allowed during the study ....................................................................................... 73 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 15 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: Randomized, Open label, Parallel-group Study Comparing the Pharmacokinetics 
and Immunogenicity of Alternating Use of SAR341402 and NovoLog® versus 
Continuous Use of NovoLog in Participants with Type 1 Diabetes Mellitus also 
Using Insulin Glargine 
Short title: 
Comparison of SAR341402 to NovoLog in Adult Patients with Type 1 Diabetes 
Mellitus also Using Insulin Glargine (Gemelli X) 
Rationale: 
Study EFC15178 (Gemelli X) is designed to generate data to support the argument that 
SAR341402 solution is interchangeable with the intended reference product, NovoLog, for the 
treatment of diabetes mellitus and that switching between SAR341402 solution and NovoLog will 
not pose an additional risk beyond that of using NovoLog alone. The study takes into 
consideration the general principles delineated in Section 351(k)(4)(A) of the Public Health 
Service (PHS) Act (Safety standards for determining interchangeability) and the FDA’s 
Considerations in Demonstrating Interchangeability with a Reference Product Guidance for 
Industry (1). 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To demonstrate similarity in pharmacokinetics (PK) of 
SAR341402 and NovoLog after 4x4-week periods of alternating 
administration of SAR341402 and NovoLog compared to 
16-week continuous use of NovoLog in participants with Type 1 
diabetes mellitus (T1DM) also using insulin glargine 
AUClast, AUC, and Cmax following injection of a predefined, fixed 
dose of SAR341402 or NovoLog (0.15 U/kg) at Week 16 
Secondary 
To compare  the effects of alternating administration of 
SAR341402 and NovoLog with continuous use of NovoLog on 
immunogenicity 
Number of participants with treatment-emergent anti-Insulin 
aspart antibodies (AIAs) during the 16-week treatment period 
 
To evaluate the safety of alternating administration of 
SAR341402 and NovoLog versus continuous use of NovoLog 
 
Safety evaluations, which will include evaluation of the 
following (for the 16-week treatment period): 
- 
Number of participants with at least one hypoglycemic 
event 
- 
Number of hypoglycemic events per participant-year 
- 
Number of participants with adverse events (AEs) (see 
Section 8.3)  
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Objectives 
Endpoints 
To compare other PK parameters between the two treatment 
arms (alternating administration of SAR341402 and NovoLog 
and continuous use of NovoLog) 
Time to Cmax (Tmax) following injection of a predefined, fixed 
dose of SAR341402 or NovoLog (0.15 U/kg) at Week 16 
 
Overall design: 
Randomized, open-label, active-controlled, 2-arm parallel-group multicenter Phase 3 trial in 
adults with T1DM also using insulin glargine. 
Upon confirmation of eligibility based on the screening procedures, participants who have not 
been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks before screening will 
complete a run-in period of up to 12 weeks during which they will be administered NovoLog and 
Lantus. Run-in period duration will be such that, at the time of randomization, the participants 
have been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks. 
Participants will be randomized 1:1 to 4x4-week periods alternating use of SAR341402 and 
NovoLog (starting with NovoLog in the first treatment period and receiving SAR341402 during 
the last of the 4 treatment periods, “switching arm”) or 16 weeks continuous use of NovoLog 
(“non-switching arm”); see flow-chart in Section 1.2. 
Randomization will be stratified by HbA1c (<8.0%, ≥8.0%) obtained at the screening visit 
(Visit 1). 
Insulin glargine 100 U/mL (Lantus) will be administered as mandatory background therapy 
throughout the treatment period of the study. 
At the end of the 16-week study treatment, participants will have blood sampling, including for 
PK determination, antibody measurements, HbA1c, and FPG. Participants need to come to the site 
fasting and without having injected any meal-time insulin (SAR341402 or NovoLog) for at least 
8 hours. After blood sampling for the trough PK measurements, participants will receive a single 
subcutaneous (SC) injection of 0.15 U/kg SAR341402 (switching arm) or NovoLog 
(non-switching arm). Subsequent PK sampling will be conducted for 8 hours according to 
assessment schedule (Table 1). During the 8-hour PK period, the Investigator must closely 
oversee the patient and manage any hypoglycemia or hyperglycemia that the patient may 
experience according to his/her medical judgement and the protocol requirements. Specifically, 
countermeasures are to be administered if hypoglycemia is experienced and human insulin must 
be administered if additional meal-time insulin is needed during this period. Alternatively, 
administration of insulin lispro at low doses, according to the Investigator’s judgement, is also 
permitted. Additionally, the breakfast content on the day of PK visit will be determined per the 
Investigator’s judgement, with focus on prevention of hypoglycemia or significant hyperglycemia 
during this period. 
An Allergic Reaction Adjudication Committee (ARAC), comprised of experts in the field of 
allergology and diabetes mellitus independent from the Sponsor and the Investigators and blinded 
for the treatment groups will adjudicate specific events, as described in Section 10.1.5. 
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Number of participants: 
Approximately 184 participants will be randomly assigned to either one of the treatment groups, 
alternating use of SAR341402 and NovoLog or continuous use of NovoLog (in a 1:1 ratio), with a 
minimum of 146 evaluable participants (73 per treatment group) for the primary PK evaluation 
expected at the end of the study.  If 146 study participants with evaluable PK data can be 
determined to have been reached before all planned 184 participants are randomized, then the 
study randomization may be stopped sooner. 
Intervention groups and duration: 
The study comprises up to 4 periods: 
 An up to 14-day screening period 
- 
For participants on a multiple (≥3) daily injection insulin regimen using NovoLog as 
mealtime insulin and insulin glargine (100 U/mL) as basal insulin for at least 12 weeks 
prior to screening (ie, who do not require a run-in period), in situations where not all 
conditions required for the participant’s randomization are met, the screening period 
may be extended by up to a maximum of 3 days after the 14-day period. This 
extension does not apply to participants who require a run-in period. 
 An up to 12-week run-in period for all eligible participants (based on the screening 
evaluations) who have not been taking NovoLog and insulin glargine (100 U/mL) for at 
least 12 weeks before screening. Those participants will be administered NovoLog as 
meal-time insulin therapy and Lantus as basal insulin, which they will take throughout the 
run-in period 
- 
To ensure that a minimum of 12-week duration on this background therapy is achieved 
and to facilitate participant’s scheduling, the run-in period may be extended by up to a 
maximum of 3 days after the 12-week period. 
 A 16-week open-label treatment period: 
- 
Participants in the non-switching arm will receive NovoLog for 16 weeks, 
- 
Participants in the switching arm will receive NovoLog for the first 4 weeks, then 
SAR341402 for 4 weeks, followed by NovoLog for 4 weeks and then SAR341402 for 
the last 4 weeks. 
 A 1-day post-treatment follow-up period. 
The study duration per participant will be less than 19 weeks (for participants who do not require 
the run-in period) and less than 31 weeks (for participants who require the run-in period). 
Study intervention 
Investigational medicinal products:  
Test drug: SAR341402 
 Formulation: 100 U/mL solution for SC injection supplied in 3-mL cartridges in a 
disposable SoloStar® pen. 
 Route of administration: self-administered by SC injection. 
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 Dose regimen: per standard of care, according to the Investigator’s judgement, based on 
the current NovoLog United States (US) package insert. 
Control drug: NovoLog-US (US-approved NovoLog) (administered during the treatment period) 
 Formulation: 100 U/mL solution for SC injection in the NovoLog FlexPen™ disposable 
pen. 
 Route of administration: self-administered by SC injection. 
 Dose regimen: per standard of care, according to the Investigator’s judgement, based on 
the current NovoLog US package insert. 
Noninvestigational medicinal product 
Insulin glargine (Lantus) 
 Formulation: 100 U/mL solution for SC injection in 3-mL cartridges as Lantus SoloStar 
disposable pen. 
 Route(s) of administration: self-administered by SC injection. 
 Dose regimen: once daily dose titrated by the Investigator according to the Lantus US 
package insert. 
NovoLog-US (US-approved NovoLog) (administered during the run-in period) 
 Formulation: 100 U/mL solution for SC injection in the NovoLog FlexPen™ disposable 
pen. 
 Route of administration: self-administered by SC injection. 
 Dose regimen: per standard of care, according to the Investigator’s judgement, based on 
the current NovoLog US package insert. 
Statistical considerations: 
 Primary analysis:  
Primary PK analysis will be based on the PK population, defined as all participants 
without deviations that could significantly impact the PK analysis (eg, missing or incorrect 
SC injection on PK profile day), and for whom PK data are considered sufficient and 
interpretable. For participants with insufficient data for some but not all PK parameters, 
the evaluable PK parameters will be included in the analysis. 
PK parameters will be summarized by treatment group using descriptive statistics. 
The impact of switching between SAR341402 and NovoLog on AUClast, AUC, and Cmax 
will be assessed. 
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For primary analysis, the natural log-transformed AUClast, AUC, and Cmax will be 
statistically analyzed using an analysis of variance, including the fixed categorical effects 
of treatment arm (SAR341402/NovoLog switching arm, NovoLog non-switching arm) and 
randomization strata. Estimate and 90% confidence interval (CI) for the ratio of geometric 
means between the two arms (SAR341402 from switching arm / NovoLog from 
non-switching arm) will be computed for AUClast, AUC, and Cmax, from the linear model 
framework using re-transformation. The 90% CI for the geometric mean ratio of AUClast, 
AUC, and Cmax should be within 80-125%. 
 Analysis of secondary endpoints: 
Immunogenicity analyses will be based on the AIA population, defined as all randomized 
and exposed participants with at least one AIA sample available for analysis. For 
descriptive purpose, the difference between the switching arm and the non-switching arm 
in the percentage of participants with treatment-emergent AIAs (AIA incidence) will be 
provided with associated 2-sided 90% CI.  
Safety endpoints will be analyzed using descriptive statistics on the safety population, 
defined as all randomized participants who receive at least one dose of IMP, regardless of 
the amount of treatment administered. 
Tmax will be summarized by treatment in the PK population using descriptive statistics.  
 Data Monitoring Committee: No
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
FPG: fasting plasma glucose; HbA1c: glycated hemoglobin A1c; PK: pharmacokinetics; T1DM: Type 1 diabetes mellitus; * prior to the screening visit 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 SoA for participants without run-in  
This SoA is valid for participants who have been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks before screening and who 
therefore will not be included in the run-in period. 
 
 
Screening  
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-2a 
-1 
b 
0  
(D1) 
4 
8 
12 
16 
EOTc 
16 + 1 day 
b 
Visit Windows: 
Visit 1: 7 to 17 days before Visit 3; 
Visit 2: may be adjusted as appropriate to accommodate  
 
Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-14a 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Informed consent 
X 
 
 
 
 
 
 
 
Prior to any study-related procedures being performed. 
Inclusion and exclusion criteria 
X 
X 
X 
 
 
 
 
 
Recheck eligibility before randomization. 
Demography, 
medical/surgical/medication 
history, diabetes history 
X 
 
 
 
 
 
 
 
Including alcohol, drug abuse, and smoking history. 
Physical examination  
X 
 
 
 
 
 
X 
 
See Section 8.2.1 
Blood pressure and heart rate 
X 
 
X 
 
 
 
X 
 
See Section 8.2.2 
Body weight 
X 
 
X 
 
 
 
X 
 
 
Height and BMI 
X 
 
 
 
 
 
 
 
 
Dispensation of study 
glucometer/supplies and diary 
X 
 
 
 
 
 
 
 
Supplies may be re-dispensed any time during the study, 
as necessary. 
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Screening  
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-2a 
-1 
b 
0  
(D1) 
4 
8 
12 
16 
EOTc 
16 + 1 day 
b 
Visit Windows: 
Visit 1: 7 to 17 days before Visit 3; 
Visit 2: may be adjusted as appropriate to accommodate  
 
Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-14a 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Training and retraining on 
glucometer use, SMPG, 
hypoglycemia awareness and 
management, diary use and 
IMP/NIMP dosage self-
adjustment  
X 
X 
X 
X 
X 
X 
 
 
Site will provide training at Visits 1 and 3; regular 
refresher instructions will be provided at noted visit or as 
necessary throughout the study. 
Diet and lifestyle counseling  
X 
X 
X 
X 
X 
X 
X 
X 
As per current practice 
IRT contact 
X 
 
X 
X 
X 
X 
X 
X 
Additional IRT contact (eg, to request additional 
IMP/NIMP) is permitted, as necessary 
Randomization 
 
 
X 
 
 
 
 
 
Randomization must be performed only after all baseline 
evaluations have been done and eligibility of the 
participant has been confirmed 
IMP and NIMP dispensation 
 
 
X 
X 
X 
X 
 
 
Additional dispensing visits are permitted if necessary 
Study intervention (IMP and 
NIMP administration) 
 
 
--------------------------------------------------- 
 
 
Review of insulin dose 
 
X 
X 
X 
X 
X 
X 
 
According to the Sponsor’s instructions 
Counting/collecting used and 
unused pens/Compliance check 
 
 
 
X 
X 
X 
X 
 
 
Diary data review and medical 
evaluation by Investigator 
 
X 
X 
X 
X 
X 
X 
 
In addition to the scheduled visits, medical evaluation 
must also be performed in between visits, if data is 
available for review by the Investigator. 
SMPGd 
X 
X 
X 
X 
X 
X 
X 
 
 
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Screening  
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-2a 
-1 
b 
0  
(D1) 
4 
8 
12 
16 
EOTc 
16 + 1 day 
b 
Visit Windows: 
Visit 1: 7 to 17 days before Visit 3; 
Visit 2: may be adjusted as appropriate to accommodate  
 
Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-14a 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
FPG 
 
 
X 
 
X 
X 
X 
 
All fasting blood samples collections should take place 
prior to IMP administration. 
Central laboratory 
 
 
 
 
 
 
 
 
 
PK samplinge 
 
 
 
 
 
 
X 
 
 
HbA1c 
X 
 
X 
 
X 
 
X 
 
 
C-peptide (fasting) 
X 
 
 
 
 
 
 
 
 
Anti-insulin aspart antibodies 
(AIA) 
 
 
X 
 
X 
X 
X 
 
Antibody sampling at least 8 hours after the last 
SAR341402 or NovoLog dose, thus participants should 
come fasting, without injecting their meal-time insulin at all 
visits where AIAs are measured.  
Anti-insulin aspart 
neutralizing antibodies 
 
 
X 
 
X 
X 
X 
 
 
Safety laboratory 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
X 
 
 See Appendix 2 (Section 10.2) 
Clinical chemistry 
X 
 
 
 
 
 
X 
 
See Appendix 2 (Section 10.2) 
Pregnancy test (WOCBP 
only) 
X 
 
X 
 
X 
 
X 
 
Serum pregnancy test for screening; urine pregnancy test 
for subsequent monitoring; additional testing per site’s 
processes is permitted 
Serum FSH and estradiol 
(Menopausal women only) 
X 
 
 
 
 
 
 
 
 
AE/SAE/AESI reporting 
Throughout the study 
Report SAE and AESI to the Sponsor within 24 hours 
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Screening  
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-2a 
-1 
b 
0  
(D1) 
4 
8 
12 
16 
EOTc 
16 + 1 day 
b 
Visit Windows: 
Visit 1: 7 to 17 days before Visit 3; 
Visit 2: may be adjusted as appropriate to accommodate  
 
Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-14a 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
2 
3 
4 
5 
6 
7 
8 
 
Concomitant medications 
Throughout the study 
 
Hypoglycemia recording 
Throughout the study 
Details must be provided in case of SMPG ≤3.9 mmol/L 
(70 mg/dL) and/or in case of symptoms suggesting 
hypoglycemia 
a In situations where not all conditions required for the participant’s randomization are met, the screening period may be extended by up to a maximum of 3 days after the 2-week period as reflected in the “Notes” 
column for the Visit 1 window 
b Mandatory telephone visit or optional on-site visit 
c Or early IMP discontinuation (note that serial PK samples should only be collected at the time of early discontinuation visit and do not need to be repeated at Visit 7 even if participant remains in the study)   
d Self-measured plasma glucose: 
- 
Regular pre- postprandial and nocturnal SMPG is recommended throughout the study for optimal adjustment of the insulin regimen. These SMPGs support optimization of the basal and meal-time 
insulin dose. The results will be discussed between Investigator and participant during scheduled and unscheduled visits at the discretion of the Investigator; 
- 
In case of hypoglycemic symptoms: whenever experienced (if possible prior to countermeasure, unless safety considerations necessitate immediate glucose/carbohydrate rescue prior to confirmation) 
e Participants have to present at the site in fasting condition without having injected meal-time insulin in the morning (last meal-time insulin injection at least 8 hours prior to blood draw). Blood will be collected for the 
determination of insulin aspart concentrations as detailed in the PK flow chart below (Table 1). If additional meal-time insulin is needed during this period, human insulin must be administered. Alternatively, 
administration of insulin lispro at low doses, according to the Investigator’s judgement, is also permitted. For study participants who definitively discontinue their IMP but continue in the study, PK blood sampling 
will be performed at the time of the Early Termination visit only (it will not be done at Visit 7 as well). Please refer to specific laboratory manual for details on blood sampling 
AE: adverse event; AESI: adverse event of special interest; AIA: anti-insulin aspart antibody; BMI: body-mass index; EOT: end of treatment; FPG: fasting plasma glucose; FSH: follicle-stimulating hormone; HbA1c: 
glycated hemoglobin A1c; IMP: investigational medicinal product; IRT: interactive response technology; NIMP: non-investigational medicinal product; PK: pharmacokinetics; SAE: serious adverse event; SMPG: 
self-measured plasma glucose; WOCBP: woman of childbearing potential 
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1.3.2 SoA for participants with run-in  
This SoA is valid for participants who have not been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks before the screening visit. 
 
 
Screening  
Run-in 
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-14 
-12- 
-1 
- 
0  
(D1) 
4 
8 
12 
16 
EOT- 
16 + 1 day 
- 
Visit Windows: 
Visit 1: 4 to 14 days before Visit RI; 
Visit RI: up to 87 days- before Visit 3 
Visit 2: may be adjusted as appropriate to 
accommodate Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-98 
-84- 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
RI 
2 
3 
4 
5 
6 
7 
8 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Prior to any study-related procedures being performed. 
Inclusion and exclusion criteria 
X 
X 
X 
X 
 
 
 
 
 
Recheck eligibility before randomization. 
Demography, 
medical/surgical/medication 
history, diabetes history 
X 
 
 
 
 
 
 
 
 
Including alcohol, drug abuse, and smoking history. 
Physical examination  
X 
 
 
 
 
 
 
X 
 
See Section 8.2.1 
Blood pressure and heart rate 
X 
 
 
X 
 
 
 
X 
 
See Section 8.2.2 
Body weight 
X 
 
 
X 
 
 
 
X 
 
 
Height and BMI 
X 
 
 
 
 
 
 
 
 
 
Dispensation of study 
glucometer/supplies and diary 
X 
 
 
 
 
 
 
 
 
Supplies may be re-dispensed any time during the 
study, as necessary. 
Training and retraining on 
glucometer use, SMPG, 
hypoglycemia awareness and 
management, diary use and 
IMP/NIMP dosage self-
adjustment  
X 
X 
X 
X 
X 
X 
X 
 
 
Site will provide training at Visits 1, RI, and 3; regular 
refresher instructions will be provided at noted visit or 
as necessary throughout the study. 
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Screening  
Run-in 
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-14 
-12- 
-1 
- 
0  
(D1) 
4 
8 
12 
16 
EOT- 
16 + 1 day 
- 
Visit Windows: 
Visit 1: 4 to 14 days before Visit RI; 
Visit RI: up to 87 days- before Visit 3 
Visit 2: may be adjusted as appropriate to 
accommodate Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-98 
-84- 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
RI 
2 
3 
4 
5 
6 
7 
8 
 
Diet and lifestyle counseling  
X 
X 
X 
X 
X 
X 
X 
X 
X 
As per current practice 
IRT contact 
X 
 
 
X 
X 
X 
X 
X 
X 
Additional IRT contact (eg, to request additional 
IMP/NIMP) is permitted, as necessary 
Background therapy dispensation 
(NovoLog and Lantus) 
 
X 
 
 
 
 
 
 
 
If necessary for NovoLog or Lantus resupply, or as 
deemed appropriate by the Investigator to ensure 
participant’s oversight, the participants may undergo 
unscheduled visit(s), as appropriate. 
Background therapy 
administration (NovoLog and 
Lantus) 
 
------------------ 
 
 
 
 
 
 
All study participants must take NovoLog and insulin 
glargine (100 U/mL) for at least 12 weeks before 
randomization 
Randomization 
 
 
 
X 
 
 
 
 
 
Randomization must be performed only after all 
baseline evaluations have been done and eligibility of 
the participant has been confirmed 
IMP and NIMP dispensation 
 
 
 
X 
X 
X 
X 
 
 
Additional dispensing visits are permitted if necessary 
Study intervention (IMP and 
NIMP administration) 
 
 
 
--------------------------------------------- 
 
 
Review of insulin dose 
 
X 
X 
X 
X 
X 
X 
X 
 
According to the Sponsor’s instructions 
Counting/collecting used and 
unused pens/Compliance check 
 
 
 
X 
X 
X 
X 
X 
 
At Visit 3, study participants will be asked to return their 
used and unused NIMP pens; no compliance check will 
be performed 
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Page 22 
 
Screening  
Run-in 
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-14 
-12- 
-1 
- 
0  
(D1) 
4 
8 
12 
16 
EOT- 
16 + 1 day 
- 
Visit Windows: 
Visit 1: 4 to 14 days before Visit RI; 
Visit RI: up to 87 days- before Visit 3 
Visit 2: may be adjusted as appropriate to 
accommodate Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-98 
-84- 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
RI 
2 
3 
4 
5 
6 
7 
8 
 
Diary data review and medical 
evaluation by Investigator 
 
X 
X 
X 
X 
X 
X 
X 
 
In addition to the scheduled visits, medical evaluation 
must also be performed in between visits, if data is 
available for review by the Investigator. 
SMPG- 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
FPG 
 
 
 
X 
 
X 
X 
X 
 
All fasting blood samples collections should take place 
prior to IMP administration. 
Central laboratory 
 
 
 
 
 
 
 
 
 
 
PK sampling- 
 
 
 
 
 
 
 
X 
 
 
HbA1c 
X 
 
 
X 
 
X 
 
X 
 
 
C-peptide (fasting) 
X 
 
 
 
 
 
 
 
 
 
Anti-insulin aspart antibodies 
(AIA) 
 
 
 
X 
 
X 
X 
X 
 
Antibody sampling at least 8 hours after the last 
SAR341402 or NovoLog dose, thus participants should 
come fasting, without injecting their meal-time insulin at 
all visits where AIAs are measured.  
Anti-insulin aspart 
neutralizing antibodies 
 
 
 
X 
 
X 
X 
X 
 
 
Safety laboratory 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
X 
 
 
 
X 
 
 See Appendix 2 (Section 10.2) 
Clinical chemistry 
X 
 
 
X 
 
 
 
X 
 
See Appendix 2 (Section 10.2) 
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13-Aug-2019 
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Screening  
Run-in 
Open-label Treatment Period  
Follow-up  
Notes 
Week 
-14 
-12- 
-1 
- 
0  
(D1) 
4 
8 
12 
16 
EOT- 
16 + 1 day 
- 
Visit Windows: 
Visit 1: 4 to 14 days before Visit RI; 
Visit RI: up to 87 days- before Visit 3 
Visit 2: may be adjusted as appropriate to 
accommodate Visit 3 date;  
Visits 4 to 6: ±2 days; Visit 7: ±3 days; Visit 8: +2 days. 
Day 
-98 
-84- 
-7 
1 
28  
56  
84  
112  
113 
Visit 
1 
RI 
2 
3 
4 
5 
6 
7 
8 
 
Pregnancy test (WOCBP 
only) 
X 
X 
 
X 
 
X 
 
X 
 
Serum pregnancy test for screening; urine pregnancy 
test for subsequent monitoring; additional testing per 
site’s processes is permitted 
Serum FSH and estradiol 
(Menopausal women only) 
X 
 
 
 
 
 
 
 
 
 
AE/SAE/AESI reporting 
Throughout the study 
Report SAE and AESI to the Sponsor within 24 hours 
Concomitant medications 
Throughout the study 
 
Hypoglycemia recording 
Throughout the study 
Details must be provided in case of SMPG ≤3.9 mmol/L 
(70 mg/dL) and/or in case of symptoms suggesting 
hypoglycemia 
- 
To ensure that the minimum of 12-week duration on NovoLog and insulin glargine (100 U/mL) is achieved and to facilitate participant’s scheduling, the run-in period may be extended by up to a 
maximum of 3 days after the 12-week period 
- 
Mandatory telephone visit or optional on-site visit 
- 
Or early IMP discontinuation (note that serial PK samples should only be collected at the time of early discontinuation visit and do not need to be repeated at Visit 7 even if participant remains in the 
study)   
- 
Self-measured plasma glucose: 
- 
Regular pre- postprandial and nocturnal SMPG is recommended throughout the study for optimal adjustment of the insulin regimen. These SMPGs support optimization of the basal and meal-time 
insulin dose. The results will be discussed between Investigator and participant during scheduled and unscheduled visits at the discretion of the Investigator; 
- 
In case of hypoglycemic symptoms: whenever experienced (if possible prior to countermeasure, unless safety considerations necessitate immediate glucose/carbohydrate rescue prior to confirmation) 
- 
Participants have to present at the site in fasting condition without having injected meal-time insulin in the morning (last meal-time insulin injection at least 8 hours prior to blood draw). Blood will be 
collected for the determination of insulin aspart concentrations as detailed in the PK flow chart below (Table 1). If additional meal-time insulin is needed during this period, human insulin must be 
administered. Alternatively, administration of insulin lispro at low doses, according to the Investigator’s judgement, is also permitted. For study participants who definitively discontinue their IMP but 
continue in the study, PK blood sampling will be performed at the time of the Early Termination visit only (it will not be done at Visit 7 as well). Please refer to specific laboratory manual for details on 
blood sampling 
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Page 24 
AE: adverse event; AESI: adverse event of special interest; AIA: anti-insulin aspart antibody; BMI: body-mass index; EOT: end of treatment; FPG: fasting plasma glucose; FSH: follicle-stimulating hormone; HbA1c: 
glycated hemoglobin A1c; IMP: investigational medicinal product; IRT: interactive response technology; NIMP: non-investigational medicinal product; PK: pharmacokinetics; SAE: serious adverse event; SMPG: 
self-measured plasma glucose; WOCBP: woman of childbearing potential 
 
1.3.3 Pharmacokinetic flow-chart  
Table 1 - Pharmacokinetic flow chart  
 
End of Treatment (Week 16 or Early Discontinuation Visit) 
Time 
0h
00
 
0h
10 
0h
20 
0h
30 
0h
40 
0h
50 
1h
00 
1h
10 
1h
20 
1h
30 
1h
40 
1h
50 
2h
00 
2h
15 
2h
30 
2h
45 
3h
00 
3h
15 
3h
30 
3h
45 
4h
00 
4h
20 
4h
40 
5h
00 
5h
20 
5h
40 
6h
00 
6h
30 
7h
00 
7h
30 
8h
00 
Win-
dow 
(min) 
 
±2 
±2 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
PK 
sample 
P00 P01 P02 P03 P04 P05 P06 P07 P08 P09 P10 P11 P12 P13 P14 P15 P16 P17 P18 P19 P20 P21 P22 P23 P24 P25 P26 P27 P28 P29 P30 
 
Predose 
PK: pharmacokinetics
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Page 25 
2 
INTRODUCTION  
SAR341402 is insulin aspart, a human insulin analog of recombinant deoxyribonucleic acid 
(DNA) origin. Insulin aspart is the active ingredient of a rapid-acting insulin product currently 
marketed as NovoLog in the US and NovoRapid® in Europe. SAR341402 solution for injection is 
being developed as interchangeable biosimilar to NovoLog in accordance with the relevant 
guidelines (2, 3, 4).  
2.1 
STUDY RATIONALE  
Per FDA Guidance (1), a biological product is considered interchangeable with the reference 
product if the information submitted is sufficient to show that the biological product “is biosimilar 
to the reference product” and “can be expected to produce the same clinical result as the reference 
product in any given patient” and that “for a biological product that is administered more than 
once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching 
between use of the biological product and the reference product is not greater than the risk of 
using the reference product without such alternation or switch.” Biosimilarity is generally 
supported by similarity in overall level of antibody produced to the proposed biosimilar and the 
reference product. Differences in immune responses may be detected in a switching study. Indeed, 
with switching between the proposed biosimilar and the reference product, repeated exposure to 
each product can prime the immune system to recognize subtle structural differences between 
products, which may theoretically increase the overall immune response. This immunologic 
response is highly dependent on the structural differences between the proposed interchangeable 
product and the comparator product and other potential differences between the products 
(eg,  impurities).  
Study EFC15178 (Gemelli X) is designed to generate data to support the argument that 
SAR341402 solution is interchangeable with the intended reference product, NovoLog, for the 
treatment of diabetes mellitus and that switching between SAR341402 solution and NovoLog will 
not pose an additional risk beyond that of using NovoLog alone. The study takes into 
consideration the general principles as delineated in Section 351(k)(4)(A) of the PHS Act (Safety 
standards for determining interchangeability) and FDA’s Considerations in Demonstrating 
Interchangeability with a Reference Product Guidance for Industry (1). 
The primary objective of study EFC15178 will be to demonstrate similarity in PK exposure of 
SAR341402 and NovoLog US after 4x4-week periods of alternating administration of 
SAR341402 and NovoLog compared to 16-week continuous use of NovoLog in participants with 
T1DM also using insulin glargine. The secondary objectives will be the comparison of the 
immunogenicity of alternating administration of SAR341402 and NovoLog versus continuous use 
of NovoLog in terms of number of participants with treatment-emergent AIAs, the comparison of 
Tmax, and the evaluation of safety (hypoglycemia and AEs, including SAEs, hypersensitivity 
reactions, and injection site reactions). Additional AIA-related parameters, including the clinical 
effects of treatment-emergent AIAs on efficacy (HbA1c), insulin dose, and safety (hypoglycemia, 
hypersensitivity reaction, injection site reaction) will be assessed as part of the tertiary objectives 
of the study.  
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2.2 
BACKGROUND  
In vitro nonclinical pharmacology and physicochemical characterization studies were conducted 
to thoroughly demonstrate the biological and structural/compositional similarity of insulin aspart 
SAR341402 and insulin aspart supplied as NovoLog and NovoRapid. Similar PK exposure and 
PD activity were demonstrated for SAR341402 solution to both NovoLog and NovoRapid, as well 
as between NovoLog and NovoRapid in a PK/PD study using the euglycemic clamp technique in 
patients with T1DM study (PDY12695). All treatments were well tolerated with no relevant 
difference in safety related parameters between the treatments. 
A Phase 3 study is currently being conducted to compare efficacy and safety including 
immunogenicity of SAR341402 and NovoLog/NovoRapid when used in combination with Lantus 
in participants with T1DM and T2DM (study EFC15081). Objectives of the study are to compare 
the efficacy, safety and immunogenicity of SAR341402 solution with NovoLog in the US and 
NovoRapid in the European Union (EU) to further support similarity of SAR341402 solution and 
NovoLog and NovoRapid. 
2.3 
BENEFIT/RISK ASSESSMENT  
Adults with T1DM who are currently on a multiple daily injection regimen will be eligible to 
participate. Due to the objectives of the study and duration of treatment, eligible participants will 
not immediately benefit from the outcome of this study. 
NovoLog, the comparator IMP used in the current study, is indicated for the treatment of patients 
with diabetes mellitus and has been marketed in the US since 2000. Its safety and efficacy profile 
is well documented. The adverse reactions observed with NovoLog (US) are known in the 
pharmacological class of blood glucose lowering drugs and common to insulin products. A 
comparable safety and efficacy profile to that of NovoLog is expected for SAR341402 solution.  
As therapeutic proteins, insulin and insulin analogues may trigger immunological responses, 
although clinically meaningful immunological reactions were reported mostly for animal insulin 
products and are rarely reported for highly purified recombinant insulin analogues (5, 6).  Based 
on these considerations, the relatively low structural complexity of insulin aspart and the 
analytical similarity of SAR341402 to NovoLog shown in physicochemical characterizations, and 
based on Phase 1 results, no meaningful differences in the immunogenicity of SAR341402 and 
NovoLog are expected to be found in study EFC15178.  
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs associated with SAR341402 may be found in the Investigator’s Brochure (7). 
Further details on NovoLog can be found in the US product information (8).  
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
To demonstrate similarity in pharmacokinetics (PK) of 
SAR341402 and NovoLog after 4x4-week periods of alternating 
administration of SAR341402 and NovoLog compared to 
16-week continuous use of NovoLog in participants with Type 1 
diabetes mellitus (T1DM) also using insulin glargine 
AUClast, AUC, and Cmax following injection of a predefined, fixed 
dose of SAR341402 or NovoLog (0.15 U/kg) at Week 16 
Secondary 
To compare  the effects of alternating administration of 
SAR341402 and NovoLog with continuous use of NovoLog on 
immunogenicity 
Number of participants with treatment-emergent anti-Insulin 
aspart antibodies (AIAs) during the 16-week treatment period 
 
To evaluate the safety of alternating administration of 
SAR341402 and NovoLog versus continuous use of NovoLog 
 
Safety evaluations, which will include evaluation of the 
following (for the 16-week treatment period): 
 
Number of participants with at least one 
hypoglycemic event 
- 
Number of hypoglycemic events per 
participant-year 
- 
Number of participants with adverse events 
(AEs) (see Section 8.3)  
 
To compare other PK parameters between the two treatment 
arms (alternating administration of SAR341402 and NovoLog 
and continuous use of NovoLog) 
 
Time to Cmax (Tmax) following injection of a predefined, fixed 
dose of SAR341402 or NovoLog (0.15 U/kg) at Week 16 
 
Tertiary/exploratory 
To compare the effects of alternating administration of 
SAR341402 and NovoLog with continuous use of NovoLog on 
insulin dose 
Change in Insulin dose (basal, meal-time [SAR341402 or 
NovoLog], total) from baseline to Week 16 
 
To compare the effects of alternating administration of 
SAR341402 and NovoLog with continuous use of NovoLog on 
glycemic control 
Change from baseline to Week 16 in HbA1c 
Change from baseline to Week 16 in FPG 
 
To compare clinical effects of treatment-emergent AIAs on 
glycemic control, insulin dose and safety  
Clinical effects of AIAs on efficacy (HbA1c), insulin dose and 
safety (hypoglycemia, hypersensitivity reactions, injection site 
reactions) 
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Objectives 
Endpoints 
To compare the effects of alternating administration of 
SAR341402 and NovoLog with continuous use of NovoLog on 
additional immunogenicity parameters 
Number of participants with treatment-induced AIA (among the 
participants AIA-negative or missing at baseline) (during the 
16-week treatment period) 
Number of participants with treatment-boosted AIA (among the 
participants AIA-positive at baseline) (during the 16-week 
treatment period) 
Number  of participants by AIA status (positive/negative) at 
baseline, Week 8, Week 12 and Week 16 
Anti-Insulin aspart antibody titer at baseline, Week 8, Week 12 
and Week 16 
Number of participants by AIA cross-reactivity to human insulin 
at baseline, Week 8, Week 12 and Week 16 
Number of participants by anti-insulin aspart neutralizing 
antibody status (positive/negative) at baseline, Week 8, Week 
12 and Week 16 
To compare clinical effects of treatment-emergent neutralizing 
antibodies on glycemic control and insulin dose 
Clinical  effects of anti-insulin aspart neutralizing antibodies on 
efficacy (HbA1c) and insulin dose 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The primary endpoints will be AUClast, AUC, and Cmax following injection of a single dose of 
0.15 U/kg SAR341402 (in the switching arm) or NovoLog (in the non-switching arm) at 
Week 16. As the rapid-acting insulins SAR341402 and NovoLog are used flexibly as prandial 
insulin at meal-times, no dosing intervals can be defined. Consequently, the primary endpoints 
will be Cmax, AUClast, and AUC and not AUCtau as proposed in the FDA Guidance for 
Interchangeability (1). Blood samples for these PK measurements will be taken for an 8-hour 
period, taking into account the PK profile of SAR341402 observed in the previous Phase 1 study 
PDY12695. In this study, a median Tmax of approximately 1.2 hour and a mean half-life of 
approximately 1.2 hours were observed for SAR341402. Thus, an 8-hour sampling period is 
deemed appropriate to sufficiently cover (90% of AUC according to FDA guidance) individual 
PK profiles.  
HbA1c is an index of average glucose over the preceding weeks-to-months. It is a "weighted" 
average of blood glucose levels during the preceding 120 days, as glucose levels in the 30 days 
prior to the measurement contribute substantially more to the level of HbA1c than do glucose 
levels 90-120 days earlier (9). HbA1c is also the most widely accepted measure of overall, 
long-term blood glucose control in patients with diabetes (4, 10). 
HbA1c will be determined in a central laboratory blinded to study treatment. The assessment of 
HbA1c and insulin dose changes will support the assessment of the clinical relevance of treatment 
emergent AIAs and any outliers identified in the PK analysis. As the study is not powered for 
efficacy evaluations, the data obtained will be considered of supportive value only to the 
(primary) PK and (secondary) immunogenicity data obtained. 
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Immunogenicity analyses will include the determination of the AIA status, AIA titers, anti-insulin 
aspart neutralizing antibodies, and cross-reactivity with human insulin. The potential impact of 
AIAs on safety, particularly as related to hypersensitivity reactions and local injection site 
reactions will be evaluated. Anti-insulin aspart antibodies may change the PK and PD of the 
insulin by binding the insulin, resulting in an overall unstable glycemic control. Therefore, the 
potential effect of AIAs on glycemic control (HbA1c), insulin dose and hypoglycemia will also be 
assessed. 
The general safety evaluation will include hypoglycemia (classification according to American 
Diabetes Association definition) (11, 12, 13), AEs, including SAEs, hypersensitivity reactions and 
injection site reactions. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a randomized, open-label, active-controlled, 2-arm parallel-group multicenter Phase 3 trial 
in adults with T1DM also using insulin glargine. 
Upon confirmation of eligibility based on the screening procedures, participants who have not 
been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks before screening will 
complete a run-in period of up to 12 weeks during which they will be administered NovoLog and 
Lantus. Run-in period duration will be such that, at the time of randomization, the participants 
have been on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks. 
Participants will be randomized 1:1 to 4x4-week periods alternating use of SAR341402 and 
NovoLog (starting with NovoLog in the first treatment period and receiving SAR341402 during 
the last of the 4 treatment periods, “switching arm”) or 16 weeks continuous use of NovoLog 
(“non-switching arm”); see flow-chart in Section 1.2. 
Randomization will be stratified by HbA1c (<8.0%, ≥8.0%) obtained at the screening visit 
(Visit 1). 
Insulin glargine 100 U/mL (Lantus) will be administered as mandatory background therapy 
throughout the treatment period of the study. 
At the end of the 16-week study treatment, participants will have blood sampling, including for 
PK determination, antibody measurements, HbA1c, and FPG. Participants need to come to the site 
fasting without having injected any meal-time insulin (SAR341402 or NovoLog) for at least 
8 hours. After blood sampling for the trough PK measurements, participants will receive a single 
SC injection of 0.15 U/kg SAR341402 (switching arm) or NovoLog (non-switching arm). 
Subsequently, PK sampling will be conducted for 8 hours according to assessment schedule 
(Table 1). During the 8-hour PK period, the Investigator must closely oversee the patient and 
manage any hypoglycemia or hyperglycemia that the patient may experience according to his/her 
medical judgement and the protocol requirements. Specifically, countermeasures are to be 
administered if hypoglycemia is experienced and human insulin must be administered if 
additional meal-time insulin is needed during this period. Alternatively, administration of insulin 
lispro at low doses, according to the Investigator’s judgement, is also permitted. Additionally, the 
breakfast content on the day of PK visit will be determined per the Investigator’s judgement, with 
focus on prevention of hypoglycemia or significant hyperglycemia during this period. 
The study will include an up to 2-week screening period, an up to 12-week run-in period (only for 
patients not treated with NovoLog and insulin glargine [100 U/mL] for at least 12 weeks before 
screening), a 16-week open-label treatment period, and a 1-day post-treatment follow up period. 
The study duration per participant will be less than 19 weeks (for participants who do not require 
the run-in period) and less than 31 weeks (for participants who require the run-in period). 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
In accordance with the FDA guidance on interchangeability (1), the study is designed to 
demonstrate PK similarity of SAR341402 and NovoLog after 4x4-week periods of alternating 
administration of SAR341402 and NovoLog compared to 16-week continuous use of NovoLog. 
The study is an open-label design as the test and control IMPs are easily identifiable. However, 
measures to minimize bias will be implemented (for details see Section 6.3). 
Participants with T1DM on insulin treatment for at least one year who have been on basal bolus 
therapy using insulin glargine (100 U/mL) for at least 12 weeks and NovoLog for at least 
12 weeks (either prior to Visit 1 or following the run-in period) are eligible for randomization in 
the study.  
Participants with T1DM are deemed adequately sensitive to detect differences in the PK (primary 
endpoint) due to their lack of endogenous insulin. Additionally, due to the underlying 
autoimmune disorder, this population is considered more sensitive to evaluate potential 
differences in the immune response and the effects of AIAs on efficacy and safety, when 
compared with the type 2 diabetes mellitus population (5).  
Due to the relatively short duration of action of SAR341402 and NovoLog and their clinical use 
as rapid-acting insulin products, no accumulation occurs and thus steady state conditions do not 
need to be established. Therefore no lead-in period is required for participants pre-treated with 
insulin glargine (100 U/mL) as basal insulin and NovoLog as meal-time insulin for at least 
12 weeks. This pre-treatment is considered to be of sufficient duration to ensure that all 
participants are on a stable insulin regimen before randomization. Participants not pre-treated with 
NovoLog and insulin glargine (100 U/mL) for at least 12 weeks need to be enrolled into a run-in 
period to establish stable conditions. 
When SAR341402 solution is approved and marketed, patients may potentially switch between 
SAR341402 solution and NovoLog. With switching, multiple exposures to each product can 
prime the immune system to recognize subtle structural differences between products, which may 
theoretically increase the overall immune response. This immunologic response is highly 
dependent on the structural differences between the proposed interchangeable product and the 
comparator product and other potential differences between the products (eg, impurities). 
The 16-week treatment duration has been chosen to ensure a sufficiently long treatment duration 
to assess HbA1c as efficacy parameter. The 4-week duration of each treatment period in the 
“switching arm” has been chosen to ensure a sufficiently long treatment duration to assess 
development of AIA in each treatment cycle. Potential allergic reactions may occur within hours 
post injection at any time during the treatment; however, as mentioned in Section 2.3, these 
reactions are very rare for highly purified insulin analogues including NovoLog (14).  
AIAs of the immunoglobulin G isotype usually appear about 2 weeks after first exposure to the 
antigen, or, in case of a re-exposure to the antigen (“secondary response”), even earlier within 
1 week  (15, 16, 17), thus, these AIA responses would occur well within the planned study period 
of 16 weeks and 4 week exposure intervals in the “switching group”. 
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4.3 
JUSTIFICATION FOR DOSE  
After randomization, participants in both treatment arms will continue to individually dose and 
titrate NovoLog per the standard of care as judged by the Investigator.    
It is recommended that the study drug doses are titrated to achieve a 2 hour postprandial plasma 
glucose of <180 mg/dL (10 mmol/L) while avoiding hypoglycemia and taking into consideration 
the content of the meal. Good clinical judgment is to be exercised while titrating the meal-time 
insulin dose. 
In both treatment arms insulin doses of 0.15 U/kg will be administered for PK assessment. This 
dose is considered sufficient to cover for carbohydrate intake during breakfast without 
significantly increasing the risk of hypoglycemia (appropriate meal-adjustments and/or potential 
administration of countermeasures are to be performed by the Investigators to ensure 
minimization and mitigation of any such risks) and also to provide interpretable insulin profiles 
over the PK assessment period of 8 hours. 
4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities. 
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 [PP]). 
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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 at least 18 years of age, inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 02. Participants with T1DM. 
I 03. Type 1 diabetes diagnosed at least 12 months before screening. 
I 04. Participants on continuous insulin treatment for at least 12 months prior to screening. 
I 05. Participants exclusively on a multiple (≥3) daily injection insulin analogue regimen using:  
a NovoLog as mealtime insulin for at least 12 weeks prior to screening. 
AND 
b Insulin glargine (100 U/mL) as basal insulin for at least 12 weeks prior to screening. 
Note: Participants not meeting this criterion may also qualify, provided that they complete 
the run-in period during which NovoLog and Lantus will be administered so that, at the 
time of randomization, the participants have been on NovoLog and insulin glargine 
(100 U/mL) for at least 12 weeks (including any potential pre-screening administration). 
Note: Off-label twice-daily (BID) dosing of insulin glargine is not permitted during the 
study and any participant administering Lantus BID prior to the study must be switched to 
once-daily (QD) dosing after signing the Informed Consent for the study (daily time of 
administration to be agreed between the participant and the study doctor). 
I 06. HbA1c less or equal to 10% (85.79 mmol/mol) at screening. 
Note: The Sponsor will monitor baseline HbA1c levels and may limit enrollment of 
participants with HbA1c values <7.0% at a certain point during the conduct of the study to 
ensure an acceptably high average HbA1c for the study. Sites will be appropriately and 
timely informed if and when such a decision has been reached. 
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Weight 
I 07. Body mass index ≤35 kg/m² at screening. 
Sex 
I 08. Male or Female. 
 Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 4 [Section 10.4]), not breastfeeding, and at least one of the following 
conditions applies: 
- 
Not a WOCBP as defined in Appendix 4 (Section 10.4), 
OR 
- 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) during the intervention period and for at least 5 weeks after the last dose 
of study intervention. 
Informed Consent 
I 09. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.3) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Any clinically significant abnormality identified either in medical history, during physical 
examination, laboratory tests, or vital signs at the time of screening or any AE during 
screening period which, in the judgment of the Investigator, would preclude safe 
completion of the study or constrains PK, immunogenicity, safety, or efficacy assessments. 
E 02. Pancreatectomy and/or islet cell transplantation. 
E 03. Severe renal disease defined as estimated glomerular filtration rate (GFR) (modification of 
diet in renal disease [MDRD] formula) <30 mL/min/1.73/m² or on renal replacement 
treatment. 
E 04. 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 05. Laboratory findings at screening: 
 Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 times upper limit 
of the normal (ULN). Or  
 Total bilirubin >1.5 times ULN (except in case of documented Gilbert’s syndrome). 
E 06. History of severe hypoglycemia requiring emergency room admission or hospitalization 
within 3 months prior to screening. 
E 07. Hospitalization for recurrent diabetic ketoacidosis within 3 months prior to screening. 
E 08. Retinopathy or maculopathy with one of the following treatments, either recent (within 
3 months of screening) or planned: intravitreal injections or laser or vitrectomy surgery. 
Prior/concomitant therapy 
E 09. Likelihood to require treatment prohibited by the protocol during the study. 
E 10. Use of glucose lowering treatments other than the multiple dose injection (MDI) and basal 
insulin regimen, as described in I 05 (including use of insulin pump therapy), within 
12 weeks prior to screening. 
E 11. Participants having received systemic glucocorticoids  for one week or more within 
3 months prior to screening (topical, nasal spray, inhaled or intra-articular applications are 
allowed). 
E 12. Participants having received systemic immunosuppressive agents within 6 month prior to 
screening (please refer to E 11 for restrictions related to glucocorticoids). 
Prior/concurrent clinical study experience 
E 13. Exposure to any investigational drugs in the last 4 weeks or 5 half-lives, whichever is 
longer, prior to screening or concomitant enrollment in any other clinical study involving 
an investigational study treatment. Patients having received SAR341402 at any time prior 
to screening are not permitted to participate in the study. 
Diagnostic assessments 
Not applicable. 
Other exclusions 
E 14. Any contraindication to use of insulin glargine and/or NovoLog as defined in the national 
product labels. 
E 15. Hypersensitivity to any of the study treatments, or components thereof. 
E 16. History of drug or alcohol abuse within 6 months prior to screening. 
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E 17. Night shift workers. 
E 18. 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. 
Additional criteria at the end of the screening period (for participants who do not undergo 
run-in) or at the end of the run-in period (for participants who undergo run-in) 
E 19. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol. 
E 20. Participants who withdraw consent during the screening period (starting from signed ICF) 
or the run-in period. 
E 21. Participants who used glucose lowering treatments other than Novolog and insulin glargine 
(100 U/mL) (including use of insulin pump therapy) during the screening period (for 
participants who do not undergo run-in) or run-in period (if applicable). 
5.3 
LIFESTYLE CONSIDERATIONS  
Lifestyle and diet recommendations will be given by trained and qualified study staff at Screening 
and during the study and should be consistent with international or local guidelines for 
participants with T1DM. Compliance with the diet and lifestyle counseling will be assessed and 
discussed with the participant throughout the study.  
Fasting conditions 
 For all on-site study visits (except for Visit RI [run-in; if applicable] and Visit 4 
[Week 4]), participants need to come to the study center after an overnight fast of at least 
8 hours, consisting of no food or liquid intake, other than water, and no meal-time insulin 
injection. 
 Fasting (pre-breakfast) SMPGs to be performed based on SoA. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention (including patients who failed study 
eligibility during the screening or run-in period). A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAE. In cases where original screen failure was due to reasons 
expected to change at rescreening and based upon the Investigator’s clinical judgment, the 
participant can be rescreened one time for this study. A participant must not be randomized more 
than once (ie, entered 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 IMPs are SAR341402 (tested drug) and NovoLog (comparator drug) for SC injection 
administered during the treatment period. 
Insulin glargine 100 U/mL (Lantus), which will be used as mandatory background insulin therapy 
during the run-in (if applicable) and treatment periods, along with NovoLog, which will be 
administered during the run-in period to the applicable participants, are considered the NIMPs. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 3 - Overview of study interventions administered  
Study 
intervention 
name 
SAR341402 
NovoLog-US 
Lantus 
Dosage formulation 
100 U/mL solution for SC 
injection supplied in 3-mL 
cartridges in a SoloStar 
disposable pen 
100 U/mL solution for SC 
injection in the NovoLog 
FlexPen disposable pen 
100 U/mL solution for SC injection in 3-mL 
cartridges as Lantus SoloStar disposable 
pen 
Unit dose 
strength(s)/Dosage 
level(s) 
Each pen contains in total 
300 units of SAR341402 
(3 mL of 100 units/mL 
SAR341402 solution). This 
pen allows dose setting in 
the range of 1 to 80 units 
with minimum of 1 unit 
increment 
Each pen contains in total 
300 units of insulin aspart 
(3 mL of 100 units/mL 
insulin aspart solution). 
This pen allows dose 
setting in the range of 1 to 
60 units with minimum of 
1 unit increment 
Each pen contains in total 300 units of 
insulin glargine (3 mL of 100 units/mL 
insulin glargine solution). This pen allows 
dose setting in the range of 1 to 80 units 
with minimum of 1 unit increment. 
Route of 
administration 
SC injection 
SC injection 
SC injection 
Dosing instructions 
Every effort will be made to inject the SAR341402 or 
NovoLog immediately (within 5-10 minutes) before a 
meal. Occasional postprandial injection soon after meal 
intake may be done if deemed necessary and if allowed 
by the national product label for NovoLog. 
 
Inject SC once daily consistent with the 
local label. Off-label twice-daily (BID) 
dosing of insulin glargine is not permitted 
during the study and any participant 
administering Lantus BID prior to the study 
must be switched to once-daily (QD) 
dosing after signing the Informed Consent 
for the study (daily time of administration to 
be agreed between the participant and the 
study doctor). 
 
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Study 
intervention 
name 
SAR341402 
NovoLog-US 
Lantus 
Dosing instructions 
(continued) 
SAR341402 and Novolog will be self-administered by SC 
injection, in the abdominal wall, buttock, thighs, or upper 
arms. The area of the injections will be consistent with 
the habits of the individual participant. Within that area, 
injection sites will be changed (rotated) at each time. 
Changes in the area of injection during the study should 
be avoided as far as possible. It is recommended that, for 
participants randomized in the IMP switching arm, 
SAR341402 and Novolog will be injected on different 
sides (left or right) of the body. 
The starting dose of NovoLog will be the same (Unit for 
Unit) as the insulin aspart dose used at the end of the 
screening or run-in period.  If the participant is not on 
insulin aspart at the end of the screening period, the 
starting dose will be determined by the Investigator in 
agreement with the national product label. 
Changes in the SAR341402 or NovoLog dose will be 
based on SMPG values and the meal content (when 
available). It is recommended that doses will be titrated 
by the participants to achieve a 2-hour PPG of 
<10 mmol/L (180 mg/dL) while avoiding hypoglycemia, 
according to the Investigator’s instructions. If pre-prandial 
glucose tests are used, the target range of 4.4 to 
7.2 mmol/L (80 to 130 mg/dL) is recommended. For the 
purpose of this protocol, 2 hours postprandial is defined 
as 2 hours after the start of the meal. 
Glycemic targets may be adapted for individual 
participants, if deemed necessary, eg, due to age, 
comorbid conditions, and individual considerations. The 
individual targets will be recorded in source documents. 
The doses of the meal-time insulin will be reviewed when 
the basal insulin dose is increased, as they may have to 
be reduced to avoid daytime hypoglycemia. 
In the non-switching arm, NovoLog will be administered 
for 16 weeks. 
In the switching arm, NovoLog will be administered 
alternately with SAR341402, starting with NovoLog for 
4 weeks, followed by SAR341402 for 4 weeks, then 
NovoLog for 4 weeks and ending with SAR341402 for the 
last 4 weeks (ie, a total of 4 x 4-week treatment periods 
with 3 switches). 
At the end of Week 16, a 0.15 U/kg of SAR341402 in the 
switching arm or NovoLog in the non-switching arm will 
be given in fasting conditions. 
Mixing of either SAR341402 or NovoLog with other 
insulin is not allowed nor is dilution. 
The area for the injection sites for Lantus 
injection must be different from that of the 
IMP. The time of injection will be fixed at 
randomization (Visit 3, Baseline) according 
to participant and Investigator’s preference 
and maintain (±2 hours) throughout the 
study. 
The starting dose of Lantus will be the 
same as the last dose of insulin glargine 
used at the end of the screening or run-in 
period. If the participant is not on Lantus at 
the end of the screening period, the 
starting dose will be determined by the 
Investigator in agreement with the national 
product label. 
Changes in the Lantus dose are based on 
fasting/ prebreakfast SMPG values. Lantus 
doses can be titrated by the participant, 
according to the Investigator’s instructions, 
to achieve fasting, pre-breakfast SMPG of 
4.4 to 7.2 mmol/L (80 to 130 mg/dL), while 
avoiding hypoglycemia.  
The increase of the Lantus dose should 
not exceed 10% of the daily dose of 
Lantus, unless deemed necessary, 
according to the clinical judgement of the 
Investigator.  
The Investigator may choose to change 
the rapid-acting insulin doses instead of 
increasing the basal insulin dose.  
Whenever the basal insulin dose is 
changed, the rapid-acting insulin doses 
need to be reviewed to avoid 
hypoglycemia. 
Mixing of Lantus with other insulin is not 
allowed nor is dilution. 
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Study 
intervention 
name 
SAR341402 
NovoLog-US 
Lantus 
Packaging and 
labeling 
Both NovoLog and Lantus will be provided during the run-in period (if applicable). Efforts will be made 
to dispense the appropriate number of kits to cover up to the randomization visit. However, if necessary 
according to the Investigator, the study participants may undergo unscheduled visits for resupply and to 
ensure Investigators’ oversight. Commercially available NovoLog (NIMP) and Lantus (NIMP) will be 
additionally labeled. The content of the labeling will be in accordance with the local regulatory 
specifications and requirements. 
Study treatment will be provided during the treatment period in accordance with the administration 
schedule. The appropriate number of kits will be dispensed to cover up to the next dispensing visit. 
Commercially available comparator NovoLog and NIMP (Lantus) will be repackaged in study specific 
kits and relabeled. The content of the labeling is in accordance with the local regulatory specifications 
and requirements for the IMP and the NIMP. 
Between the protocol-scheduled on-site visits, interim visits may be required for both IMP and 
NIMP dispensing. As an alternative to these visits, IMP and/or NIMP may be supplied from the 
site to the participant via a Sponsor-approved courier company where allowed by local regulations 
and approved by the participant. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP and 
NIMP in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures. 
Control of storage conditions for IMP and NIMP provided by the Sponsor, especially control of 
temperature (eg, refrigerated storage) and information on in-use stability and instructions for 
handling the IMP and NIMP will be managed according the rules provided by the Sponsor. 
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
The site will instruct the participant to store the in-use prefilled pens (IMP and NIMP) in 
accordance with the storage conditions indicated on the label of each product. 
Any quality issue noticed with the receipt or use of an IMP/NIMP (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure  
(see Section 8.3.6). 
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A potential defect in the quality of IMP/NIMP 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 and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party (except for 
direct-to-patient shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP/NIMP to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP in any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
All participants will be centrally assigned to randomized study treatment using an IRT system. 
Randomization will be stratified by HbA1c obtained at the Visit 1 (<8.0% versus ≥8.0%). 
Randomization ratio is 1:1. 
A randomized participant is a screened participant who has a treatment kit number allocated and 
recorded in the IRT database, regardless of whether the treatment kit was used. A participant 
cannot be randomized more than once in the study. 
The treatment kit number list is generated centrally by Sanofi. The IMPs and NIMPs for the 
treatment period are packaged in accordance with this list. Designated Sanofi personnel provide 
the treatment kit number list and the randomization scheme to the centralized treatment allocation 
system (IRT). Then, the IRT generates the participant randomization list according to which it 
allocates treatment arms to the participants.  
The treatment kits for the treatment period, open-label boxes identified with treatment numbers, 
are allocated to the participants by the IRT using the treatment number of the boxes. 
At Visit 1, the Investigator or designee contacts the IRT for allocation of the participant number. 
The participant identification (participant number) is composed of 12-digit number containing the 
3-digit country code, the 4-digit center code and the 5-digit participant chronological number 
(which is 00001 for the first participant screened in a center, 00002 for the second participant 
screened in the same center etc.). 
At Visit 3 (Day 1, Randomization), the Investigator or designee has to contact the IRT for the first 
treatment kit(s) allocation (randomization) by providing some information (such as participant 
number provided by IRT at Visit 1, etc.). Afterwards the IRT is contacted again each time a new 
treatment kit(s) allocation is necessary, ie, the visits as indicated in the SoA (see Section 1.3) or 
when additional IMP/NIMP supplies are needed. 
Returned IMPs and NIMPs must not be re-dispensed to the participants. 
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SAR341402 in the SAR341402 SoloStar pen and the control drug, NovoLog in the NovoLog 
FlexPen are distinguishable. Therefore administration of SAR341402/NovoLog throughout the 
trial is to be open-label. Potential bias will be reduced by the following steps:  
 The specific IMP to be taken by a participant will be assigned centrally using an IRT. 
 Pharmacokinetic values, antibodies, blood glucose values from samples collected at the 
sites, as well as HbA1c values are determined in central laboratories blinded to the 
treatment received. 
 Selected AEs (see Section 10.1.5) will be adjudicated in a blinded fashion. 
 The Sponsor study team involved in the data review and analysis will remain blinded to 
treatment group until database lock: 
- 
Investigators will be requested not to report unblinded information related to IMP in 
the electronic case report form (eCRF) and SAE reports, 
- 
Members of the study team may review compliance with dosing and titration blinded 
to treatment (monitoring team is not blinded when reviewing), 
- 
The study team will review data in descriptive statistics without treatment assignment 
during data review meetings, 
- 
The unblinded treatment group allocation variable will be included in the clinical study 
database only at the time of the database lock, to perform the corresponding analyses; 
summary results by treatment arm will therefore not be available to anyone before 
database lock. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Measures taken to ensure and document treatment compliance and IMP/NIMP accountability 
include the following: 
 At each visit, the Investigator or his/her delegate asks the participant about administered 
doses of IMP (SAR341402 or NovoLog) and NIMP (Lantus). 
 All medication treatment kits (whether empty, partially used 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 
completing the appropriate Product Accountability forms. 
 The mandatory background NIMP (including Novolog and Lantus administered during the 
run-in period) will be recorded in the eCRF. 
6.4.1 Return and/or destruction of treatment  
The Investigator will not destroy any IMP/unused NIMP unless the Sponsor provides written 
authorization. A detailed treatment log of the destroyed IMP/unused NIMP will be established 
with the Investigator (or the pharmacist) and countersigned by the Investigator and the monitoring 
team.  
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The destruction is recommended to be performed at site depending on IMP/NIMP specificities 
and local requirements but IMP/NIMP can be returned to the Sponsor for destruction. 
A potential defect in the quality of IMP/NIMP may initiate 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 IMP/NIMP and eliminate potential hazards. 
6.5 
CONCOMITANT THERAPY  
A concomitant medication is any treatment received by the participant from the time of Screening 
through EOT visit. 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 
signing the ICF or receives during the study must be recorded in the eCRF. 
The following drugs are not permitted during the screening period (if no run-in period is 
required), the run-in period (if applicable), and the randomized open-label treatment periods: 
 Any glucose-lowering agents other than the IMP, ie, authorized insulin analog 
SAR341402 or NovoLog, and the background NovoLog and basal anti-diabetic therapy 
(insulin glargine 100 U/mL). 
Note:  
- 
Short term therapy (up to 10 days maximum) with either basal insulin or short acting 
insulin that may occur due to acute illness or surgery is allowed after the first 
administration of IMP but not during the screening and run-in periods, 
- 
Any antidiabetic medication, according to local standard of care, per the Investigator’s 
judgment can be used after definitive premature IMP discontinuation, 
- 
Administration of additional meal-time insulin during the 8-hour PK period, according 
to the Investigator’s judgement is also permitted. Due to considerations related to the 
sensitivity of the insulin aspart PK assay, human insulin must be used during this 
timeframe. Alternatively, administration of insulin lispro at low doses, according to the 
Investigator’s judgement, is also permitted. 
 Systemic glucocorticoids for more than 10 days (topical, nasal spray, inhaled or 
intra-articular applications are allowed). 
 Immunosuppressive agents. 
 Any other investigational product (ie, participation in another clinical trial). 
Concomitant medications should be kept to an absolute minimum and doses should be kept stable 
unless safety concerns indicate changes of dose. 
There is no rescue therapy defined in this study. Hypoglycemia will be managed as appropriate, 
by administering countermeasures, according to the clinical judgement of the Investigator.  
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6.5.1 Evaluation of participants not meeting glycemic goals  
 In case of SMPG not meeting the target in spite of successive insulin dose titration, the 
Investigator should ensure and document that no reasonable explanation exists for 
insufficient glucose control and in particular that: 
- 
Fasting plasma glucose was actually measured in fasting condition (ie, after at least 
8 hours fasting), 
- 
Rebound hyperglycemia is excluded, 
- 
IMP/NIMP doses are properly adjusted, 
- 
Correction doses for pre-prandial glucose values above goal are used by participant, 
- 
There is no inter-current disease which may jeopardize glycemic control (eg, infectious 
disease), 
- 
Compliance to diet and lifestyle is appropriate, in particular, dosage adjustment for 
changes in meal content and SMPG. 
 If any of the above can reasonably explain the insufficient glycemic control, the 
Investigator should undertake appropriate action, eg: 
- 
Further titrate the IMP/NIMP, if deemed safe by the Investigator, 
- 
Set up adequate investigation and treatment of inter-current disease (to be reported in 
AE/SAE/concomitant medication parts of the eCRF), 
- 
Stress the absolute need to be compliant to treatment, 
- 
Stress the importance of consistency in meals and insulin dosing, particularly during 
this time of poor glycemic control, 
- 
Monitor night time glucose, 
- 
If deemed appropriate, organize a specific interview with a Registered Dietician or 
other medically qualified person to stress on the absolute need to be compliant to diet 
and lifestyle recommendations, in particular with attention to awareness of the meal 
content and covering all snacks with a dose of rapid-acting insulin. 
6.6 
DOSE MODIFICATION  
Study participants adjust dose of IMP and NIMP as described in Table 3 and with site oversight 
according to standard of care. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The IMPs/NIMP will not be provided after the end of the treatment period. 
When an individual’s participation in the study ends, he/she will consult with his/her Investigator 
to decide on best available treatment. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Withdrawal of consent for treatment should be distinguished from (additional) withdrawal of 
consent for follow-up visits and from withdrawal of consent for non-participant contact follow-up 
(eg, medical record checks). The site must specifically document the type for each case of 
withdrawal of consent. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
The IMP should be continued whenever possible.  
In case the IMP is stopped, it should be determined whether the stop can be made temporary; 
definitive 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. 
Definitive 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 are encouraged to discuss their intent of stopping the IMP 
with the site before doing so in order for questions to be addressed, concomitant therapy to be 
adjusted if needed, and a follow-up assessment arranged. All efforts must be made to document 
the reasons for treatment discontinuation in the source documents and in the eCRF. 
A participant should withdraw from treatment with IMP and NIMP in case of the following: 
 Temporary discontinuation of the IMP of more than 10 days in total. 
 Intercurrent conditions that require discontinuation of IMP/NIMP (eg, for laboratory 
abnormalities according to the decision tree in Appendix 5 [Section 10.5] as long as the 
abnormality persists and if the casual relationship of the concerned event and the 
IMP/NIMP is possible according to the Investigator’s best medical judgment). 
 If, in the Investigator’s opinion, continuation with the administration of IMP/NIMP would 
be detrimental to the participant’s well-being. 
 Pregnancy (in female participants). 
 Confirmed intolerance to the allocated dose of IMP/NIMP. 
 At the participant’s own request, ie, withdrawal of consent for treatment. 
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It is important to collect data for all participants, under treatment or not, during the whole duration 
of the study. A high rate of missing data could jeopardize interpretation of the study results. Refer 
to the SoA (Section 1.3) for data to be collected at the time of IMP discontinuation and follow-up 
and for any further evaluations that need to be completed. 
Note: as an exception to the requirement mentioned above, participants who prematurely and 
definitively discontinue IMP will have their serial PK samples (0 to 8 hours) collected at the time 
of the early discontinuation visit, not at the time of Week 16 visit (Visit 7) as planned per SoA 
(Section 1.3).  
Any clinically-significant abnormal laboratory value will be rechecked for confirmation as soon 
as possible before making a decision of definitive discontinuation of the IMP for the concerned 
participant. 
Handling of participants after definitive intervention discontinuation 
Every effort should be made to maintain participants in the study. Participants will be followed 
according to the study procedures specified in this protocol up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed as specified in this 
protocol, whichever comes last. 
If possible, the participants will be assessed using the procedure planned for the EOT Visit 
(Visit 7) before the definitive discontinuation of the IMP, or as soon as possible after 
discontinuation. For participants who discontinue intervention but remain in the study, the 
remaining visits should occur as scheduled where possible, including the assessments planned in 
SoA (Section 1.3) except serial PK samples that should only be collected at the time of early 
discontinuation visit and do not need to be repeated at Visit 7. The Investigator should discuss 
with them key visits to attend. 
The value of all their study data collected during their continued involvement will be emphasized 
to study participants as important to 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 definitive 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 IMP discontinuation corresponds to more than 1 dose not administered to the 
participant. 
All IMP discontinuation should initially be considered as temporary unless definitive 
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 a limit to up to 
10 days in total (during the study) for IMP discontinuations to be deemed as temporary. If the sum 
of temporary discontinuations durations exceeds 10 days, discontinuation should be considered 
and managed as definitive. 
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Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or due to any other reason.    
7.1.2.1 Rechallenge 
Reinitiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 5.1 and 
Section 5.2). In case of IMP intolerance, a one-time rechallenge is recommended following 
temporary discontinuation before deciding to definitively discontinue the IMP. 
Note: To allow for rechallenge, IMP discontinuation should not be reported in the IRT until 
definitive discontinuation is confirmed. 
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 
definitive (see Section 7.1.1), then the participant should be considered as definitively 
discontinued and the corresponding eCRF page should be completed. Please note that definitive 
discontinuation should be a last resort. 
It is in the interest of the participant to monitor plasma glucose during the temporary 
discontinuation period, therefore SMPG or other regular determination of plasma glucose is 
recommended to be performed and documented. 
During any temporary treatment discontinuation, doses of alternative treatment used for plasma 
glucose control will be recorded in the eCRF. 
Use of a different insulin during the time of temporary treatment discontinuation is recorded as 
concomitant medication (such as during a hospitalization) with the name and doses recorded in 
the eCRF. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the Sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the Investigator must document this in the site study records. 
See SoA (Section 1.3) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 
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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 in the study. Their 
inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (eg, contact patient's family or private 
physician, review available registries). Attempts to contact such patients (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods) must 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. 
 Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct. 
 All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
 In addition to the scheduled laboratory samples collection, as presented in the SoA 
(Section 1.3), repeat or unscheduled samples may be collected for safety reasons or due to 
technical issues with the samples. 
8.1 
EFFICACY ASSESSMENTS   
8.1.1 Glycated hemoglobin A1c  
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” (NGSP) central laboratory. 
Conversion of HbA1c values between % and mmol/mol units will be done according to the 
International Federation of Clinical Chemistry – National Glycohemoglobin Standardization 
Program (IFCC NGSP). 
8.1.2 Self-monitored plasma glucose  
At the screening visit, the Investigator or a member of the investigational staff will provide 
participants with a glucometer and corresponding supplies (lancets, test strips, etc.). Intensive 
training on the correct handling of the glucometer will be provided as appropriate at the screening 
visit, run-in visit (if applicable) and at the randomization visit. Regular refresher instructions will 
be provided at each appropriate visit throughout the study. Participants will be instructed to bring 
the glucometers provided by the Sponsor with them to each office visit. If applicable, the 
glucometers must be calibrated according to manufacturer’s instructions and the investigational 
site must also check regularly the glucometers using the provided control solutions for data 
validity. All self-monitored plasma glucose values collected in the study have to be measured by 
the participant using the sponsor-provided glucometer (and not by using the participant’s personal 
glucometer or continuous glucose monitoring [CGM] device), unless occasionally deemed 
necessary for the safety of the participant. 
Study participants will be provided with a diary and will receive detailed instructions for its use. 
The diary needs to be brought to each on-site visit.  
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Self-monitored plasma glucose measurements are scheduled as follows: 
 SMPG to support basal and meal-time insulin titration/dosing is recommended daily 
during the first weeks of study treatment until reaching target ranges for SMPG, and 
thereafter on at least 3 days during the week before each visit or more frequently as 
requested by the Investigator; pre-meal, 2-hour postprandial, and nocturnal SMPG will be 
used consistent with standard of care. The results will be discussed between Investigator 
and participant during scheduled and unscheduled visits at the discretion of the 
Investigator. 
For SMPG ≤3.9 mmol/L (≤70 mg/dL), the participant will be required to complete the 
hypoglycemia specific information. 
 SMPG during episodes of symptoms of hypoglycemia: whenever the participants feel 
hypoglycemic symptoms, plasma glucose should be measured by the participant (or 
others, if applicable), if possible. 
8.1.3 Fasting plasma glucose  
Blood samples for FPG measurement are taken and measured at central laboratory according to 
the SoA (Section 1.3).   
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
 A complete physical examination (including, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems) 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 EOT a limited physical examination focused on any affected body area or organ or 
organ system will be performed. 
 Height will be measured and BMI will be calculated at Visit 1 only. 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
 Any clinically-significant new finding or worsening of previous finding must be reported 
as an AE. 
8.2.2 Vital signs  
Vital signs parameters are heart rate (HR), systolic blood pressure (BP) and diastolic BP. 
 Blood pressure and HR measurements will be performed for each participant according to 
the schedule displayed in the SoA (Section 1.3) prior to procedures involving venipuncture 
or injections. 
 Devices for BP measurement should be regularly recalibrated according to manufacturers’ 
instructions. 
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8.2.3 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.  
 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/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 laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF as an AE/SAE, as 
appropriate.  
 Decision trees for the management of certain laboratory abnormalities are provided in 
Appendix 5 (Section 10.5). 
8.2.4 Hypoglycemia  
8.2.4.1 Documentation and Classification of Hypoglycemia  
During the study, participants must be instructed to document all hypoglycemia episodes in their 
diary as soon after the event as possible. Hypoglycemia will be recorded or integrated in the 
specific eCRF page. Hypoglycemia fulfilling the seriousness criteria will be documented in 
addition on the AE/SAE form in the eCRF. 
Hypoglycemic events will be categorized (11, 12, 13) 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 
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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, must not be considered a “requiring assistance” incident. 
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria (see 
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 treated with oral carbohydrate. 
 Relative hypoglycemia: (termed in 12 “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 hypoglycemia and asymptomatic hypoglycemia with a measured 
plasma glucose concentration less than 3.0 mmol/L (54 mg/dL) will also be analyzed (13). 
Hypoglycemic events will be evaluated regardless the time of onset during the day. 
8.2.4.2 Self-measured plasma glucose during symptomatic hypoglycemia  
Whenever the participants feel hypoglycemic symptoms, plasma glucose should be measured by 
the participant (or others, if applicable), if possible. The study glucometer must be used for these 
measurements. Participants should be instructed to measure plasma glucose levels prior to 
carbohydrate intake or administration of glucose whenever symptomatic hypoglycemia is 
suspected, unless safety considerations necessitate immediate carbohydrate/glucose rescue prior to 
confirmation. 
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Exceptionally, and only during hypoglycemic events during which there is no possibility to use 
the study glucometer, plasma glucose may be recorded with other devices. These events are to be 
recorded in the diary by the study participants, ensuring that most complete information 
(including but not limited to the event date and the plasma glucose value, if available) is provided. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification (within 
24 hours) by the Investigator to the Sponsor is required. Such events may require further 
investigation in order to characterize and understand them. Adverse events of special interest may 
be added, modified or removed during a study by protocol amendment. 
 Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP. 
- 
It will be qualified as an SAE only if it fulfills one of the seriousness criteria 
(see Appendix 3 [Section 10.3]), 
- 
In the event of pregnancy in a female participant, IMP should be discontinued, 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
 Symptomatic overdose (serious or nonserious) with IMP/NIMP. 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the participant and resulting 
in clinical symptoms and/or signs and considered a "significant overdose" by the 
Investigator. It will be recorded in the eCRF in all cases and will be qualified as an 
SAE only if it fulfills the SAE criteria. 
 Increase in ALT>3 × ULN (see Section 10.5). 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention and/or study (see Section 7).  
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Adverse events requiring specific monitoring 
An AE requiring specific monitoring is a serious or nonserious AE of scientific and medical 
concern specific to the Sponsor’s product or program, for which ongoing monitoring may be 
appropriate. Such events may require further investigation to characterize and understand them. 
These events should be reported on the AE page and additional information required on the 
specific eCRF page (where applicable) and will only qualify for expedited reporting when serious 
(fulfilling SAE criteria). 
The AEs requiring specific monitoring for this study are as follows:  
 Injection site reactions. 
In case the Investigator or the participant recognizes any sign related to local non-allergic 
reactions at the IMP/NIMP injection site, this should be recorded on the AE page in the 
eCRF. 
If a participant reports an injection site reaction between the on-site visits or during a 
phone call visit, it is recommended that the Investigator ask him/her to come to the study 
site on the same or the next day or as clinically appropriate, so that the event can be 
properly assessed and reported. 
 Hypersensitivity reactions. 
Allergic reactions or possible allergic reactions will be adjudicated by the ARAC 
(see Appendix 1, Section 10.1.5).  
If a participant reports a hypersensitivity reaction between the on-site visits or during a 
phone call visit, it is recommended that the Investigator ask him/her to come to the study 
site on the same or the next day or as clinically appropriate, so that the event can be 
properly assessed and reported. 
Virtually all symptoms listed on the allergic reaction complementary form are possible 
adverse reactions that may be allergic in nature and may need to be addressed after 
medical judgment, excluding another etiology than allergy. 
Sometimes transient injection site reactions, irritant in nature may occur requiring no 
intervention and are of dubious significance. These reactions would not be considered to 
be allergic reactions. Adverse events that are obviously not of allergic origin (eg, local 
injection site reactions) should not be recorded on the designated Allergic Reaction eCRF 
Form. 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the ICF until the follow-up visit. 
All SAEs and AESI will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
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Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  At the pre-specified study end-date, all SAEs and 
non-serious AESIs 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  
 Prompt (within 24 hour) notification by the Investigator to the Sponsor of an SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.  
 The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
 Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
 Adverse events that are considered expected will be specified in the reference safety 
information. 
 An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
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8.3.5 Pregnancy  
 Pregnancies in female participants and female partners of male participants will be 
reported after the start of study intervention until the follow-up visit.  
 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). 
 Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
The Sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, it is recommended that the Investigator take the following actions: 
1. Contact the Medical Monitor, if deemed necessary. 
2. Closely monitor the participant for any hypoglycemia, AEs/SAEs and laboratory 
abnormalities, as appropriate. 
3. Document appropriately in the eCRF (see Section 8.3). 
Decisions regarding dose interruptions or modifications will be made by the Investigator based on 
the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
 Whole blood samples will be collected for measurement of plasma concentrations of 
insulin aspart as specified in the PK flow chart (see Section 1.3). Instructions for the 
collection and handling of biological samples will be provided by the Sponsor or designee. 
The actual date and time (24-hour clock time) of each sample must be recorded. 
 Samples will be used to evaluate the PK of SAR341402/insulin aspart. Each plasma 
sample will be divided into 2 aliquots (1 each for PK and a back-up). Samples collected 
for analyses of SAR341402/insulin aspart plasma concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
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8.6 
PHARMACODYNAMICS  
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
GENETICS  
Genetics are not evaluated in this study. 
8.8 
BIOMARKERS  
8.8.1 Immunogenicity assessments  
Antibodies to insulin aspart, including neutralizing antibodies, will be evaluated in plasma 
samples collected from all participants according to the SoA (Section 1.3). Additionally, plasma 
samples should also be collected at the final visit from participants who discontinued study 
intervention. Participants need to come to the site fasting without having injected any meal-time 
insulin (SAR341402 or NovoLog) for at least 8 hours. Blood samples for antibody measurements 
will be collected before any insulin is administered and in a fasting state. All samples will be 
tested by a central laboratory blinded to intervention allocation. 
Plasma samples will be screened for antibodies binding to insulin aspart and the titer and 
cross-reactivity to human insulin of confirmed positive samples will be reported. Other analyses 
including assessment of neutralizing capacity of confirmed positive samples may be performed to 
further characterize the immunogenicity of insulin aspart. 
The detection and characterization of antibodies to insulin aspart will be performed using a 
validated assay method by or under the supervision of the Sponsor. Antibodies may be further 
characterized and/or evaluated for their ability to neutralize the activity of the study 
intervention(s). Further analyses of immune responses to insulin aspart may be conducted up to 
two years after the last sample collection. 
8.9 
HEALTH ECONOMICS  
Health Economics and Health Economics parameters are not evaluated in this study. 
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9 
STATISTICAL CONSIDERATIONS   
9.1 
STATISTICAL HYPOTHESES  
The primary analysis will be performed based on natural log-transformed AUClast, AUC, and 
Cmax. The 90% CI for the ratio of geometric means for AUClast, AUC, and Cmax between the two 
treatment arms (SAR341402/NovoLog switching arm and NovoLog non-switching arm) should 
be within 80-125%, corresponding to the following composite null and alternative hypotheses 
tested at an alpha level of 0.05: 
 H0: The ratio of geometric means for AUClast, AUC, or Cmax between 
SAR341402/NovoLog switching arm and NovoLog non-switching arm is outside the 
pre-defined acceptance range 80-125%. 
 H1: The ratio of geometric means for AUClast, AUC, and Cmax between 
SAR341402/NovoLog switching arm and NovoLog non-switching arm is within the 
pre-defined acceptance range 80-125%. 
9.2 
SAMPLE SIZE DETERMINATION   
Approximately 184 participants will be randomly assigned to either one of the treatment groups, 
alternating use of SAR341402 and NovoLog or continuous use of NovoLog (in a 1:1 ratio), with a 
minimum of 146 evaluable participants (73 per treatment group) for the primary PK evaluation 
expected at the end of the study.  If the number of study participants with evaluable PK data is 
determined to have been reached before all planned 184 participants are randomized, then the 
study randomization may be stopped sooner. 
The sample size calculations are performed based on the expected variability of the primary PK 
endpoints AUClast, AUC, and Cmax following injection of a predefined, fixed dose of SAR341402 
or NovoLog (0.15 U/kg) at Week 16. 
A sample size of 146 evaluable participants (73 participants per arm) will ensure that the 90% CI 
for the estimated treatment ratio is within the acceptance range of [0.8 – 1.25] with at least 
90% power; assuming a true ratio between 0.95 and 1.05 (switching arm / non-switching arm) and 
a total standard deviation on natural log scale of 0.35 or lower. 
Sample size calculations were made using SAS® Software Version 9.4.  
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9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 4): 
Table 4 - Populations for analyses  
Population 
Description 
Screened  
All participants who sign the ICF 
Randomized 
All screened participants who have a treatment kit number allocated and recorded in 
the IRT database, regardless of whether the treatment kit was used 
Evaluable for PK (PK) 
All participants without deviation that could significantly impact the PK analysis  
(eg, missing or incorrect SC injection on PK profile day) and for whom PK data are 
considered sufficient and interpretable 
Intent to Treat (ITT) 
All randomized participants, irrespective of compliance with the study protocol and 
procedures, analyzed in the treatment group to which they are randomized 
Per Protocol (PP) 
Subset of the ITT population, which includes all randomized and exposed 
participants, who do not definitively discontinue IMP allocated by randomization 
during the 16-week period, who perform Week 16 visit and who do not present major 
or critical protocol deviations that could significantly impact the analysis 
Safety 
All randomized participants who receive at least one dose of IMP (regardless of the 
amount of IMP administered). Participants will be analyzed according to the 
intervention they actually received. 
Immunogenicity (AIA) 
All participants from the safety population with at least one AIA sample available for 
analysis (ie, collected during the on-treatment period and at least 8 hours after the 
last administration of meal-time insulin). Participants will be analyzed according to the 
intervention they actually received. 
AIA: anti insulin aspart antibody; ICF: informed consent form; IMP: investigational medicinal product; IRT: interactive response technology; 
ITT: intent to treat; PK: pharmacokinetic; PP: per protocol; SC: subcutaneous 
9.4 
STATISTICAL ANALYSES  
A statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints and any changes to the planned analyses will be 
addressed in the SAP. 
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9.4.1 Pharmacokinetic analyses  
Table 5 - Pharmacokinetic analyses  
Endpoint 
Statistical Analysis Methods 
Primary: AUClast, 
AUC, Cmax 
following injection 
of a predefined, 
fixed dose of 
SAR341402 or 
NovoLog 
(0.15 U/kg) at  
Week 16 
Primary PK analysis will be based on the PK population. For participants with insufficient data for some but 
not all PK parameters, the evaluable PK parameters will be included in the analysis. 
PK parameters will be summarized by treatment using descriptive statistics. 
The impact of switching between SAR341402 and NovoLog on AUClast, AUC, and Cmax will be assessed. 
For primary analysis, the natural log-transformed AUClast, AUC, and Cmax will be statistically analyzed using 
an analysis of variance, including the fixed categorical effects of treatment arm (SAR341402/NovoLog 
switching arm, NovoLog non-switching arm) and randomization strata. Estimate and 90% CI for the ratio of 
geometric means between the two arms (SAR341402 from switching arm / NovoLog from non-switching 
arm) will be computed for AUClast, AUC, and Cmax, from the linear model framework using re-transformation. 
The 90% CI for the ratio of geometric means of AUClast, AUC, and Cmax should be within 80-125%.  
Secondary: Time to 
Cmax (Tmax) 
following injection 
of a predefined, 
fixed dose of 
SAR341402 or 
NovoLog 
(0.15 U/kg) at  
Week 16 
Tmax will be summarized by treatment in the PK population using descriptive statistics. 
 AUC: area under the concentration curve; Cmax: maximum concentration; PK: pharmacokinetic; Tmax: time to maximum concentration 
9.4.2 Immunogenicity analyses  
Table 6 - Immunogenicity analyses  
Endpoint 
Statistical Analysis Methods 
Secondary: Number of 
participants with 
treatment-emergent AIA 
during the 16-week 
treatment  
 
Immunogenicity analyses will be based on the AIA population. Only AIA results from samples 
collected during the on-treatment period and at least 8 hours after the last administration of 
meal-time insulin will be taken into account in the analysis. 
For descriptive purpose, the difference between the switching arm and the non-switching arm in the 
percentage of participants with treatment-emergent AIAs (AIA incidence) will be provided with 
associated 2-sided 90% CI. Results will be obtained by fitting a binomial regression model with an 
identity-link function. The model will include fixed categorical effects for the treatment group and 
randomization strata. The risks within each treatment group and risk difference will be provided with 
their 90% CI using the adjusted least squares mean estimates of the treatment effect. 
AIA: anti insulin aspart antibody; IMP: investigational medicinal product 
9.4.3 Safety analyses  
 All safety analyses will be descriptive and performed on the Safety Population.  
The observation period for safety data is divided into 3 main segments: 
 The pre-treatment period is defined as the time from informed consent up to the time of 
the first injection of IMP. 
 The on-treatment period is defined as the time from the first injection of IMP up to 1 day 
after the last injection of IMP. 
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 The post-treatment period is defined as the time starting 1 day after last injection of IMP 
(after the on-treatment period). 
The AE observations will be classified per the observation periods of safety data as defined 
above:  
 Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
 Treatment-emergent AEs are AEs that developed or worsened or became serious during 
the on-treatment period. 
 Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
Analyses will focus on safety observations during the on-treatment period. 
The baseline value for safety variables will be defined as the last available value prior to the first 
injection of IMP. 
Table 7 - Safety analyses  
Endpoint 
Statistical Analysis Methods 
Secondary: Number of 
participants with at least one 
hypoglycemic event for the 
16-week treatment period 
Proportions of participants with at least one hypoglycemic event will be presented overall and by 
type of event for each treatment group. 
 
Secondary: Number of 
hypoglycemic events per 
participant-year for the 
16-week treatment period 
Incidences of hypoglycemia per participant-year will be computed as: 365.25 x (number of 
episodes of hypoglycemia)/(number of days exposed) and summarized overall and by type of 
event for each treatment group.  
For exploratory purpose, odds-ratios and rate ratios of hypoglycemic event may be provided for 
SAR341402/NovoLog switching group versus NovoLog non-switching group, overall and for 
some categories of hypoglycemia. Details will be provided in the SAP. 
Further analyses (eg, by subgroup, over time) may be done as appropriate and will be detailed in 
the SAP. 
Secondary: Number of 
participants with AE for the 
16-week treatment period 
All AEs will be coded using the version of MedDRA currently in use by the sponsor at the time of 
database lock. 
Adverse event incidence tables will present using the MedDRA hierarchy, the number and 
percentage of participants experiencing an AE for each treatment group. 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment-emergent SAEs, all TEAEs leading to definitive treatment discontinuation 
and all TEAEs leading to death. 
The number and proportion of participants with injection site and hypersensitivity reactions 
(identified by MedDRA search) will also be summarized by treatment group, and events 
adjudicated as possible hypersensitivity reactions by the ARAC will be described. 
AE: adverse event; MedDRA: Medical Dictionary for Regulatory Activities; SAE: serious adverse event; TEAE: treatment-emergent adverse 
event 
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9.4.4 Other analyses  
Other AIA endpoints will be derived from AIA assessments (status, titer) as follows: 
a Participants with treatment-induced AIAs will be defined as participants with AIAs that 
developed de novo (seroconversion) following the IMP administration. 
b Participants with treatment-boosted AIAs will be defined as participants with pre-existing AIAs 
that were boosted to a significant higher titer following the IMP administration (at least 4 fold 
increase in titer values). 
c Participants with treatment-emergent AIAs (AIA incidence) will be defined as participants with 
treatment-induced or treatment-boosted AIAs. 
Analysis of tertiary/exploratory endpoints (other AIA endpoints, clinical effects of AIA, change in 
insulin dose, and efficacy analyses) will be described in the statistical analysis plan finalized 
before database lock. 
9.5 
INTERIM ANALYSES   
No interim analysis is planned. 
9.5.1 Data Monitoring Committee (DMC)  
Not applicable. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and Ethical Considerations  
 This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) Guidelines, 
- 
Applicable laws and regulations. 
 The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
 Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
 The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC, 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 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 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
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10.1.3 Informed Consent Process  
 The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative 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.  
 The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
 A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
Participants who are rescreened are required to sign a new ICF. 
10.1.4 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).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Subject race and ethnicity will be collected in this study as part of the data comprising the 
baseline characteristics of the population. 
 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. 
 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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10.1.5 Committees Structure  
An ARAC, a committee of experts in the field of allergology and diabetes mellitus independent 
from the Sponsor and the Investigators, blinded for the treatment groups, will adjudicate 
hypersensitivity reactions, hypersensitivity-like reactions, and events of potential loss of efficacy, 
according to criteria as defined in the ARAC charter. The ARAC members may recommend 
additional follow-up (ie, AIA titers measurement) after the end of study per SoA (Section 1.3) in 
specific participants with treatment-emergent AIAs at the end of study with potential impact on 
glycemic control or safety. Details of these activities and assessments are being outlined in the 
ARAC charter. 
10.1.6 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, EU clinical trial register (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials.   Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.7 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 eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
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 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for at least 15 years after the end of the clinical study 
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.  
10.1.8 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. 
10.1.9 Study and site closure  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
 Inadequate recruitment of participants by the Investigator. 
 Discontinuation of further study intervention development. 
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10.1.10 Publication Policy  
 The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 8 will be performed by the central laboratory.  
 Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
 Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 8 - Protocol-required laboratory assessments  
Laboratory 
assessments 
 
Parameters 
Hematology 
Platelet count  
Red blood cell 
(RBC) count 
Hemoglobin 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
Creatinine 
Potassium 
AST 
Total bilirubin (if values above the normal 
range, differentiation in conjugated and 
non-conjugated bilirubin) 
 
Albumin 
Sodium 
ALT 
Estimated GFR (MDRD formula) 
 
 
 
Alkaline 
phosphatase 
 
Efficacy laboratory 
HbA1c  
Glucose fasting  
 
Anti-insulin aspart  
Anti-insulin aspart antibodies; if positive, titer, cross-reactivity to human insulin, and neutralizing capacity 
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Laboratory 
assessments 
 
Parameters 
Other screening 
tests 
 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing potential 
only) 
 
Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential) at Screening 
 
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 pregnancyb  
 
C-peptide 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 10.5. All events of ALT >3 × upper limit of normal (ULN) and bilirubin >2 × ULN (>35% direct bilirubin) or ALT >3 × ULN 
and international normalized ratio (INR) >1.5, if INR measured which may indicate severe liver injury (possible Hy’s Law) must be reported 
as an SAE 
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
ALT: alanine aminotransferase; AST: aspartate aminotransferase; GFR: glomerular filtration rate; HbA1c: glycated hemoglobin A1c; 
hCG: human chorionic gonadotropin; IEC: Independent Ethics Committee; INR: international normalized ratio; IRB: Institutional Review 
Board; MDRD: modification of diet in renal disease; ULN: upper limit of the normal; RBC: red blood cells; WBC: white blood cells. 
Investigators must document their review of each laboratory safety report. 
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, electrocardiogram [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), ie: 
- 
Symptomatic, and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP/NIMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
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 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.  
 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. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death. 
b) Is life-threatening. 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
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c) Requires inpatient hospitalization or prolongation of existing hospitalization. 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity. 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions, 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect. 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
Examples of such events include: 
- 
Invasive or malignant cancers, intensive treatment in an emergency room or at home 
for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse, 
- 
Laboratory results that may indicate severe liver injury (possible Hy’s Law, 
see Table 8). 
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. 
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 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 AE/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. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
 Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
 Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
 The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 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 Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 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 makes an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor 
representative. 
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 The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
 The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor 
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 make every effort to provide the Sponsor representative 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 data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAEs 
SAE reporting to the Sponsor representative via an electronic data collection tool 
 The primary mechanism for reporting an SAE 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 data collection tool. 
 The site will enter the SAE 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 from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form or to the Sponsor 
representative by telephone. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal. 
2. Female with 1 of the following: 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy. 
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female. 
- 
A postmenopausal state is defined as no menses for at least 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in women not 
using hormonal contraception or hormonal replacement therapy (HRT). However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient,  
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE 
Female participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 9. 
In addition, WOCBP must refrain from donating ova for the duration of the study and for 5 weeks 
after the last dose of study intervention. 
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Table 9 - Contraceptives allowed during the study  
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that are user dependent Failure rate of <1% per year when used 
consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationc  
 
Oral  
 
Intravaginal  
 
Transdermal 
 
Injectable 
Progestogen only hormonal contraception associated with inhibition of ovulationc 
 
Oral 
 
Injectable 
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. 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used 
consistently and correctly. 
 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
 
Intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS)b 
 
Bilateral tubal occlusion 
 
Vasectomized partner  
(Vasectomized partner is a highly effective contraception method provided that the partner is the sole 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. Spermatogenesis cycle is approximately 90 days.) 
Acceptable methodsd 
 
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action 
 
Male or female condom with or without spermicidee 
 
Cervical cap, diaphragm, or sponge with spermicide 
 
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods)c 
NOTES:  
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates may differ from those when used consistently 
and correctly.   
c Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with Clinical Trial Facilitation Group 
(CTFG) guidelines, acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
d Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. 
e Male condom and female condom should not be used together (due to risk of failure with friction). 
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PREGNANCY TESTING: 
 WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive serum pregnancy test. 
 Additional pregnancy testing during the intervention period as presented in the SoA 
(see Section 1.3) and as required locally. 
 Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.  
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
 The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
 After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
 The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
 Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention or be withdrawn from the study. 
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10.5 
APPENDIX 5: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS   
INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.   In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. 
The algorithm does not apply to the instances of increase in ALT during screening. 
 
See Section 10.3 for guidance on safety reporting. 
 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
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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. 
10.8 
APPENDIX 8: ABBREVIATIONS  
 
AE: 
adverse event 
AESI: 
adverse event of special interest, adverse event of special interest 
AIA: 
anti-insulin aspart antibody 
ALT: 
alanine aminotransferase 
ARAC: 
Allergic Reaction Adjudication Committee 
AST: 
aspartate aminotransferase 
AUC: 
area under the concentration curve 
BID: 
twice daily 
BMI: 
body-mass index, body-mass index 
BP: 
blood pressure 
CFR: 
Code of Federal Regulations 
CGM: 
continuous glucose monitoring 
CI: 
confidence interval 
CIOMS: 
Council for International Organizations of Medical Sciences 
Cmax: 
maximum concentration 
CONSORT: 
Consolidated Standards of Reporting Trials 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
EOT: 
end of treatment, end of treatment 
EU: 
European Union 
FDA: 
Food and Drug Administration 
FPG: 
fasting plasma glucose, fasting plasma glucose 
FSH: 
follicle-stimulating hormone, follicle-stimulating hormone 
GCP: 
Good Clinical Practice 
GDPR: 
Global Data Protection Regulation 
GFR: 
glomerular filtration rate 
H0: 
null hypothesis 
H1: 
alternative hypothesis 1 
HbA1c: 
glycated hemoglobin A1c 
hCG: 
human chorionic gonadotropin 
HIPAA: 
Health Insurance Portability and Accountability Act 
HR: 
heart rate 
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HRT: 
hormonal replacement therapy 
IB: 
investigator's brochure 
ICF: 
informed consent form 
ICH: 
International Conference on Harmonization 
IEC: 
Independent Ethics Committee 
IFCC: 
International Federation of Clinical Chemistry 
INR: 
international normalized ratio 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology, interactive response technology 
ITT: 
intent to treat 
IUD: 
intrauterine device 
IUS: 
intrauterine hormone-releasing device 
MDI: 
multiple dose injection 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NGSP: 
National Glycohemoglobin Standardization Program 
NIMP: 
noninvestigational medicinal product 
PD: 
pharmacodynamic(s) 
PHS: 
Public Health Service 
PK: 
Pharmacokinetic(s) 
PP: 
per protocol 
PPG: 
postprandial plasma glucose 
QD: 
once daily 
RBC: 
red blood cells 
SAE: 
serious adverse event, serious adverse event 
SAP: 
statistical analysis plan 
SC: 
subcutaneous 
SMPG: 
self-measured plasma glucose, self-measured plasma glucose 
SoA: 
schedule of activities 
SUSAR: 
suspected unexpected serious adverse reaction 
T1DM: 
type 1 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
Tmax: 
time of maximum concentration 
ULN: 
upper limit of the normal 
US: 
United States 
WBC: 
white blood cells 
WOCBP: 
woman of childbearing potential, woman of childbearing potential 
 
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10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Amendment 01 (27 February 2019) 
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The standardized meal test has been removed from this study because the Food and Drug 
Administration (FDA) noted several safety and methodological concerns associated with its 
performance, and because the standardized meal test would not add clinical value to the study. 
The study can adequately evaluate the effect of switching on pharmacodynamics (PD) parameters 
without the standardized meal test through collection of data on insulin dose over time and on the 
most clinically relevant measures of glycemia (glycated hemoglobin A1c [HbA1c] and fasting 
plasma glucose [FPG]). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis; Section 1.2 
Schema; Section1.3 Schedule of 
Activities (SoA); Section 3 Objectives 
and Endpoints; Section 3.1 
Appropriateness of Measurements; 
Section 4.1 Overall Design; Section 
8.1.3 Standardized Meal Test; 
Section 8.1.4 Fasting Plasma 
Glucose; Appendix 2 Clinical 
Laboratory Tests 
Standardized meal test has been 
removed 
Several safety and methodological concerns 
were associated with standardized meal test 
performance and the standardized meal test 
would not have added any clinical value to 
the study 
Section 1.1 Synopsis; Section1.3 
Schedule of Activities; Section 4.1 
Overall Design; Section 6.5 
Concomitant Therapy 
Add recommendations regarding the 
management of participants’ glycemia 
during the end of treatment (EOT) visit 
Additional meal-time insulin will likely be 
needed in all patients for the duration of the 
8-hour PK assessment. The listed insulins 
do not interfere with the reliability of PK 
measurements 
Section 6.5 Concomitant Therapy 
Mention that hypoglycemia will be 
managed as appropriate by administering 
carbohydrates according to the clinical 
judgement of the Investigator 
Clarification 
Section 4.3 Justification for Dose; 
Section 6.1 Study intervention(s) 
administered 
Remove mention that the dosing regimen 
will be continued after each switch as it 
was used prior to the switch 
To ensure consistency with the instruction 
that the Investigators should titrate 
SAR341402 and NovoLog according to the 
NovoLog label and their clinical judgement 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 4: Contraceptive guidance 
and collection of pregnancy 
information 
All female participants with documented 
hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy are not 
considered of childbearing potential 
Clarification 
Section 5.2 Exclusion Criteria E21; 
Section 6.5 Concomitant Therapy 
Exclusion of participants who used 
glucose lowering treatments other than 
the MDI and basal insulin regimen, as 
described in inclusion criterion I05 
(including use of insulin pump therapy) 
during the screening period 
To ensure a similar baseline in all 
participants in terms of insulin treatment 
before the start of the study treatment period 
Section 5.1 Inclusion Criteria I01 
Mention that participants must be at least 
18 years old to participate to the study 
Clarification 
Section 5.1 Inclusion Criteria I06 
Mention that participants must have 
“HbA1c less or equal to 10%” instead of 
“below 10% (inclusive)” 
Clarification 
Section 1.3 Schedule of Activities 
(SoA) 
“Documentation of insulin dose” replaced 
with “Review of insulin dose” 
Clarification that dose is documented on an 
ongoing basis but reviewed at the study 
visits 
Section 1.3 Schedule of Activities 
(SoA) 
Mention that blood samples for 
measuring fasting plasma glucose should 
be taken before IMP administration 
Clarification 
Section 6.1 Study intervention(s) 
administered 
Mention that the Lantus dose may be 
increased by more than 10% if deemed 
necessary by the Investigator 
Clarification 
Section 8.3 Adverse Events and 
Serious Adverse Events 
The following sentences were removed: 
“Note: Asymptomatic overdose has to be 
reported as a standard AE” 
“In case a participant experiences an 
event identified as a potential 
hypersensitivity reaction (an allergic 
reaction or an allergic-like reaction), this 
has to be reported as an AE and 
recorded in the eCRF on the AE page, 
selecting the “suspected allergic event” 
category; additional information is 
collected on specific eCRF forms. ” 
Asymptomatic overdose does not meet the 
definition of an AE 
 
These operational details are subject to 
change 
Appendix 3: Adverse events: 
definitions and procedures for 
recording, evaluating, follow-up, and 
reporting 
Addition of guidance on which laboratory 
abnormalities to be considered clinically 
significant 
To limit the number of queries related to 
laboratory abnormalities 
 
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11 
REFERENCES  
1. U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and 
Research (CDER), Center for Biologics Evaluation and Research (CBER); Guidance for 
Industry. Considerations in Demonstrating Interchangeability with a Reference Product. 
2019:1-23. 
2. U.S. Department of Health and Human Services, FDA, Center for Drug Evaluation and 
Research (CDER). Guidance for Industry. Applications covered by Section 505(b)(2). Draft. 
1999:1-15. 
3. US Department of Health and Human Services, FDA, CEDR. Guidance for Industry. 
Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015:1-24. 
4. US Department of Health and Human Services, FDA, CEDR. Guidance for Industry. Diabetes 
Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention. 
Contains Nonbinding Recommendations; Draft-Not for Implementation. FDA. 2008:1-34. 
5. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. 
Immunological Responses to Exogenous Insulin. Endocrine Reviews. 2007;28(6):625–52. 
6. Schernthaner G. Immunogenicity and Allergenic Potential of Animal and Human Insulins. 
Diabetes Care. 1993;16 Suppl 3:155-65. 
7. Investigator’s Brochure SAR341402, latest Edition. 
8. NovoLog(R) (insulin aspart injection 100 Units/mL) US Prescribing information 12/2018. 
9. NGSP. HbA1c and Estimated Average Glucose (eAG) [Online]. [cited 2017 May 30]. 
Available from: URL:http://www.ngsp.org/A1ceAG.asp. 
10. American Diabetes Association. Standards of Medical Care in Diabetes-2017. Diabetes Care. 
2017;40(Suppl 1):11-56. 
11. American Diabetes Association Workgroup on Hypoglycemia. Defining and Reporting 
Hypoglycemia in Diabetes, Diabetes Care.2005;28(5):1245-9. 
12. 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(5):1384-95. 
13. International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L 
(54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 
2017;40(1):155-7. 
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Page 81 
14. Lindholm A, Jensen LB, Home PD, Raskin P, Boehm BO, Rastam J. Immune Responses to 
Insulin Aspart and Biphasic Insulin Aspart in People With Type 1 and Type 2 Diabetes. 
Diabetes Care. 2002;25(5):876-82. 
15. Uhr JF, Finkelstein MS. The kinetics of antibody formation. Prog Allergy. 1967;10:37-83. 
16. Ogra PL, Kerr-Grant D, Umana G, Dzierba J, Weintraub D. Antibody response in serum and 
nasopharynx after naturally acquired and vaccine-induced infection with rubella virus. NEJM. 
1971;285(24):1333-9. 
17. Ogra PL, Karzon DT, Righthand F, MacGillivray M. Immunoglobulin response in serum and 
secretions after immunisation with live and inactivated poliovaccicne and natural infection. 
NEJM. 1968;279(17):893-900. 
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
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: QSD-002643 VERSION 7.0 (20-FEB-2019) 
STATISTICAL ANALYSIS PLAN 
Randomized, Open label, Parallel-group Study Comparing the Pharmacokinetics 
and Immunogenicity of Alternating Use of SAR341402 and NovoLog® versus 
Continuous Use of NovoLog in Participants with Type 1 Diabetes Mellitus also 
Using Insulin Glargine 
SAR341402-EFC15178 
NCT identifier: NCT03874715
STATISTICIAN: 
 
Statistical Project Leader: 
 
DATE OF ISSUE: 24-Jul-2020 
Total number of pages: 
58 
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Statistical Analysis Plan  
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Version number: 2 
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Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 7 
1.2.3 
Tertiary/exploratory objectives ......................................................................................................... 7 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 9 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 13 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 13 
2.1.1 
Demographic and baseline characteristics .................................................................................... 13 
2.1.2 
Prior or concomitant medications ................................................................................................... 14 
2.1.3 
Pharmacokinetic endpoints ............................................................................................................ 15 
2.1.3.1 
Primary pharmacokinetic endpoints ............................................................................................... 15 
2.1.3.2 
Secondary pharmacokinetic endpoints .......................................................................................... 15 
2.1.4 
Immunogenicity variables .............................................................................................................. 15 
2.1.5 
Safety endpoints ............................................................................................................................ 17 
2.1.5.1 
Hypoglycemia ................................................................................................................................. 18 
2.1.5.2 
Adverse events variables ............................................................................................................... 19 
2.1.5.3 
Deaths ............................................................................................................................................ 20 
2.1.5.4 
Laboratory safety variables ............................................................................................................ 21 
2.1.5.5 
Vital signs variables ....................................................................................................................... 21 
2.1.5.6 
Electrocardiogram variables .......................................................................................................... 21 
2.1.6 
Efficacy endpoints .......................................................................................................................... 21 
2.1.7 
Pharmacodynamic/genomics endpoints ........................................................................................ 22 
2.1.8 
Quality-of-life endpoints ................................................................................................................. 22 
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2.1.9 
Health economic endpoints ............................................................................................................ 22 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 22 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 24 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 25 
2.3.1 
Pharmacokinetic population ........................................................................................................... 25 
2.3.2 
Safety population ........................................................................................................................... 25 
2.3.3 
Anti-insulin antibody population ..................................................................................................... 26 
2.3.4 
Efficacy population ......................................................................................................................... 26 
2.3.4.1 
Intent–to-treat population ............................................................................................................... 26 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 26 
2.4.2 
Prior or concomitant medications ................................................................................................... 27 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 27 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 27 
2.4.3.2 
Compliance .................................................................................................................................... 30 
2.4.4 
Analyses of pharmacokinetic endpoints......................................................................................... 30 
2.4.4.1 
Analyses of primary pharmacokinetic endpoints ........................................................................... 30 
2.4.4.2 
Analysis of secondary pharmacokinetic endpoints ........................................................................ 31 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 31 
2.4.4.4 
PK parameters at premature end of trial ........................................................................................ 31 
2.4.5 
Analyses of safety data .................................................................................................................. 31 
2.4.5.1 
Analyses of Hypoglycemia ............................................................................................................. 32 
2.4.5.2 
Analyses of adverse events ........................................................................................................... 33 
2.4.5.3 
Deaths ............................................................................................................................................ 35 
2.4.5.4 
Analyses of laboratory variables .................................................................................................... 35 
2.4.5.5 
Analyses of vital sign variables ...................................................................................................... 36 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 36 
2.4.6 
Analyses of anti-insulin aspart antibody data ................................................................................ 37 
2.4.6.1 
Analyses of anti-insulin aspart antibody data ................................................................................ 37 
2.4.6.2 
Analyses of anti-insulin aspart neutralizing antibody data ............................................................. 39 
2.4.7 
Analyses of efficacy endpoints ....................................................................................................... 41 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 41 
2.5.1 
General conventions ...................................................................................................................... 41 
2.5.2 
Missing data ................................................................................................................................... 42 
2.5.2.1 
Handling of missing PK parameters ............................................................................................... 42 
2.5.2.2 
Handling of other missing parameters ........................................................................................... 42 
2.5.3 
Visit allocation ................................................................................................................................ 44 
2.5.4 
Unscheduled visits ......................................................................................................................... 45 
2.5.5 
Pooling of centers for statistical analyses ...................................................................................... 45 
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2.5.6 
Study-specific conventions ............................................................................................................ 45 
2.5.7 
Handling for pharmacokinetic data ................................................................................................ 46 
2.5.7.1 
Individual PK parameters ............................................................................................................... 46 
2.5.7.2 
Descriptive analyses ...................................................................................................................... 46 
2.5.8 
Statistical technical issues ............................................................................................................. 46 
3 
INTERIM ANALYSIS ..................................................................................................................... 47 
4 
DATABASE LOCK ........................................................................................................................ 48 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 49 
6 
REFERENCES ............................................................................................................................... 50 
7 
LIST OF APPENDICES ................................................................................................................. 51 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 52 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AEs: 
adverse events 
AESI: 
adverse event of special interest 
AIA: 
anti-insulin aspart antibodies  
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferases 
ARAC: 
Allergic Reaction Assessment Committe 
ATC: 
anatomical therapeutic chemical 
BMI: 
body mass index 
CMQ: 
customized MedDRA queries 
COVID-19: 
coronavirus disease 2019 
CV: 
coefficient of variance 
DBP: 
diastolic blood pressure 
EOS: 
end of study 
EOT: 
end of treatment 
GFR: 
glomerular filtration rate 
HbA1c: 
Glycated hemoglobin 
HLGT: 
high level group term 
HLT: 
high level term 
IMP: 
investigational medicinal product 
IRT: 
Interactive response technology 
ITT: 
intent-to-treat 
KM: 
Kaplan-Meier 
LLOQ: 
lower limit of quantification 
LPLV: 
last patient last visit 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NAb: 
neutralizing antibody 
NIMP: 
non-investigational medicinal product 
PCSA: 
Potentially clinically significant abnormality 
PEOT: 
premature end of trial 
PT: 
preferred term 
RBC: 
red blood cell 
SAEs: 
serious adverse events 
SBP: 
systolic blood pressure 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
T1DM: 
type 1 diabetes mellitus 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
This Statistical Analysis Plan (SAP) provides a comprehensive and detailed description of 
strategy and statistical technique to be used to realize the analysis of data for study SAR341402 
/EFC15178. 
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a randomized, open-label, active-controlled, 2-arm parallel-group multicenter Phase 3 trial 
comparing alternating use of SAR341402 solution for injection (100 U/mL) and NovoLog® 
(100 U/mL) versus continuous use of NovoLog in adults with type 1 diabetes mellitus (T1DM) 
also using insulin glargine (100 U/mL). 
Participants with T1DM diagnosed for at least 12 months before screening, and who have been on 
a multiple daily injection regimen using NovoLog as mealtime insulin and insulin glargine 
100 U/mL (Lantus®) as basal insulin for at least 12 weeks prior to screening, are eligible for the 
study. Patients who are not on NovoLog and insulin glargine (100 U/mL) for at least 12 weeks 
before screening are included in a run-in period of up to 12 weeks during which they are 
administered NovoLog and Lantus. 
Patients are centrally randomized via Interactive Response Technology (IRT) (using permuted 
random block randomization schedule) in a 1:1 ratio to one of the following treatment groups: 
• 4x4-week periods alternating use of SAR341402 and NovoLog (starting with NovoLog 
in the first treatment period and receiving SAR341402 during the last of the 4 treatment 
periods, “switching arm”) or  
• 16 weeks continuous use of NovoLog (“non-switching arm”); see study design in 
Section 1.4. 
Insulin glargine 100 U/mL (Lantus) is to be administered as mandatory background therapy 
throughout the treatment period of the study and during the run-in period if applicable, and is 
considered as non-investigational medicinal product (NIMP). NovoLog is also considered as 
NIMP during the run-in period, if applicable. 
Approximately 184 patients were planned to be randomized at approximately 33 sites in the US. 
Randomization is being stratified by glycated hemoglobin (HbA1c) (<8.0%, ≥8.0%) measurement 
obtained at the screening visit (Visit 1).  
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1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate similarity in pharmacokinetics (PK) of 
SAR341402 and NovoLog after 4x4-week periods of alternating administration of SAR341402 
and NovoLog compared to 16-week continuous use of NovoLog in participants with T1DM also 
using insulin glargine (100 U/mL). 
1.2.2 Secondary objectives 
The secondary objectives of this study are: 
• To compare the effects of alternating administration of SAR341402 and NovoLog with 
continuous use of NovoLog on immunogenicity 
• To evaluate the safety of alternating administration of SAR341402 and NovoLog versus 
continuous use of NovoLog 
• To compare other PK parameters between the two treatment arms (alternating 
administration of SAR341402 and NovoLog and continuous use of NovoLog)  
1.2.3 Tertiary/exploratory objectives 
The tertiary/exploratory objectives of this study are: 
• To compare the effects of alternating administration of SAR341402 and NovoLog with 
continuous use of NovoLog on insulin dose 
• To compare the effects of alternating administration of SAR341402 and NovoLog with 
continuous use of NovoLog on glycemic control 
• To compare clinical effects of treatment-emergent AIAs (anti-insulin aspart antibodies) on 
glycemic control, insulin dose and safety 
• To compare the effects of alternating administration of SAR341402 and NovoLog with 
continuous use of NovoLog on additional immunogenicity parameters 
• To compare clinical effects of treatment-emergent neutralizing antibodies on glycemic 
control and insulin dose 
1.3 
DETERMINATION OF SAMPLE SIZE 
Approximately 184 participants are planned to be randomly assigned to either one of the 
following treatment groups: alternating use of SAR341402 and NovoLog or continuous use of 
NovoLog (in a 1:1 ratio), with a minimum of 146 evaluable participants (73 per treatment group) 
for the primary PK evaluation expected at the end of the study. If the number of study participants 
with evaluable PK data is determined to have been reached before all planned 184 participants are 
randomized, then the study randomization may be stopped sooner. 
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The sample size calculations were performed based on the expected variability of the primary PK 
endpoints AUClast, AUC, and Cmax following injection of a predefined, fixed dose of SAR341402 
or NovoLog (ie, 0.15 U/kg) at Week 16. 
A sample size of 146 evaluable participants (73 participants per arm) will ensure that the 90% CI 
for the estimated treatment ratio is within the acceptance range of [0.8 – 1.25] with at least 90% 
power; assuming a true ratio between 0.95 and 1.05 (switching arm / non-switching arm) and a 
total standard deviation on natural log scale of 0.35 or lower. 
Sample size calculations were made using SAS® Software Version 9.4.  
1.4 
STUDY PLAN 
The following figure describes the design of the study: 
 
FPG: fasting plasma glucose; HbA1c: glycated hemoglobin A1c; PK: pharmacokinetics; T1DM: Type 1 diabetes mellitus; * prior to the screening visit 
The study comprises up to 4 periods: 
• An up to 14-day screening period 
• An up to 12-week run-in period (only for patients not treated with NovoLog and insulin 
glargine (100 U/mL) for at least 12 weeks before screening) 
• A 16-week open-label treatment period: 
- 
Participants in the non-switching arm will receive NovoLog for 16 weeks, 
- 
Participants in the switching arm will receive NovoLog for the first 4 weeks, then 
SAR341402 for 4 weeks, followed by NovoLog for 4 weeks and then SAR341402 for 
the last 4 weeks. 
• A 1-day post-treatment follow-up period. 
The study duration per participant will be less than 19 weeks (for participants who do not require 
the run-in period) and less than 31 weeks (for participants who require the run-in period). 
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At the end of the 16-week open-label treatment period, patients will have blood sampling, 
including for PK determination, antibody measurements, HbA1c, and FPG. After blood sampling 
for the trough PK measurements, patients will receive a single SC injection of 0.15 U/kg 
SAR341402 (switching arm) or NovoLog (non-switching arm). Subsequently, PK sampling will 
be conducted for 8 hours according to assessment schedule; see pharmacokinetic flow chart in 
Section 1.3 of the protocol. 
The end of treatment (EOT) is at Visit 7 (Week 16) after randomization. The end of the study 
(EOS) is a follow-up contact (Visit 8, recorded as Visit 8010 in the clinical database) at the time 
of Week 16 plus 1 day. 
In case of premature permanent investigational medicinal product (IMP) discontinuation, the 
patients will have a premature treatment discontinuation visit (recorded as Visit 8000 in the 
clinical database), which will consist of all procedures planned for Visit 7 and is intended to be 
conducted before the definitive discontinuation of the IMP, or as soon as possible after 
discontinuation.  
Patients who discontinue study intervention should remain in the study, with the remaining visits 
occurring as scheduled where possible, including the assessments planned in the SoA (see 
Section 1.3 of the protocol) except serial PK samples that should only be collected at the time of 
early discontinuation visit and do not need to be repeated at Visit 7 (Week 16).  
 
• During the period of the COVID-19  (Coronavirus disease 2019) pandemic, protocol 
deviations may occur due to lockdown restrictions. On-site visits may not be performed 
according to the protocol schedule for some patients. In such cases, changes in study visit 
schedule are allowed as needed, to accommodate patient’s safe access to study sites and 
study medication while minimizing risks to trial integrity and data collection:Intermediary 
on-site visits (Visits 5 and 6) may be replaced by over-the-phone or at-home visits, if 
feasible.  
• The end of treatment visit (Visit 7), which is the most critical one for primary endpoint 
assessment, may be delayed so that the visit can be conducted on-site while preserving the 
patient’s safety. 
Consequently, the open-label treatment period and study duration may be extended by up to 
approximately 8 weeks, and the assessments collected at “Week 16” visit may be performed up to 
approximately 24 weeks after randomization. All delayed assessments will be included in the 
analyses. No risk is foreseen by continuing treatment with IMP beyond the planned 16 weeks in 
both treatment arms. These changes are temporary and will not be sustained once the pandemic is 
over. Any delayed assessments will be recorded in the protocol deviations. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after study start (after the first patient was enrolled). 
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The protocol history table below gives the timing, rationale, and key details of major changes to 
the protocol statistical section. 
The first patient was randomized on 19-March-2019. There are no planned interim analyses. 
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
1 
27-Feb 2019 
Removal of the standardized 
meal test  
Remove the 2 endpoints :  
Change from baseline to Week 16 in the 30-minute, 
1-hour and 2 hour postprandial plasma glucose 
(PPG) during the standardized meal test 
 
Change from baseline to Week 16 in plasma 
glucose excursion (30-minute, 1-hour and 2-hour 
PPG minus preprandial plasma glucose) during the 
standardized meal test 
Keep the endpoint “Change from baseline to Week 
16 in FPG” as an independent tertiary endpoint. 
 
 
2 
13-Aug-2019 
Change in sample size 
If the planned number of study participants with 
evaluable PK data can be assumed to be reached 
before all planned 184 participants are randomized, 
then the study randomization may be stopped 
sooner. 
 
 
 
Simplification of the secondary 
PK endpoint analysis  
Remove the Hodges-Lehmann estimate with 90% 
CI for the shift in location between treatment groups 
for Tmax. 
 
 
 
 
 
 
Change of the “secondary” and 
“tertiary/exploratory” status for 
immunogenicity endpoints  
 
Secondary immunogenicity endpoint replaced by the 
evaluation of the number of participants with 
treatment-emergent anti-Insulin aspart antibody 
(AIA) during the 16-week treatment period. The 
number of participants by anti-Insulin aspart 
antibody (AIA) status (positive/negative) at baseline, 
Week 8, Week 12 and Week 16 becomes a 
tertiary/exploratory immunogenicity endpoint.  
For descriptive purpose, the difference between the 
switching arm and the non-switching arm in the 
percentage of participants with treatment-emergent 
AIAs (AIA incidence) will be provided with 
associated 2-sided 90% CI. Results will be obtained 
by fitting a binomial regression model with an 
identity-link function. The model will include fixed 
categorical effects for the treatment group and 
randomization strata. The risks within each 
treatment group and risk difference will be provided 
with their 90% CI using the adjusted least squares 
mean estimates of the treatment effect. 
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Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
 
 
 
 
 
 
Addition of a tertiary/ 
exploratory immunogenicity 
objective and endpoint 
Add the new objective “To compare clinical effects 
of treatment-emergent neutralizing antibodies on 
glycemic control and insulin dose” and the new 
endpoint “Clinical effects of anti-insulin aspart 
neutralizing antibodies on efficacy (HbA1c) and 
insulin dose” 
 
 
 
 
 
 
Simplification of the description 
of the secondary safety 
endpoint related to adverse 
events 
 
Remove the sentence : “All AEs will be coded to a 
"LLT", “PT”, "HLT", “HLGT” and primary “SOC” 
using the version of MedDRA currently in use by the 
sponsor at the time of database lock”, as these 
details are provided in the SAP. 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
The statistical analysis plan history table below gives the timing, rationale, and key details for 
major changes to the statistical analysis features in the statistical analysis plan and/or protocol. 
Changes listed under SAP Version 2 are additional analyses not defined in the protocol and/or 
protocol amendments at the time of that SAP version. 
Table 2 - Statistical analysis plan Statistical changes 
SAP Version 
Number 
Date 
Approved 
Rationale 
Description of Statistical Changes 
2.0 
7-Jul-2020 
 
 
 
 
 
 
 
 
 
 
Addition of COVID-19 related analyses 
Update of the disposition section to include the 
treatment/study discontinuations related to COVID-
19. 
Add a table of patient disposition by visit according 
to COVID-19 impact. 
Add the definition of patients impacted by COVID-
19, a table of the number of patients impacted or 
not by the COVID-19, along with the type of impact, 
and a listing of patients impacted. 
Add a table of major or critical protocol deviations 
by COVID-19 impact. 
Update the categories in the extent of IMP 
exposure table. Add an extent of IMP exposure 
table and IMP exposure tables by COVID-19 
impact (Non-impacted, Impacted) 
Add table of the number (%) of patients 
experiencing at least one treatment-emergent 
COVID-19 related adverse event by primary SOC 
and PT 
Add immunogenicity, safety and efficacy subgroup 
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SAP Version 
Number 
Date 
Approved 
Rationale 
Description of Statistical Changes 
analyses by COVID-19 impact (Non-impacted, 
Impacted). 
2.0 
7-Jul-2020 
 
Addition of PK sensitivity analyses 
Add PK sensitivity analyses 
 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value for safety variables will be the last available value prior to the first injection of 
IMP. For patients randomized and not treated, the baseline value is defined as the last available 
value obtained up to the date and time of randomization. 
The baseline value for efficacy variables is defined as the last available value before or on the day 
of randomization, and before the time of first IMP injection if on the day of randomization.  
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the summary statistics in the safety and efficacy sections (Section 2.4.5 and Section 2.4.6). 
Demographic characteristics 
• 
Age (years) (as reported in the e-CRF), 
• 
Age group (<65, ≥65 to <75, ≥75 years of age) 
• 
Sex (Male, Female) 
• 
Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Islander, More than One Race, Unknown, Not reported), 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown, Not Reported),  
• 
Country (US), 
• 
Baseline weight (kg), 
• 
Baseline body mass index (kg/m², calculated in the e-CRF), 
• 
Baseline BMI by categories (<25, ≥25 to <30, ≥30 kg/m²),  
• 
Baseline estimated glomerular filtration rate (GFR, modification of diet in renal disease 
[MDRD] formula, mL/min/1.73m²), 
• 
Baseline estimated GFR categories (≥90, ≥ 60 to <90, ≥30 to <60, <30 mL/min/1.73m²), 
• 
Randomization stratum of screening HbA1c categories (<8%, ≥8%) 
Medical or surgical history 
Medical or surgical history at baseline will be coded to a “preferred term (PT)”, “high level term 
(HLT)”, “high level group term (HLGT)”, and associated primary “system organ class (SOC)” 
using the version of Medical Dictionary for Regulatory Activities (MedDRA) currently in effect 
at Sanofi at the time of database lock. 
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Medical history of allergy and subject family history of allergy will also be recorded using 
summary tables. 
Disease characteristics at baseline  
• Fasting C-peptides (nmol/L) (values below the Lower Limit Of Quantitation (LLOQ) are 
imputed to the LLOQ/2), 
• Fasting C-peptides (<0.023, ≥0.023 to <0.42, ≥0.42 nmol/L)  
• Duration of type 1 diabetes (years), 
• Duration of type 1 diabetes (<10, ≥10 years), 
• Age (years) at onset of type 1 diabetes, 
• Duration of basal insulin treatment (years), 
• Duration of mealtime insulin treatment (years), 
• Previous basal insulin treatment: 
- 
Type (insulin glargine (100U/mL)), 
- 
Duration (years), 
• Previous mealtime insulin treatment:  
- 
Type (NovoLog), 
- 
Duration (years), 
• Diabetic complications at baseline: 
- 
Diabetic retinopathy (Yes, No, Unknown), including type (proliferative/non-
proliferative), 
- 
Diabetic neuropathy (Yes, No, Unknown), 
- 
Diabetic nephropathy (Yes, No, Unknown), 
• Family history of diabetes (Yes, No), 
• History of gestational diabetes for female (Yes, No). 
A listing of patients with fasting C-peptide ≥0.42 nmol/L at baseline will also be provided. 
Any technical details related to computation, dates, and imputations for missing data are described 
in Section 2.5.1. 
2.1.2 Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those reported on the CRF (as per CRF completion instructions, it 
corresponds to the medications taken within 3 months before screening visit date) and 
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taken before the day of first IMP intake (excluded) for the non-antidiabetic medications or 
up to the day of first IMP (included) for the antidiabetic medications. Prior medications 
can be discontinued before first administration or can be ongoing during treatment phase.  
• Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, defined as follows: 
- 
For non-antidiabetic medications: any treatments received from first injection of IMP 
(included) to the last injection of IMP +1 day (included).  
- 
For antidiabetic medications: any treatments received from the first injection of IMP + 
1 day (included) to the day before the last injection of IMP (included).  
- 
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 
post-treatment period (as defined in the observation period in Section 2.1.5).  
• Post-treatment medications are defined as follows: 
- 
For non-antidiabetic medications: medications taken in the period running from the 
last injection of IMP + 2 days (included) to the end of the study.  
- 
For antidiabetic medications: medications taken in the period running from the day of 
last injection of IMP (included) to the end of the study. 
Anti-diabetic medications will be identified by a list of anatomical therapeutic chemical (ATC) 
codes. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5.  
2.1.3 Pharmacokinetic endpoints 
2.1.3.1 Primary pharmacokinetic endpoints 
The primary pharmacokinetic variables are the AUClast, AUC, and Cmax parameters following 
injection of a predefined, fixed dose of SAR341402 or NovoLog (0.15 U/kg) at Week 16. Further 
details for the derivation of PK parameters are given in Section 2.5.7.1. Secondary 
pharmacokinetic endpoint. 
 
2.1.3.2 Secondary pharmacokinetic endpoints 
 
The secondary pharmacokinetic variable is tmax which is the time to reach Cmax following 
injection of a predefined, fixed dose of SAR341402 or NovoLog (0.15 U/kg) at Week 16. 
2.1.4 Immunogenicity variables  
As per protocol, only the number of patients with treatment-emergent anti-insulin aspart 
antibodies (AIA) during the 16-week treatment period is secondary. All other immunogenicity 
endpoints are tertiary/exploratory. 
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If a patient discontinues the treatment prematurely, the process described in Section 2.5.1 will 
be applied to retrieve immunogenicity assessments performed at the end of treatment visit 
(Visit 8000). 
AIA measurements will be performed in a blinded fashion at a central laboratory (see study 
flowchart in Section 1.3 of the protocol) using a validated anti-insulin aspart antibody binding 
assay methodology. Only AIA results from samples collected during the on-treatment period and 
at least 8 hours after the last administration of mealtime insulin will be taken into account in the 
analysis. 
Anti-insulin aspart antibodies evaluation will consist of: 
• Anti-SAR341402/ NovoLog antibody positive/negative status 
• Anti-SAR341402/ NovoLog antibody titer  
• Cross-reactivity to human insulin positive/negative status 
The following definitions will be used to identify patients with a change in AIA response during 
the on-treatment period (see Section 2.1.4) (1) : 
• 
Patients with treatment-induced AIAs will be defined as patients with AIAs that 
developed de novo (seroconversion) following the IMP administration (ie, patients with at 
least one positive AIA sample at any time during the on-treatment period, in those patients 
without pre-existing AIA or with missing sample at baseline).  
• 
Patients with treatment-boosted AIAs will be defined as patients AIA positive at 
baseline that were boosted to a significant higher titer following the IMP administration 
(ie, patients with at least one AIA sample with at least a 4-fold increase in titers compared 
to baseline value at any time during the on-treatment period, in those patients with 
preexisting AIA). The 4-fold increase in titer corresponds to an increase of two dilution 
steps within the titration experiment. A single dilution difference (2-fold titer increase) is 
within the expected imprecision of the titration method and is therefore not considered a 
relevant change. 
Patients with treatment-emergent AIA (Yes, No, Inconclusive) will be derived as follows: 
• 
Patients with treatment-emergent AIAs (AIA incidence) will be defined as patients with 
treatment-induced or treatment-boosted AIAs. 
• 
Patients without treatment-emergent AIAs will be defined as patients without treatment 
induced or treatment-boosted AIAs. 
• 
Inconclusive patients will be defined as patients who cannot irrefutably be classified as 
patients without treatment-emergent AIAs. Inconclusive patients will not be included in 
the above categories and will be listed separately. 
The peak titer will be defined as the maximal titer observed during the on-treatment period.  
Anti-insulin aspart neutralizing antibody status (positive/negative) of confirmed AIA positive 
samples will also be part of the immunogenicity analyses, as tertiary/exploratory endpoint. 
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Anti-insulin aspart neutralizing antibody (NAb) status (positive/negative) and NAb titers of 
confirmed AIA positive samples will also be part of the immunogenicity analyses, as 
tertiary/exploratory endpoints. A patient with an AIA-negative sample at a given visit (thus not 
tested for NAbs) will be considered as NAb-negative for this visit. 
The following definitions will be used to identify patients with a change in NAb response during 
the on-treatment period (see Section 2.1.4) (2): 
• 
Patients with treatment-induced NAbs will be defined as patients with NAbs that 
developed de novo (seroconversion) following the IMP administration (ie, patients with at 
least one positive NAb sample at any time during the on-treatment period, in those patients 
without pre-existing NAb or with missing sample at baseline). 
• 
Patients with treatment-boosted NAbs will be defined as patients NAb positive at 
baseline that were boosted to a significant higher NAb titer following the IMP 
administration (ie, patients with at least one NAb sample with at least a 4-fold increase in 
NAb titers compared to baseline value at any time during the on-treatment period, in those 
patients with preexisting NAb). The 4-fold increase in NAb titer corresponds to an 
increase of two dilution steps within the titration experiment. A single dilution difference 
(2-fold titer increase) is within the expected imprecision of the titration method and is 
therefore not considered a relevant change. 
Patients with treatment-emergent NAbs (Yes, No, Inconclusive) will be derived as follows: 
• 
Patients with treatment-emergent NAbs (NAb incidence) will be defined as patients with 
treatment-induced or treatment-boosted NAbs. 
• 
Patients without treatment-emergent NAbs will be defined as patients without treatment-
induced or treatment-boosted NAbs. 
• 
Inconclusive patients will be defined as patients who cannot irrefutably be classified as 
patients without treatment-emergent NAbs. Inconclusive patients will not be included in 
the above categories and will be listed separately. 
The peak NAb titer will be defined as the maximal NAb titer observed during the on-treatment 
period. 
2.1.5 Safety endpoints 
The following safety endpoints are secondary and will be derived based on the following safety 
assessments collected during the 16-week treatment period: 
• Hypoglycemia (according to ADA Workgroup on Hypoglycemia) (3)(4)(5), 
• Adverse events (AEs), serious adverse events (SAEs), adverse events of special interest 
(AESIs), 
• Adverse events requiring specific monitoring (injection site reactions, hypersensitivity 
reactions), 
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The following safety parameters will also be summarized: 
• Laboratory parameters, 
• Vital signs: heart rate, systolic blood pressure (SBP) and diastolic blood pressure (DBP), 
• Body weight. 
In case of premature permanent IMP discontinuation, the process described in Section 2.5.1 will 
be applied to retrieve safety assessments performed at the premature end of treatment visit 
(Visit 8000). 
Safety observation period  
The observation period for safety data will be divided into 3 main segments: 
• The pre-treatment period is defined as the time from informed consent up to the time of 
the first injection of IMP. 
• The on-treatment period is defined as the time from the first injection of IMP up to the 
last injection of IMP + 1 day (included). 
• The post-treatment period is defined as the time from the last injection of IMP + 2 days 
(included). 
Analyses will focus on safety observations during the on-treatment period.  
The on-study observation period is defined as the time from first injection of IMP until the end 
of the study (defined as the date of end of participation). 
2.1.5.1 Hypoglycemia 
All hypoglycemia will be reported by the patient in the e-diary, transferred to the dedicated 
hypoglycemia event page in the e-CRF and reviewed by the investigator, or directly completed in 
other dedicated hypoglycemia event pages in the e-CRF by the investigator. For the analyses, the 
investigator items will be used when available.  
All hypoglycemia will be categorized according to the ADA definitions (3)(4)(5) as described 
below: 
• Severe hypoglycemia: Severe hypoglycemia will be derived as an event requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other 
resuscitative actions (response “Required assistance because subject was not capable of 
helping self” to the question “Assistance Required?” in the e-CRF).  
• Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia will 
be derived as an event with symptoms of hypoglycemia and with a measured plasma 
glucose concentration less than or equal to 3.9 mmol/L (70 mg/dL). 
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• Asymptomatic hypoglycemia: Asymptomatic hypoglycemia will be derived as an event 
without 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 will be 
derived as an event with symptoms of hypoglycemia and missing plasma glucose 
concentration. 
• Relative hypoglycemia: Relative hypoglycemia (also termed “pseudo-hypoglycemia”) 
will be derived as an event with symptoms of hypoglycemia but with a measured plasma 
glucose concentration greater than 3.9 mmol/L (70 mg/dL).  
Hypoglycemia not classified in one of the above categories will be presented separately as non-
classified hypoglycemia. Any technical details to categorize hypoglycemia in case of missing 
hypoglycemia information are described in Section 2.5.1.  
In addition to the threshold of plasma glucose of less than or equal to 3.9 mmol/L (70 mg/dL), 
documented symptomatic hypoglycemia and asymptomatic hypoglycemia with a measured 
plasma glucose concentration less than 3.0 mmol/L (54 mg/dL) will also be described.  
Hypoglycemia observation period  
• Pre-treatment hypoglycemia are events that occurred during the pre-treatment period. 
• Treatment-emergent hypoglycemia are events that occurred during the on-treatment period 
(see Section 2.1.5). 
• Post-treatment hypoglycemia are events that occurred during the post-treatment period. 
2.1.5.2 Adverse events variables 
All AEs (including serious adverse events [SAEs], adverse events of special interest [AESI] and 
adverse events requiring specific monitoring) will be coded to a PT, HLT, HLGT and associated 
primary SOC using the version of MedDRA currently in effect at the sponsor at the time of 
database lock. 
Adverse event observation period  
The AE observations will be classified per the observation periods of safety data as defined in 
Section 2.1.5 :  
• Pre-treatment AEs are AEs that developed or worsened or became serious during the pre-
treatment period. 
• Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became 
serious during the on-treatment period. 
• Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
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Adverse events requiring specific monitoring 
The AEs requiring specific monitoring for this study are as follows:  
• Injection site reactions: any sign related to local non-allergic reactions at the IMP/NIMP 
injection site. 
• Hypersensitivity reactions: allergic reactions or possible allergic reactions. 
Hypersensitivity reactions will be adjudicated by the Allergic Reaction Assessment 
Committee (ARAC).  
For the statistical analysis, injection site and hypersensitivity reactions will be identified based on 
the AE forms (also based on ARAC diagnosis in order not to miss any event), using the following 
MedDRA codes: 
• Injection site reactions will be identified using the following MedDRA searches: under 
HLGT “Administration site reactions” and HLTs “Administration site reactions NEC”, 
“Injection site reactions”, “Infusion site reactions” and “Application and instillation site 
reactions” and excluding HLTs “Implant and catheter site reactions” and “Vaccination site 
reactions”. 
• Hypersensitivity reactions will be identified using the following MedDRA searches: 
Angioedema standardized MedDRA query (SMQ) [Narrow], Severe cutaneous adverse 
reactions SMQ [Broad], Hypersensitivity SMQ [Broad and Narrow] and excluding PTs 
related to administration, application, injection and infusion sites. HLT “Anaphylactic 
Responses” are included in those SMQs. 
Adverse events of special interest  
Adverse events of special interest (AESI) include: 
• Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP, 
• Symptomatic overdose (serious or non-serious) with IMP/NIMP,  
• Increase in alanine aminotransferases (ALT) > 3 x ULN. 
 These events will be identified through the AESI category in the adverse event page of the CRF. 
2.1.5.3 Deaths 
The deaths observation period are per the observation periods defined above.  
• Death on-study: deaths occurring during the on-study observation period 
• Death on-treatment: deaths occurring during the on-treatment period  
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2.1.5.4 Laboratory safety variables 
Clinical laboratory data consists of blood analysis, including hematology and clinical chemistry. 
Clinical laboratory values after conversion will be analyzed into standard international units and 
international units will be used in all listings and tables. Results will also be presented in 
conventional units. 
Only laboratory data collected according to the protocol (see study flowchart in Section 1.3 of 
the protocol) will be analyzed. The laboratory parameters will be classified as follows: 
• Hematology: 
- 
Red blood cells and platelets including hemoglobin, hematocrit, red blood cell count 
and platelet count, 
- 
White blood cells including white blood cell count, neutrophils, lymphocytes, 
monocytes, basophils and eosinophils. 
• Clinical chemistry: 
- 
Metabolism : albumin, 
- 
Electrolytes including sodium, potassium, 
- 
Renal function including creatinine and estimated GFR (MDRD), 
- 
Liver function including alanine aminotransferase (ALT), aspartate aminotransferases 
(AST), alkaline phosphatase (ALP) and total bilirubin (in case of values above the 
normal range, differentiation in conjugated and non-conjugated bilirubin). 
Technical formulas are described in Section 2.5.1. 
2.1.5.5 Vital signs variables 
Vital signs include heart rate (bpm), and systolic and diastolic blood pressure (mmHg) (see study 
flowchart in Section 1.3 of the protocol). 
Body weight (kg) will be presented with the vital signs. 
2.1.5.6 Electrocardiogram variables 
Not applicable 
2.1.6 Efficacy endpoints 
Efficacy endpoints are tertiary/exploratory. 
HbA1c and FPG are measured in a blinded fashion at a central laboratory, for scheduled 
(see study flowchart in Section 1.3 of the protocol) and unscheduled assessments. 
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In case of premature permanent IMP discontinuation, the process described in Section 2.5.1 will 
be applied to retrieve efficacy assessments performed at the end of treatment visit (Visit 8000). 
Efficacy observation period  
• The randomized period for efficacy variables is defined as the time from randomization 
date up to Week 16 (Visit 7), regardless of study treatment discontinuation. 
Efficacy endpoints  
All efficacy endpoints will be derived on the randomized period using the intent-to-treat (ITT) 
population. All HbA1c/FPG values will be used, regardless of adherence to treatment.  
The following efficacy endpoints will be calculated:  
• 
Change from baseline to Week 16 in HbA1c (%), defined as the HbA1c value at Week 16 
- HbA1c value at baseline. 
• 
Change from baseline to Week 16 in FPG (in mg/dL and mmol/L), defined as the FPG 
value at Week 16 - FPG value at baseline. 
2.1.7 Pharmacodynamic/genomics endpoints 
Not applicable. 
2.1.8 Quality-of-life endpoints  
Not applicable. 
2.1.9 Health economic endpoints  
Not applicable. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary tables 
• Screened patients, defined as all patients who signed the informed consent. 
• Screen failure patients and reasons for screen failure. 
• Randomized patients, as defined in Section 2.3. 
• Treated but not randomized patients. 
• Randomized and not treated patients. 
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• Randomized and treated patients, 
- 
Completed patients: Patients who completed the treatment period (as reported on the 
EOT CRF page). 
- 
Patients who did not complete the study treatment as per protocol. 
- 
Patients who discontinued the study treatment by main reason (related to COVID-19 
or not for reasons “Adverse event” and “Other”) for definitive treatment 
discontinuation. 
- 
Patient’s reason (related to COVID-19 or not for reasons “Adverse event” and 
“Other”) for permanent treatment discontinuation. 
• Patients who completed the study period (as reported on the EOS CRF page). 
- 
Patients who discontinued the study by main reason (related to COVID-19 or not for 
reason “Other”) for premature study discontinuation. 
• Status at last study contact  
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. 
Patients with the following deviations will be identified and described in separate listings: 
• Treated but not randomized patients. 
• Randomized and not treated patients. 
• Randomized but not treated as randomized. 
Kaplan-Meier (KM) plots/estimates of the cumulative incidence of IMP discontinuation due to 
any reason, or due to AE, will be provided. Time to treatment discontinuation will be defined as 
the number of days from the first dose of IMP until the day of treatment discontinuation. All 
completers will be considered as censored observations. The censoring time will be the number of 
days from the first dose of IMP until the last dosing date. 
Lists of participants who prematurely discontinued treatment and/or study will be provided with 
reasons for discontinuation, including reasons related to COVID-19. 
All critical or major protocol deviations (including randomization and drug-dispensing 
irregularities, see Section 2.2.1) will be summarized by treatment group among randomized 
patients (number and percentages). Critical or major protocol deviations will also be summarized 
according to COVID-19 impact. 
Patients impacted by COVID-19 are defined as patients with major impact of COVID-19 on study 
conduct, including premature EOT/EOS due to COVID-19 and/or critical or major protocol 
deviations related to COVID-19. The number and percentage of patients impacted or not by 
COVID-19 will presented, along with the type of impact, and a listing of participants impacted by 
COVID-19 will be provided. 
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A table of patient disposition by visit according to COVID-19 impact will also be provided, based 
on the eCRF comment page. Each impacted visit will be described according to the following 
categories:  
• Visit not done, 
• Visit partially done on site, 
• Visit partially done by phone,  
• Complete visit but delayed. 
Additionally, the analysis populations for pharmacokinetic, immunogenicity, safety and efficacy 
will be summarized in a table by patient counts on the randomized population: 
• PK population as defined in Section 2.3.1, 
• Anti-insulin aspart antibody population as defined in Section 2.3.3, 
• Safety population as defined in Section 2.3.2, 
• Efficacy population: ITT population as defined in Section 2.3.4. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program 
error.  
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than 
as randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
The major or critical randomization and drug-dispensing irregularities will be documented in the 
clinical study report. If the number of irregularities is large enough to make a tabular summary 
useful, the irregularities will be categorized and summarized among randomized patients (number 
and percentages). Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
• Kit dispensation without IRT transaction 
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• Erroneous kit dispensation 
• Randomization by error 
• Patient randomized twice 
• Stratification error 
2.3 
ANALYSIS POPULATIONS 
Patients who are dispensed study drug without calling the IRT at Visit V3 (treated but not 
randomized) or before calling the IRT are considered nonrandomized patients. They are excluded 
from any population for analysis, including safety. However, if these patients experienced any 
significant safety event, they will be documented separately in the clinical study report. 
The randomized population consists of all screened patients who have a treatment kit number 
allocated and recorded in the IRT database, regardless of whether the treatment kit was used. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
2.3.1 Pharmacokinetic population 
The pharmacokinetic population is defined as all randomized participants without deviation that 
could significantly impact the PK analysis (eg, missing or incorrect IMP injection on PK profile 
day) and for whom PK data are considered sufficient and interpretable.  
All exclusions from the PK population (before and after database lock) will be documented in the 
CSR together with their reasons. 
2.3.2 Safety population 
The safety population is defined as all randomized patients who receive at least one dose of IMP, 
analyzed according to the treatment actually received. 
In addition: 
• If a patient is dispensed IMP and is lost to follow-up without any documented evidence 
whether or not the patient took IMP, the patient will be considered exposed and included 
in the safety population. 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
• Non randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately. 
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• Randomized patients having taken at least one kit of SAR341402 will be considered in the 
switching arm. Patients randomized in the switching arm but having taken only Novolog 
as treatment will be considered in the non-switching arm. 
2.3.3 Anti-insulin antibody population 
The AIA population is defined as all patients from the safety population with at least one AIA 
sample available for analysis (ie, collected during the on-treatment period and at least 8 hours 
after the last administration of mealtime insulin). Patients will be analyzed according to the 
treatment actually received.  
2.3.4 Efficacy population 
2.3.4.1 Intent–to-treat population 
The efficacy population will be the ITT population, which includes all randomized patients, 
irrespective of compliance with the study protocol and procedures. 
Patients will be analyzed for efficacy analyses in the treatment group to which they are 
randomized. 
2.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group (switching arm or non-switching arm) 
using, if not stated otherwise, the number of observations available (N), mean, SD, minimum, 
median, and maximum. These apply to all data, except PK data which will be described as 
detailed in Section 2.5.7. 
Categorical and ordinal data (except PK data, see Section 2.5.7) will be summarized by treatment 
group (switching arm or non-switching arm) using the number and percentage of patients. 
In general, descriptive statistics of parameters (result and change from baseline, if applicable) 
by scheduled post-baseline visits will be provided on observed cases, ie, including only patients 
having non-missing assessments at a specific visit. All statistical analyses (descriptive statistics, 
plots, and statistical models) will be performed on visits defined using the reallocation algorithm 
of premature end of treatment provided in Section 2.5.3. 
2.4.1 Demographics and baseline characteristics 
Parameters will be summarized on the randomized population analyzed in the treatment group to 
which they were randomized.  
Analyses for the PK population will be performed if the size of the PK population is less than 
90% the size of the randomized population for any treatment group. 
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Parameters described in Section 2.1.1 will be summarized by treatment group and overall, using 
descriptive statistics. 
Medical/surgical history will be summarized by primary SOC and PT in each treatment group and 
overall. Events will be sorted by SOC internationally agreed order and decreasing frequency of 
PT based on incidence in the overall treatment group. 
No statistical test for the between-group difference will be performed. 
2.4.2 Prior or concomitant medications  
The prior, concomitant and post-treatment medications will be presented on the randomized 
population, separately for anti-diabetic medications and non-anti-diabetic medications. 
Anti-diabetic medications will be identified by a pre-defined list of ATC codes. 
Medications will be summarized by treatment group and overall (only for prior medications) 
according to the WHO-DD dictionary. Non-anti-diabetic medications will be summarized 
considering the first digit of the ATC class (anatomic category) and the first 3 digits of the ATC 
class (therapeutic category). All ATC codes corresponding to a medication will be summarized, 
and patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore, patients may be counted several times for the same medication. Anti-
diabetic medications will be presented by pharmacological class (ATC3), chemical class (ATC4), 
and standardized medication name. 
The tables for prior medications will be sorted by decreasing frequency within the ATC categories 
presented based on the overall incidence across treatment groups. In case of equal frequency, 
alphabetical order will be used. 
The tables for concomitant and post-treatment medications will be sorted by decreasing frequency 
within the ATC categories presented based on the incidence in the switching arm. In case of equal 
frequency, alphabetical order will be used.  
Frequency statistics including number of patients and percentage will be provided. No statistical 
test for the between-group difference will be performed. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure will be assessed and summarized by actual treatment within the 
safety population (Section 2.3.2).  
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of the open-label IMP exposure and 
daily insulin doses (basal, mealtime, total). 
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Observation period  
The observation period for exposure is defined as the time from the first injection of IMP up to the 
day of last injection of IMP.  
Duration of exposure 
The duration of exposure will be the total number of days of administration of the open-label 
IMP, ignoring temporary drug discontinuation (see Section 2.5.1 for calculation in case of missing 
or incomplete data). 
The duration of exposure to the open-label IMP will be defined in days as: 
(Date of the last IMP administration – date of the first IMP administration) + 1 
The process described in Section 2.5.1 will be applied to define the date of the last IMP 
administration. If this date is missing, the IMP exposure duration should be left as missing. 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum). The number (n) and proportion (%) of patients 
exposed to the open-label IMP will be presented by specific time periods for each treatment group 
in the safety population.  
The time periods of interest are grouped as follows:  
• Up to 4 weeks, 
• >4 to 8 weeks,  
• >8 to 12 weeks,  
• >12 to 15 weeks, 
• >15 to 16 weeks, 
• >16 to 24 week, 
• >24 weeks. 
The cumulative duration of exposure will be described using the following time periods: 
• ≥ 1 day, 
• >4 weeks,  
• >8 weeks,  
• >12 weeks,  
• >15 weeks, 
• >16 weeks, 
• >24 weeks. 
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Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient-years. 
If the number of patients impacted by COVID-19 is sufficient, the duration of IMP exposure will 
also be presented by subgroup of COVID-19 impact (Non-impacted, Impacted) (see definition 
Section 2.2). 
Daily insulin doses 
All insulin doses will be reported by patient in e-diary, transferred to the IMP/NIMP e-diary page 
of the eCRF and reviewed by the investigator in dedicated items. In case the insulin doses 
reported by the patient are incorrect, the investigator will invalidate them and enter correct doses 
in the IMP/NIMP back-up e-diary page of the eCRF. For the analyses, the investigator entries will 
prevail when compared from the transferred e-diary data.  
The process described in Section 2.5.3 will be applied to assign visits to the insulin doses 
transferred from the e-diary webportal into the clinical database, and to retrieve doses in case of 
premature treatment discontinuation.  
At baseline, the daily basal, mealtime, and total (basal plus mealtime) insulin doses (U and U/kg 
body weight) will be calculated as follows: 
• Daily basal insulin dose at baseline (U and U/kg) = median of daily basal insulin doses 
available up to 7 days before the day of first IMP, 
• Daily mealtime insulin dose at baseline (U and U/kg) = median of daily mealtime insulin 
doses available up to 7 days before the day of first IMP, 
• Daily total insulin dose at baseline (U and U/kg) = median of daily total insulin doses 
available up to 7 days before the day of first IMP. 
At Visit 3, daily insulin doses (basal, mealtime, and total) will be calculated as the median of daily 
insulin doses available in the week after the day of first IMP. At further visits, the daily insulin 
doses (basal, mealtime, and total) will be calculated as the median of daily insulin doses available 
in the week before the visit. Technical details related to the computation and handling of missing 
data are described in Section 2.5.  
The daily insulin doses (basal, mealtime, total) will be described at baseline, during the week after 
the date of the first IMP administration, then at each visit, and the changes from baseline will be 
presented. Figures will be provided. 
The ratio of the daily basal insulin/total insulin dose observed and change from baseline will be 
described at baseline and at each visit. 
The daily insulin doses (basal, mealtime, total) will be summarized according to categories of 
HbA1c change from baseline to Week 16 (<-1%, ≥-1% to ≤1%, >1%). 
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If the number of patients impacted by COVID-19 is sufficient, daily insulin doses will also be 
presented by subgroup of COVID-19 impact (Non-impacted, Impacted) (see definition 
Section 2.2). 
Any technical details related to the calculation of doses and the imputations for missing data are 
described in Section 2.5.1.  
2.4.3.2 Compliance  
Not applicable. 
2.4.4 Analyses of pharmacokinetic endpoints 
2.4.4.1 Analyses of primary pharmacokinetic endpoints 
Primary analysis 
The primary analysis will be performed on the PK population, based on natural log-transformed 
AUClast, AUC, and Cmax. The 90% CI for the ratio of geometric means for AUClast, AUC, and 
Cmax between the two treatment arms (switching arm versus non-switching arm) should be within 
80-125%, corresponding to the following composite null and alternative hypotheses tested at an 
alpha level of 0.05: 
• H0: The ratio of geometric means for AUClast, AUC, or Cmax between the switching arm 
and the non-switching arm is outside the predefined acceptance range 80-125% 
• H1: The ratio of geometric means for AUClast, AUC, and Cmax between the switching arm 
and the non-switching arm is within the predefined acceptance range 80-125% 
 
For primary analysis, the natural log-transformed AUClast, AUC, and Cmax will be statistically 
analyzed using an analysis of variance, including the fixed categorical effects of treatment arm 
(switching arm, non-switching arm) and randomization stratum (screening HbA1c <8.0%, 
≥8.0%).  
Estimate and 90% CI for the ratio of geometric means between the two arms (switching arm / 
non-switching arm) will be computed separately for AUClast, AUC, and Cmax, from the linear 
model framework using re-transformation. The 90% CIs for the ratio of geometric means of 
AUClast, AUC, and Cmax should be within 80–125%. 
Additionally, PK parameters will be summarized by treatment using descriptive statistics (for 
details, see Section 2.5.7). 
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Subgroup analyses 
If it will be deemed necessary for interpretation of results, PK parameters may also be 
summarized for selected subgroups.  
Sensitivity analyses 
Exploratory statistical sensitivity analyses may be performed for primary PK parameters. They 
will be performed in a corresponding manner as the primary analysis, with 
• Inclusion of those primary PK parameters affected by major deviations (ie., excluded from 
primary PK analysis)  
• Exclusion of implausible PK parameters and PK parameters suspected to result from 
apparent but not documented PK irregularities. 
2.4.4.2 Analysis of secondary pharmacokinetic endpoints 
 
Tmax will be summarized by treatment group in the PK population using descriptive statistics. 
2.4.4.3 Multiplicity issues 
The type of analysis for multiple primary PK endpoints cannot inflate the type 1 error risk 
above 0.05. No adjustment of alpha/confidence level will be performed.  
Further PK endpoints will be analyzed purely descriptively.  
2.4.4.4 PK parameters at premature end of trial 
For patients with a PK profile at premature end of trial (PEOT), PK parameters will be derived. 
Descriptive statistics of PK parameters from profiles at PEOT will be generated per treatment 
arm. 
 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group.  
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 patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. 
• The baseline value is defined as the last available value prior to the first injection of IMP. 
When the time of assessment is not available, the value is considered as baseline if 
assessment date is the date of 1st IMP intake. 
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• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, and vital signs, (PCSA criteria are provided in the ADaM metadata and in 
Appendix A). 
• PCSA criteria will determine which patients had at least 1 PCSA during the on-treatment 
period, taking into account all evaluations performed during the on-treatment period, 
including nonscheduled or repeated evaluations. The number of all such patients will be 
the numerator for the on-treatment PCSA percentage. 
• The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the on-treatment period by 
treatment group on the safety population. 
• For quantitative safety parameters based on central laboratory measurements, descriptive 
statistics will be used to summarize results and change from baseline values by visit and 
treatment group. Summaries will include the last on-treatment value. The last on treatment 
value is defined as the value collected at the same day/time of the last dose of IMP. If this 
value is missing, this on-treatment value is the closest one prior to the last dose intake. 
• The analysis of the safety variables will be descriptive, and no systematic testing is 
planned. 
2.4.5.1 Analyses of Hypoglycemia 
All analyses of hypoglycemia will be performed on the safety population, using events occurring 
during the on-treatment period (as defined in Section 2.1.5).  
Incidence of patients with at least one hypoglycemia 
• Incidence of patients with at least one hypoglycemia will be presented by treatment group 
for any hypoglycemia and for each hypoglycemia category (as described in 
Section 2.1.5.1). Non classified hypoglycemia will be displayed. 
• For any hypoglycemia, severe and documented symptomatic hypoglycemia category, 
incidence of patients with at least one hypoglycemia will be compared for the switching 
arm versus the non-switching arm using a logistic regression method. The model will 
include fixed-effect terms for treatment group and the randomization stratum of screening 
HbA1c (<8%, ≥8). If the logistic model does not converge (e.g., due to sparse data), the 
randomization stratum may be removed from the model. Odds-ratios and 95% CIs will be 
displayed using forest plots. 
• 
The number (%) of patients with at least one hypoglycemia leading to permanent IMP 
discontinuation will be provided by treatment group. 
• 
Incidence of patients with at least one severe hypoglycemia with neuroglycopenic 
symptoms and/or SMPG <2.8 mmol/L (50 mg/dL) will be summarized. 
• 
If the number of patients impacted by COVID-19 is sufficient, the incidence of patients 
with at least one hypoglycemia (any, severe, documented symptomatic) will also be 
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presented by subgroup of COVID-19 impact (Non-impacted, Impacted) (see definition 
Section 2.2) and compared between treatment groups using a similar logistic regression 
model as described above, with added fixed-effect terms for the subgroup and the 
subgroup-by-treatment interaction. Odds-ratios and 95% CIs will be presented across 
subgroups using forest plots. The significance level of the subgroup-by-treatment 
interaction will also be provided for descriptive purpose. 
Number and rate of hypoglycemia per patient-year 
• Number and rate of hypoglycemia per patient-year (computed as 365.25 x [total number of 
episodes of hypoglycemia] / [total number of days exposed]) will be summarized by 
treatment group for any hypoglycemia and for each hypoglycemia category (as described 
in Section 2.1.5.1). Non classified hypoglycemia will be displayed. 
• For any hypoglycemia the cumulative mean number of hypoglycemia per patient will be 
summarized over time using Nelson-Aalen estimates. Figures will be provided. 
• For any hypoglycemia, severe and documented symptomatic hypoglycemia category, 
number and rate of hypoglycemia per patient-year will be compared for the switching arm 
versus the non-switching arm using an overdispersed Poisson regression model with a 
log-link function, and the logarithm of the treatment-emergent period as offset (using 
PROC GENMOD). The dispersion parameter will be estimated by Pearson’s chi-square 
statistic divided by its degrees of freedom (option SCALE=PEARSON). The model will 
include fixed-effect terms for treatment group and the randomization stratum of screening 
HbA1c (<8%, ≥8%). If a model does not converge (eg, due to sparse data), the 
randomization stratum may be removed from the model. Rate ratios and 95% CIs will be 
displayed using forest plots. 
• The number of severe hypoglycemia with neuroglycopenic symptoms and/or SMPG <2.8 
mmol/L (50 mg/dL) per patient-year of exposure will be summarized by treatment group. 
2.4.5.2  Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events. 
Pretreatment and posttreatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or posttreatment. The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or posttreatment. Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.1.  
Adverse event incidence tables will present by SOC and/or PT, the number (n) and percentage 
(%) of patients experiencing an adverse event. Multiple occurrences of the same event in the same 
patient will be counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group.  
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Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and posttreatment). For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified. Sorting will be based on results 
for the switching arm. 
Analyses of all TEAE(s) will be generated for the safety population.  
Analysis of all TEAE(s) 
• Overview of TEAEs, summarizing number (%) of patients with any 
- 
TEAEs, 
- 
Serious TEAEs, 
- 
TEAEs leading to death, 
- 
TEAEs leading to permanent treatment discontinuation. 
• Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT in the switching group. 
• All TEAEs by primary SOC and PT, showing number (%) of patients with at least one 
TEAE, sorted by SOC internationally agreed order and decreasing incidence of PT in the 
switching group within SOC. This sorting order will be applied to all other tables, unless 
otherwise specified. If the number of patients impacted by COVID-19 is sufficient, TEAEs 
will also be presented by subgroup of COVID-19 impact (Non-impacted, Impacted) (see 
definition Section 2.2). 
• All TEAEs regardless of relationship and related to IMP by primary SOC and PT, showing 
number (%) of patients with at least one TEAE, sorted by the sorting order defined above. 
• All TEAEs by maximal severity, presented by primary SOC and PT, showing number (%) 
of patients with at least one TEAE by severity (ie, mild, moderate, or severe), sorted by the 
sorting order defined above. 
Analysis of all treatment-emergent SAE(s) 
• All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC and PT, showing number (%) of patients with at least 1 serious 
TEAE, sorted by SOC internationally agreed order and decreasing incidence of PTs 
according to all TEAE summary within SOC. 
Analysis of all TEAE(s) leading to treatment discontinuation 
• All treatment-emergent adverse events leading to permanent IMP discontinuation, by 
primary SOC and PT, showing the number (%) of patients sorted by the internationally 
agreed SOC order and decreasing incidence of PTs according to all TEAE summary 
within SOC. 
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Analysis of all TEAE(s) requiring specific monitoring 
• All TEAE(s) related to injection site reactions, hypersensitivity reactions, or events 
confirmed as allergic reactions by ARAC regardless of relationship and related to IMP by 
PT, showing number (%) of patients sorted by decreasing incidence of PT based on results 
for the switching group. 
• The number of events sent for adjudication to the ARAC and the number (%) of events 
positively adjudicated as allergic reaction or not by the ARAC will be summarized for 
each treatment group. 
• A listing of all events adjudicated by ARAC will be provided with the result of ARAC 
adjudication. 
Analysis of adverse events of special interest 
• Number (%) of patients experiencing AESI presented by categories described in 
Section 2.1.5.2.  
Analysis of pretreatment and posttreatment adverse events  
• Depending on the number, a listing or a table of all pre-treatment and post-treatment AEs 
will be provided. 
Analysis of TEAEs related to COVID-19 
All TEAEs related to COVID-19 by primary SOC and PT, showing the number (%) of patients 
with at least one TEAE related to COVID-19, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs according to all TEAE summary within SOC. TEAEs related to 
COVID-19 will be identified using a CMQ (customized MedDRA queries) list. 
2.4.5.3 Deaths 
The following deaths summaries will be generated on the safety population. 
• Number (%) of patients who died by study period (on-study, on-treatment and reasons for 
death. 
• All TEAEs leading to death (death as an outcome on the adverse event e-CRF page as 
reported by the investigator), by primary SOC and PT, showing number (%) of patients 
sorted by SOC internationally agreed order and decreasing incidence of PTs according to 
all TEAE summary within SOC. 
• A listing of all deaths. 
2.4.5.4 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, Week 16, and last on-treatment value) 
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by treatment group. This section will be organized by biological function as specified in 
Section 2.1.5.4.  
The incidence of PCSAs (list provided in Appendix A) at any time during the on-treatment period 
will be summarized by biological function and treatment group whatever the baseline level and 
according to the following baseline status categories:  
• Normal/missing, 
• Abnormal according to PCSA criterion or criteria. 
For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment for each parameter. 
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified by treatment (eg, patients with any elevated 
ALT>3 x ULN, and associated with an increase in bilirubin >2 x ULN) will be provided with 
ALT, AST, alkaline phosphatase, total bilirubin, and the following complementary parameters 
(if available): conjugated bilirubin and prothrombin time/international normalized ratio (INR), 
creatine phosphokinase (CPK), serum creatinine and complete blood count. 
2.4.5.5 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables (raw values and changes from baseline) described in 
Section 2.1.5.5 including body weight, will be calculated for each visit or study assessment 
(baseline, Week 16, last on-treatment value) by treatment group.  
The incidence of PCSAs at any time during the on-treatment period will be summarized by 
treatment irrespective of the baseline level.  
2.4.5.6 Analyses of electrocardiogram variables 
Not applicable. 
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2.4.6 Analyses of anti-insulin aspart antibody data 
2.4.6.1 Analyses of anti-insulin aspart antibody data 
The analyses of immunogenicity data will be descriptive (no formal statistical testing) and based 
on the AIA population. 
Anti-insulin antibody response 
The number and percentage of patients will be provided by treatment group for each of the 
following categories: 
• Patients with treatment-induced AIAs, 
• Patients with treatment-boosted AIAs, 
• Patients with treatment-emergent AIA (AIA incidence), 
• Patients without treatment-emergent AIA, 
• Patients with pre-existing AIAs or treatment-induced AIAs (AIA prevalence). 
For exploratory purposes, the difference between the switching arm and the non-switching arm in 
the percentage of patients with treatment-emergent AIAs (AIA incidence) will be provided with 
associated 2-sided 90% CI. Patients with inconclusive results will not be part of the analysis. 
Results will be obtained by fitting a binomial regression model with an identity-link function. 
The model will include fixed categorical effects for treatment and the randomization stratum of 
screening HbA1c (<8%, ≥8%). If the model does not converge (e.g., due to sparse data), 
randomization strata may be removed from the model. The risks within each treatment group and 
risk difference will be provided with their 90% CIs using the adjusted LS mean estimates of the 
treatment effect. 
For patients with treatment-induced and treatment-boosted AIAs, the peak titer will be described 
using median, Q1 and Q3. 
The number and percentage of patients with treatment-induced, treatment-boosted and 
treatment-emergent AIAs will also be presented by visit in each treatment group using tables 
and/or graphs. 
Boxplots of the peak AIA titer will be presented by treatment group and according to the 
treatment-emergent AIA status (Yes, No). These graphs will be used to identify AIA ‘outliers’, 
defined as peak AIA titers higher than the boxplot upper whiskers (ie, higher than 1.5 times the 
interquartile range above the third quartile). 
A listing with inconclusive patients will be provided. 
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Anti-insulin aspart antibody data by visit 
The number and percentage of patients with anti-SAR341402/NovoLog antibody positive and 
antibody negative samples will be summarized by treatment group at each visit. The number and 
percentage of patients with anti-SAR341402/NovoLog antibody positive sample will be displayed 
graphically by visit.  
On the group of patients with anti-SAR341402/NovoLog antibody positive sample at a given 
visit, anti-SAR341402/NovoLog antibody titers will be summarized (using descriptive statistics 
by number (N), median, Q1, Q3, variation coefficient, minimum, maximum, geometric mean, SD, 
and 95% CI), and the number and percentage of patients with cross-reactivity to human insulin 
will be provided.  
Boxplots of AIA titers will be presented at each visit. 
The above by-visit summaries will be performed on the overall AIA population and for patients 
with treatment-emergent AIAs. 
Subgroup analyses 
Exploratory analyses will be performed by the subgroups defined by the Anti-
SAR341402/NovoLog antibody status at baseline (Positive, Negative), and by COVID-19 impact 
(Non-impacted, Impacted; see subgroup definition in Section 2.2). The second subgroup analysis 
will be performed only if the number of patients is sufficient. Further subgroup analyses may be 
performed if deemed necessary for interpretation of results. 
Relationship between immunogenicity endpoints and efficacy/safety assessments 
Subgroup analyses and scatterplots will be conducted to assess the relationship between 
immunogenicity endpoints and efficacy/safety assessments.  
The following safety/efficacy assessments will be summarized by treatment-emergent AIA (Yes, 
No) and for each treatment group: 
• Hypoglycemia (any, severe, documented symptomatic): the proportion of patients with at 
least one event will be compared between treatment groups using the same statistical 
model as described in Section 2.4.5.1 for hypoglycemia subgroup analyses. 
• TEAEs: descriptive statistics presented by primary SOC and PTs, showing number (%) of 
patients with at least one TEAE, sorted by SOC internationally agreed order and 
decreasing incidence of PTs according to all TEAE summary within SOC. 
• Serious TEAEs: descriptive statistics by primary SOC and PTs, showing number (%) of 
patients sorted by SOC internationally agreed order and decreasing incidence of PTs 
according to all TEAE summary within SOC.  
• Injection site and hypersensitivity reactions: descriptive statistics by PT, showing number 
(%) of patients sorted by decreasing incidence of PT in the switching group. 
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• Efficacy endpoint (change from baseline to Week 16 in HbA1c): descriptive statistics by 
visit. 
• Change in daily insulin doses (basal, mealtime, total) as defined in Section 2.4.3: 
descriptive statistics by visit. 
The relationship between the AIA titer and the efficacy and safety assessments will be explored 
using scatter-plots of the peak AIA titer versus the parameters below for patients from the AIA 
population with titer available: 
• Rate per year of treatment-emergent hypoglycemia during the on-treatment period (severe 
hypoglycemia, documented symptomatic < 3.0 mol/L [54 mg/dL]) 
• Presence/absence of treatment-emergent hypersensitivity reactions during the on-treatment 
period 
• Presence/absence of treatment-emergent injections site reactions during the on-treatment 
period 
• Efficacy endpoint (change from baseline to Week 16 in HbA1c)  
• Change in daily insulin doses (U/kg) from baseline to Week 16 
The scatterplots will also be presented separately for patients with treatment-emergent AIAs. 
Listings of baseline characteristics, insulin doses, HbA1c, hypoglycemia, hypersensitivity 
reactions, and injection site reactions will be provided for patients with treatment-emergent AIAs 
and high AIA titers (AIA ‘outliers’ as defined above). 
Listings of anti-insulin aspart antibody, insulin doses, and HbA1c data will be provided for 
patients with treatment-emergent AIAs and HbA1c change from baseline > 1% at Week 16.  
A listing of patients with treatment-emergent AIA at end of treatment and potential effects on 
glycemic control will be provided with the result of adjudication by the ARAC diabetologist 
(including AIA-mediation and potential need for AIA post-study follow-up).  
2.4.6.2 Analyses of anti-insulin aspart neutralizing antibody data 
Neutralizing antibody response 
The number and percentage of patients will be provided by treatment group for each of the 
following categories: 
• 
Patients with treatment-induced NAb, 
• 
Patients with treatment-boosted NAb, 
• 
Patients with treatment-emergent NAb (NAb incidence), 
• 
Patients without treatment-emergent NAb, 
• 
Patients with pre-existing NAb or treatment-induced NAb (NAb prevalence). 
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For patients with treatment-induced and treatment-boosted NAbs, the peak NAb titer will be 
described using median, Q1 and Q3. 
The number and percentage of patients with treatment-induced, treatment-boosted and 
treatment-emergent NAbs will also be presented by visit in each treatment group using tables 
and/or graphs. 
A listing with inconclusive patients will be provided. 
Anti-insulin aspart neutralizing antibody data by visit 
The number and percentage of patients with anti-SAR341402/NovoLog neutralizing antibody 
positive and negative samples will be summarized by treatment group at each visit. The number 
and percentage of patients with anti-SAR341402/NovoLog neutralizing antibody positive sample 
will be displayed graphically by visit.  
The above by-visit summaries will be performed on the overall AIA population and separately for 
patients with treatment-emergent NAbs. 
On the group of patients with anti-SAR341402/NovoLog neutralizing antibody positive sample at 
a given visit, anti-SAR341402/NovoLog neutralizing antibody titers will be summarized (using 
descriptive statistics by number (N), median, Q1, Q3, variation coefficient, minimum, maximum, 
geometric mean, SD, and 95% CI). 
Boxplots of NAb titers will be presented at each visit. 
The above by-visit summaries will be performed on the overall AIA population and separately for 
patients with treatment-emergent NAbs. 
Subgroup analyses 
Exploratory analyses will be performed for the subgroup defined by the Anti- 
SAR341402/NovoLog neutralizing antibody status at baseline (Positive, Negative). Further 
subgroup analyses may be performed if deemed necessary for interpretation of results. 
Relationship between immunogenicity endpoints and efficacy assessments 
Subgroup analyses and scatterplots will be conducted to assess the relationship between 
immunogenicity endpoints and efficacy assessments.  
The following efficacy assessments will be summarized by treatment-emergent NAb (Yes, No) 
and for each treatment group: 
• Efficacy endpoint (change from baseline to Week 16 in HbA1c): descriptive statistics by 
visit. 
• Change in daily insulin doses (basal, mealtime, total) as defined in Section 2.4.3: 
descriptive statistics by visit. 
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The relationship between the NAb titer and the efficacy assessments will be explored using 
scatter-plots of the peak NAb titer versus the parameters below for patients from the AIA 
population with NAb titer available: 
• Efficacy endpoint (change from baseline to Week 16 in HbA1c). 
• Change in daily insulin doses (U/kg) from baseline to Week 16. 
The scatterplots will also be presented separately for patients with treatment-emergent NAbs. 
A listing of AIA/NAb status, insulin doses, and HbA1c data will be provided for patients with 
treatment-emergent NAbs and HbA1c change from baseline > 1% at Week 16. 
2.4.7 Analyses of efficacy endpoints 
Analyses of efficacy endpoints (change in HbA1c and FPG from baseline to Week 16 as defined 
in the Section 2.1.6) will be descriptive with no formal statistical testing, and based on the ITT 
population (ie, regardless of adherence to treatment, as per definition) . All post-baseline data 
available during the randomized period will be described.  
HbA1c, FPG and change from baseline values (% for HbA1c and mmol/L and mg/dL for FPG) 
will be presented by visit for each treatment group, using descriptive statistics and/or graphs. 
Additionally, if the number of patients impacted by COVID-19 is sufficient, efficacy endpoints 
will also be presented by subgroup of COVID-19 impact (Non-impacted, Impacted) (see 
definition Section 2.2). 
2.5 
DATA HANDLING CONVENTIONS 
This section describes general rules for data handling conventions, especially for patients with 
missing data. 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Reference day 
The reference day for the calculation of extent of exposure, time to onset and relative days is the 
day of the first administration of open-label IMP, denoted as Day 1. 
Disease characteristics formulas 
Duration of diabetes (years) = (Date of informed consent – date of diagnosis of diabetes 
+1)/365.25. 
Age at onset of diabetes (years) = (Date [DD-MM-YYYY] of diagnosis of diabetes – date 
[DD-MM-YYYY] of birth +1) /365.25. In case of unavailable date of birth, only the year of the 
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date of diabetes diagnosis and the year of the date of birth (retrieve using the age recorded at 
screening) will be considered in the age at onset calculation. 
Duration of previous mealtime insulin treatment (years) = (Date of informed consent – Date of 
first intake of mealtime Anti-hyperglycemic therapy +1)/365.25. 
Duration of basal insulin treatment (years) = (Date of informed consent – Date of first intake of 
Basal Anti-hyperglycemic therapy +1)/365.25 
Renal function formula  
GFR will be derived using MDRD formula: 
GFR (mL/min/1.73m2) = 




female)
 
(if
 
0.742
 x 
black)
 
(if
 
1.212
 x 
Age
 x 
 
(mg/dL)
 
Creatinine
 
Serum
175x 
-0.203
-1.154
 
2.5.2 Missing data 
2.5.2.1 Handling of missing PK parameters 
For participants with insufficient data for some but not all PK parameters, the evaluable PK 
parameters will be included in the analysis. No imputations of missing PK parameters are 
planned.  
2.5.2.2 Handling of other missing parameters 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Derived variables are considered missing if the original variables required to calculate them are 
missing unless otherwise specified. For example, if either a baseline assessment or an endpoint 
assessment is missing for a particular patient, then the change from baseline at endpoint is 
missing. Depending upon the assessment, analyses may not include all patients in the analysis 
population, because certain patients in the intended population may have missing data. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing  
For the calculation of the treatment duration, the date of the last dose of IMP will be defined as 
the date of last administration reported on the end-of-treatment case report form page. If this date 
is missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
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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 adverse event / hypoglycemia onset dates and times will be imputed so that if 
the partial event onset date/time information does not indicate that the event started prior to 
treatment or after the on-treatment period, the event will be classified as treatment-emergent. No 
imputation of event 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 event resolution. 
Handling of adverse events/ hypoglycemia when date and time of first IMP administration is 
missing 
When the date and time of the first IMP administration is missing, all adverse events/ 
hypoglycemia that occurred on or after the day of randomization should be considered as 
treatment-emergent. The exposure duration should be kept as missing. 
Handling of hypoglycemia classification when some classification items are missing 
Rules for handling missing data in classification items for hypoglycemia will be provided in 
ADaM metadata. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of potentially clinically significant abnormalities 
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
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Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.  
Handling of missing data in the calculation of insulin doses 
The daily mealtime insulin dose will be calculated as the sum of the mealtime insulin doses 
collected on the same day. At least 3 available mealtime insulin doses for the main meal 
(breakfast, lunch and dinner) and no more than 1 snack will be required to calculate the daily 
mealtime insulin dose. For the days with more than one snack or more than one main meal with 
an insulin dose of 0 unit, the daily dose won’t be calculated.  
The daily total insulin dose will be calculated as the sum of the daily basal (only the doses not null 
will be kept) and daily mealtime insulin doses. If one of the daily insulin doses is missing (basal 
or mealtime), the daily total insulin dose will not be calculated. 
At baseline, daily insulin doses (basal, mealtime, and total) will be calculated as the median of the 
daily insulin doses (as previously calculated) available in the 7 days before the day of first IMP. 
At Visit 3, daily insulin doses (basal, mealtime, and total) will be calculated as the median of the 
daily insulin doses (as previously calculated) available in the 7 days after the day of first IMP. At 
further visits, the daily insulin doses (basal, mealtime, and total) will be calculated as the median 
of the daily insulin doses (as previously calculated) available in the 7 days before the visit. No 
minimum number of available doses will be required. For insulin doses in U/kg, if the body 
weight measurement is missing at a given visit, the last available measurement from previous visit 
(unscheduled or not) will be used. 
2.5.3 Visit allocation 
The following process will be applied for visit re-allocation. Re-allocated visits will be used in all 
statistical analyses (descriptive statistics, plots, and statistical models).  
No re-allocation will be performed for nominal visits already provided in the clinical database 
(Visit 1 to Visit 8), and for unscheduled assessments. No reallocation of visit will be performed 
for PK. 
Insulin doses 
In the clinical database, insulin doses transferred from the e-diary will not be assigned to a 
protocol visit. For the analysis, they will be assigned to the next on-site visit actually performed 
by the patient after the date of data collection (Visit 3 to Visit 7, or Visit 8000). 
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End of treatment visit 
If a patient discontinues the treatment prematurely, end of treatment (Visit 8000) assessments will 
be re-allocated to the next scheduled on-site visit for the patient, except for the PK assessments, as 
the PK profiles of patients who prematurely discontinued the treatment will not be included in the 
primary PK analysis.  
The next scheduled on-site visit for each patient will be determined as the next on-site visit that 
should be performed as per protocol, following the last visit actually performed by the patient 
before Visit 8000. 
For a given parameter, the value will not be re-allocated in the following cases: 
• If the parameter is not planned to be collected at the re-allocation visit. 
• If a value is already available for the parameter at the re-allocation visit. 
This process will be used to retrieve all assessments (except PK assessment) performed at the end 
of treatment visit (Visit 8000) and will apply to insulin doses assigned to Visit 8000 following the 
process described above.  
2.5.4 Unscheduled visits 
The determination of baselines for safety and efficacy parameter variables is based on all 
measurements from both scheduled and unscheduled visits (measurements from the central 
laboratory only), as mentioned in Section 2.5.3. The determination of the last on-treatment value 
for safety parameters is also based on all assessments from both scheduled and unscheduled visits 
(measurements from the central laboratory only). 
Measurements from the unscheduled visits (measurements from the central laboratory only) are 
also considered for PCSA summary of safety parameters. 
Unscheduled visit measurements are not included in the by-visit summaries. 
2.5.5 Pooling of centers for statistical analyses 
All centers will be pooled for statistical analysis. Centers will not be taken into account in the 
statistical analysis. 
2.5.6 Study-specific conventions  
In the statistical appendices and in-text tables, the following treatment labels will be used:  
• Switching arm 
• Non-Switching arm  
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2.5.7 Handling for pharmacokinetic data 
2.5.7.1 Individual PK parameters 
Individual PK parameters will be provided by a vendor. 
AUC values extrapolated by more than 20% will be excluded from any pharmacokinetic statistical 
analysis. 
2.5.7.2 Descriptive analyses 
Descriptive analyses and graphical descriptive display of PK parameters will be provided by a 
vendor, under responsibility of PK function. 
For ease of presentation, mean values will be arithmetic mean unless specified. 
Individual concentration values below the lower limit of quantification (LLOQ) will be treated as 
zero in calculating mean values but reported as <LLOQ. Mean values below LLOQ will be 
reported as <LLOQ in the tables. 
Mean calculations and their associated statistics will be generated from unrounded numbers and 
may differ slightly from those values that would be determined using the rounded numbers 
displayed in the tables. 
Values expressed in tables will be for ease of presentation and will not be meant to imply 
accuracy to more than 3 significant figures. 
Plasma concentrations and pharmacokinetic parameters will be summarized by arithmetic mean, 
geometric mean, SD, SE, CV(%), minimum, median, maximum, and number of observations by 
treatment. 
2.5.8 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
No interim analysis is planned.  
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4 
DATABASE LOCK 
It is planned to lock the database approximately 7 weeks after the last patient last visit (LPLV). 
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5 
SOFTWARE DOCUMENTATION 
Descriptive analyses for PK parameters will be generated using version 6.4 of Phoenix 
WinNonlin. 
All other summaries and statistical analyses will be generated using SAS 9.4 or higher. 
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6 
REFERENCES 
 
1. Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, et al. American 
Association of Pharmaceutical Scientists.. Assessment and reporting of the clinical 
immunogenicity of therapeutic proteins and peptides-harmonized terminology and tactical 
recommendations. AAPS J. 2014 Jul;16(4):658-73. 
2. Kock GG. Comments on 'Current issues in non-inferiority trials' by Thomas R. Fleming, 
Statistics in Medicine, DOI: 10.1002/sim.2855. Stat Med. 2008 Feb 10;27(3):333-42. 
3. American Diabetes Association Workgroup on Hypoglycemia. Defining and Reporting 
Hypoglycemia in Diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005 May;28(5):1245-9. 
4. 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(5):1384-95. 
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(1):155-7. 
  
 
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7 
LIST OF APPENDICES 
Appendix A: 
Potentially clinically significant abnormalities criteria 
 
 
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Appendix A Potentially clinically significant abnormalities criteria 
 
CRITERIA for POTENTIALLY CLINICALLY 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. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-by-case basis. 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment phase, whatever 
the interval between measurements. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following one mentioning zero 
can be deleted. 
 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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Statistical Analysis Plan  
24-Jul-2020 
SAR341402-EFC15178 - insulin aspart 
Version number: 2 
 
 
Property of the Sanofi group - strictly confidential 
 
Page 54 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
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. 
VV-CLIN-0540289 3.0


Statistical Analysis Plan  
24-Jul-2020 
SAR341402-EFC15178 - insulin aspart 
Version number: 2 
 
 
Property of the Sanofi group - strictly confidential 
 
Page 55 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
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. 
VV-CLIN-0540289 3.0


Statistical Analysis Plan  
24-Jul-2020 
SAR341402-EFC15178 - insulin aspart 
Version number: 2 
 
 
Property of the Sanofi group - strictly confidential 
 
Page 56 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
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. 
VV-CLIN-0540289 3.0


Statistical Analysis Plan  
24-Jul-2020 
SAR341402-EFC15178 - insulin aspart 
Version number: 2 
 
 
Property of the Sanofi group - strictly confidential 
 
Page 57 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
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 
<40 bpm 
<40 bpm and decrease from baseline ≥20 bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 bpm 
 
>90 bpm 
>90 bpm and increase from baseline ≥20bpm 
>100 bpm  
>100 bpm and increase from baseline ≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
> 220 ms 
>220 ms and increase from baseline ≥25% 
> 240 ms 
> 240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
VV-CLIN-0540289 3.0


Statistical Analysis Plan  
24-Jul-2020 
SAR341402-EFC15178 - insulin aspart 
Version number: 2 
 
 
Property of the Sanofi group - strictly confidential 
 
Page 58 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
QRS 
>110 ms 
>110 msec and increase from baseline ≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT correction formula.  
Absolute values categories are cumulative 
 
QTc >480 ms and QTc>60 ms are the 2 PCSA categories 
to be identified in individual subjects/patients listings. 
 
 
 
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