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
Phase: PHASE3
Conditions: Type 1 Diabetes Mellitus
Sponsor: Sanofi

 
 
 
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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
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consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
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According to template: Version 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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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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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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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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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  
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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. 
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5. Fineberg SE, Kawabata TT, Finco-Kent D, Fountaine RJ, Finch GL, Krasner AS. 
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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. 
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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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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 
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NEJM. 1968;279(17):893-900. 
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