A Randomized, 24 Weeks, Active-controlled, Open-label, 2-arm Multicenter Study Comparing the Efficacy and Safety of iGlarLixi to IDegAsp in Chinese Type 2 Diabetes Mellitus Participants Insufficiently Controlled With Oral Antidiabetic Drug(s)
Phase: PHASE3
Conditions: Type 2 Diabetes Mellitus
Sponsor: Sanofi

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According to Template: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 01 
Protocol title: 
A randomized, 24 weeks, active-controlled, open-label, 2-
arm multicenter study comparing the efficacy and safety 
of iGlarLixi to IDegAsp in Chinese type 2 diabetes 
mellitus participants suboptimally controlled with oral 
antidiabetic drug(s)  
Protocol number: 
LPS17396 
Amendment number: 
01 
Compound number: 
(INN/Trademark): 
HOE901/AVE0010 
iGlarLixi/Soliqua® 
Brief title: 
Acronym: 
iGlarLixi vs IDegAsp in Chinese participants on OAD(s) 
SoliD – (Soliqua – iGlarLixi in Chinese patients after 
OAD[s]) 
Study phase: 
Phase 3 
Sponsor name: 
Monitoring team’s 
representative name 
and contact information 
Regulatory agency identifier number(s): 
IND: 
Not applicable 
EudraCT: 
Not applicable 
NCT: 
Not applicable 
WHO: 
U1111-1267-2772 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Date: 16-June-2022 
Total number of pages: 100 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 01 
All 
16 June 2022, version 1 (electronic 2.0) 
Original Protocol 
All 
14 Sept 2021, version 1 (electronic 1.0) 
 
Amended protocol 01 (16 June 2022) 
This amended protocol 01 (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 
This amendment (01) is intended to support further evaluation of the therapeutic effect of 
iGlarLixi on ß-cell function in the study population.  In addition to the primary objective to 
demonstrate the non-inferiority of iGlarLixi versus IDegAsp (Ryzodeg 70/30) on glycemic 
control, an additional secondary outcome is included to assess the status of ß-cell function after  
24 weeks of treatment with iGlarlixi versus iDegAsp, which could provide evidence of the effect 
of the evaluated treatment on ß-cell function. Additionally, assessment of ß-cell function at 
baseline will allow to evaluate clinical outcomes with iGlarlixi vs IDegAsp in subgroup 
population according to baseline ß-cell functionality.  
C-peptide is a widely used measure of pancreatic ß-cell function. It will be evaluated at the 
baseline (Visit 2/Week 0) and at the end of the treatment (Visit 14/Week 24). Correspondingly, 
the change in fasting C-peptide from baseline to Week 24 will be added into the “other objective 
and endpoints” for statistical analyses. 
 
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title page and 
throughout 
 
 
 
 
 
Document title updated to “Amended Clinical 
Trial Protocol 01”. 
Updated Amendment information. 
Protocol Amendment Summary of changes, 
including, document history, Overall rationale for 
the amendment and protocol amendment 
summary of changes table, added. 
Added “Acronym: SoliD (Soliqua – iGlarLixi in 
Chinese patients after OAD[s])” 
Updated all other formatting, reference orders, 
header, etc, relating to protocol amendment, and 
corrected any formatting inconsistencies. 
Title page amendments added as per Sanofi standards. 
 
 
 
 
 
An acronym is available for the study. 
 
Formatting updated throughout as per Sanofi standards. 
Section 1.1 
Synopsis 
Section 3 
Objectives and 
Endpoints 
“Change in fasting C-peptide from baseline to 
Week 24” was added to “Other secondary 
endpoints”. 
 
To add an additional endpoint for the assessment of the 
“other secondary objective”. 
Throughout the 
document 
Capitalize the i in IDegAsp. 
Consistency.  
Section 1.3 
Schedule of 
Activities (SOA) 
Added “Fasting C-peptide” to “Central Laboratory 
test” with check-marks X at Visit 2/Week 0, and 
Visit 14/Week 24. 
“FPG” was transferred in a separate row. “X” was 
added to Visit 2. 
Footnote “m Participants must be in fasting 
status, not have any food and drinks (except for 
water) for at least 8 hours” was added. 
Footnote “n Fasting C-peptide sample at Visit 
14/Week 24 should be only collected for 
participants who have C-peptide samples 
collected at Visit 2/Week0” was added. 
Fasting C-peptide: Added “X” in the E/D column. 
 
Footnote i: Added “in any two days in the week 
prior to the visit. Participants should be reminded 
to perform the 7-point SMPG profile or, the onsite 
visit should be postponed allowing for the 
performances”. 
Measurement of fasting C-peptide at Visit 2 and Visit 14 
by central lab for assessment of the additional 
endpoints. 
FPG will be measured also at randomization as a 
reference for IMP starting dose. 
The samples for measurement of C-peptide and FPG 
should be collected at the fasting state. 
 
Clarification that paired samples (baseline/end of study) 
of fasting C-peptide are needed for endpoint analysis. 
 
 
Fasting C-peptide will be measured in case of E/D. 
 
Clarification that the 7-point SMPG profile must be 
completed before the onsite visit. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 3.1 
Appropriateness 
of measurements 
“ß-cell function will be assessed by fasting C-
peptide at baseline and Week 24. The glycemic 
biomarker (HbA1c) will be further evaluated 
based on the baseline fasting C-peptide levels 
and therefore to provide evidence that iGlarLixi is 
effective regardless of baseline ß-cell function in 
patients with T2DM suboptimal controlled with 
OADs. The effect of iGlarLxi in preservation of ß-
cell function could also be evaluated via the 
change in fasting C-peptide from baseline to 
Week 24” was added. Added citation “(16)”. 
Fasting C-peptide is widely used to measure ß-cell 
function. 
Section 6.8.1 
Background 
therapy 
Added that for the participants who are eligible 
for randomization and treated with an SU, a 
glinide, an alpha-GI, or a DPP-4 inhibitor, the 
treatment will be stopped before or on the 
randomization day (V2). 
Treatment with insulin secretagogues should be stop 
earlier to V2, if possible, to have the minimum insulin 
stimulating effect on the day fasting C-peptide sample is 
collected. 
Section 8.1 
Efficacy 
assessments 
Title of Section 8.1.1 “HbA1c and FPG 
measurement” changed to “HbA1c, FPG and 
fasting C-peptide measurement”. The 
measurement of fasting C-peptide was included. 
Fasting C-peptide is added as one of the efficacy 
measurements. 
Section 8.4.2.1 
Randomization 
visit (V2, Week 0, 
Day 1) 
Added that for the randomization visit the 
participant must return to the investigational site 
in the morning in fasting status, ”i.e., not having 
any food or drinks (except for water) for at least 8 
hours” 
The samples for measurement of C-peptide and FPG 
should be collected at the fasting state. 
 
Section 9.3.2 
Analyses of 
primary endpoint 
Added “Baseline fasting C-peptide level by 
quartiles” in the “Subgroup analyses of the 
primary estimand”. 
A prespecify subgroup analysis by baseline fasting C-
peptide levels will be conducted to evaluate clinical 
outcomes with iGlarlixi vs IDegAsp according to 
baseline ß-cell functionality. 
Section 9.3.3.2 
Other secondary 
endpoints 
Fasting C-peptide was added in the analysis of 
“Other secondary endpoints”. 
“… FPG, and 7-point self-monitored plasma 
glucose (SMPG)…” changed to “…FPG, 7-point 
self-monitored plasma glucose (SMPG) and 
fasting C-peptide….” 
Analysis of fasting C-peptide endpoint for the 
assessment of the “other secondary objective”. 
Section 10.1.3 
Informed consent 
process 
Removed text “The ICF contains 2 separate 
sections… for any reason during the storage 
period”. 
Consistency with ICF. 
Section 10.2 
Appendix 2 
Clinical laboratory 
tests 
Fasting C-peptide added to “Other study specific 
tests” of Table 8. 
Fasting C-peptide is added as one of the central 
laboratory measurements. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.3.3 
Recording and 
follow-up of AE 
and/or SAE 
Update the assessment of intensity categories. 
“Mild: An event that is easily tolerated by the 
participant, causing minimal discomfort and not 
interfering with everyday activities.” was replaced 
with “Mild: Asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated.” 
“Moderate: An event that causes sufficient 
discomfort to interfere with normal everyday 
activities.” was replaced with “Moderate: Minimal, 
local or noninvasive intervention indicated; 
limiting age-appropriate instrumental Activities of 
Daily Living (ADL). Instrumental ADL refers to 
preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, 
etc.” 
“Severe: An event that prevents normal everyday 
activities. An AE that is assessed as severe 
should not be confused with an SAE.” was 
replaced with “Severe: Severe or medically 
significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization 
indicated; disabling, limiting self care ADL. Self 
care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking 
medications, and not bedridden.” 
Protocol template was updated as per Sanofi standards 
to be aligned with CDISC.  
Section 10.5 
Appendix 5 
Liver And Other 
Safety: 
Suggested 
Actions And 
Follow-Up 
Assessments 
Remove duplicated text under figure “Increase in 
ALT”. Added cross-reference to “Section 10.3” for 
guidance on safety reporting. 
Correction missed in protocol. 
Section 2.3.1 Risk 
assessment 
Section 5.2 
Exclusion criteria 
Section 6.1.2 
Training for 
injection devices 
Section 10.3.2 
Definition of SAE 
Section 8.3.7 
Hypoglycemia 
Minor grammatical and editorial revisions. 
 
 
 
 
 
 
 
Added Citation “(17)”. 
Editorial changes to clarify or correct protocol 
inconsistencies. 
 
 
 
 
 
 
ADA 2021 recommendation for hypoglycemia 
classification. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.7 
Appendix 7: 
Abbreviations and 
throughout the 
document 
Added “IMP: Investigational medicinal product” 
and “SMPG: Self-monitored plasma glucose”. 
Formatting updated throughout as per Sanofi standards. 
Section 11 
References 
Added references 16 (Ferrannini et al 2022) and 
17 (American Diabetes Association 2021). 
References to support the rationale of adding C-peptide 
analyses and the hypoglycemia classification, 
respectively. 
 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 12 
LIST OF FIGURES ........................................................................................................................................ 12 
1 
PROTOCOL SUMMARY ............................................................................................................... 13 
1.1 
SYNOPSIS ..................................................................................................................................... 13 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 20 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 23 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 25 
2.3.1 
Risk assessment ............................................................................................................................ 25 
2.3.2 
Benefit assessment ........................................................................................................................ 25 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 26 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 27 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 27 
4 
STUDY DESIGN ............................................................................................................................ 29 
4.1 
OVERALL DESIGN ........................................................................................................................ 29 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 29 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 30 
4.4 
DURATION OF STUDY PARTICIPATION .................................................................................... 30 
4.4.1 
Duration of study participation for each participant ........................................................................ 30 
4.4.2 
Determination of end of clinical trial (all participants) .................................................................... 30 
5 
STUDY POPULATION .................................................................................................................. 31 
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5.1 
INCLUSION CRITERIA .................................................................................................................. 31 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 32 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 33 
5.4 
SCREEN FAILURES...................................................................................................................... 33 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION ........................................................................................................................ 34 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 35 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 35 
6.1.1 
Devices: ......................................................................................................................................... 36 
6.1.2 
Training for injection devices ......................................................................................................... 37 
6.1.3 
Dosage schedule ........................................................................................................................... 37 
6.1.4 
Starting dose and dose modification .............................................................................................. 38 
6.1.4.1 
iGlarLixi .......................................................................................................................................... 38 
6.1.4.2 
IDegAsp: ........................................................................................................................................ 39 
6.2 
STUDY INTERVENTION PACKAGING AND LABELING ............................................................. 40 
6.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 40 
6.4 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 41 
6.5 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 42 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 42 
6.7 
MANAGEMENT OF OVERDOSE .................................................................................................. 42 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 43 
6.8.1 
Background therapy ....................................................................................................................... 43 
6.8.2 
Allowed concomitant therapy ......................................................................................................... 43 
6.8.3 
Prohibited concomitant therapy ..................................................................................................... 44 
6.8.4 
Rescue medicine ............................................................................................................................ 44 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 46 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 46 
7.1.1 
Permanent discontinuation ............................................................................................................ 46 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 46 
7.1.3 
Temporary discontinuation ............................................................................................................. 47 
7.1.4 
Rechallenge ................................................................................................................................... 47 
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7.1.4.1 
Study intervention restart or rechallenge after liver stopping criteria met ...................................... 48 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 48 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 49 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 50 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 50 
8.1.1 
HbA1c, FPG and fasting C-peptide measurement ........................................................................ 50 
8.1.2 
Body weight .................................................................................................................................... 50 
8.1.3 
Self-monitored plasma glucose (SMPG) measurements, glucometer, participant diary and 
training ........................................................................................................................................... 51 
8.1.3.1 
Fasting SMPG: ............................................................................................................................... 51 
8.1.3.2 
Seven-point SMPG Profile: ............................................................................................................ 51 
8.1.3.3 
Self-monitored plasma glucose during episodes of hypoglycemia: ............................................... 52 
8.1.3.4 
Diary ............................................................................................................................................... 52 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 53 
8.2.1 
Physical examinations ................................................................................................................... 53 
8.2.2 
Vital signs ....................................................................................................................................... 53 
8.2.3 
Electrocardiograms ........................................................................................................................ 54 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 54 
8.2.5 
Pregnancy testing .......................................................................................................................... 54 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 54 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 55 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 55 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 55 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 55 
8.3.5 
Pregnancy ...................................................................................................................................... 56 
8.3.6 
Adverse event of special interest ................................................................................................... 56 
8.3.7 
Hypoglycemia ................................................................................................................................. 57 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 58 
8.4 
STUDY PROCEDURES ................................................................................................................ 58 
8.4.1 
Screening period (Week -2 to Week 0) and Visit 1 ........................................................................ 58 
8.4.2 
Open-label randomized treatment period (Week 0 to Week 24) ................................................... 60 
8.4.2.1 
Randomization visit (V2, Week 0, Day 1) ...................................................................................... 60 
8.4.2.2 
Phone call visits (Visits 3, 5, 7, 9, 11 and 13): ............................................................................... 61 
8.4.2.3 
Onsite visits (Visits, 4, 6, 8, 10, and 12)......................................................................................... 61 
8.4.2.4 
Final on-treatment assessment/end of treatment visit (V14, Week 24) ......................................... 62 
8.4.3 
Post-treatment follow-up phone call visit (V15) ............................................................................. 62 
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8.5 
PHARMACOKINETICS .................................................................................................................. 63 
8.6 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 63 
8.7 
BIOMARKERS ............................................................................................................................... 63 
8.8 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 63 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 63 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 63 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 64 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 64 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 64 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 65 
9.3.1 
General considerations .................................................................................................................. 65 
9.3.2 
Analyses of primary endpoint ......................................................................................................... 65 
9.3.3 
Analyses of secondary endpoints .................................................................................................. 68 
9.3.3.1 
Key secondary endpoints analysis ................................................................................................. 68 
9.3.3.2 
Other secondary endpoints ............................................................................................................ 69 
9.3.4 
Multiplicity adjustment .................................................................................................................... 70 
9.3.5 
Safety analysis ............................................................................................................................... 71 
9.3.5.1 
Adverse events .............................................................................................................................. 72 
9.3.5.2 
Analyses of hypoglycemia ............................................................................................................. 73 
9.3.5.3 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 73 
9.3.5.4 
Study treatment duration and compliance ..................................................................................... 74 
9.4 
INTERIM ANALYSES .................................................................................................................... 74 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 75 
10.1 
APPENDIX 1:  REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ...... 75 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 75 
10.1.2 
Financial disclosure........................................................................................................................ 76 
10.1.3 
Informed consent process .............................................................................................................. 76 
10.1.4 
Data protection ............................................................................................................................... 77 
10.1.5 
Dissemination of clinical study data ............................................................................................... 79 
10.1.6 
Data quality assurance .................................................................................................................. 80 
10.1.7 
Source documents ......................................................................................................................... 81 
10.1.8 
Study and site start and closure ..................................................................................................... 81 
10.1.9 
Publication policy ........................................................................................................................... 82 
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10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 82 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 84 
10.3.1 
Definition of AE .............................................................................................................................. 84 
10.3.2 
Definition of SAE ............................................................................................................................ 86 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 87 
10.3.4 
Reporting of SAEs.......................................................................................................................... 89 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 90 
10.4.1 
Definitions ...................................................................................................................................... 90 
10.4.2 
Contraception guidance ................................................................................................................. 91 
10.5 
APPENDIX 5: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 92 
10.6 
APPENDIX 6: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 97 
10.7 
APPENDIX 7: ABBREVIATIONS ................................................................................................... 98 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY .................................................................. 98 
11 
REFERENCES ............................................................................................................................... 99 
 
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LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 25 
Table 2 - Objectives and endpoints ............................................................................................................... 27 
Table 3 - Overview of study interventions administered ............................................................................... 35 
Table 4 - Arms and associated interventions ................................................................................................ 36 
Table 5 - Dose adjustment algorithm for iGlarLixi ......................................................................................... 38 
Table 6 - Dose adjustment algorithm for IDegAsp ........................................................................................ 39 
Table 7 - Populations for analyses ................................................................................................................ 64 
Table 8 - Protocol-required laboratory tests .................................................................................................. 83 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
Figure 2 - Graphical illustration of the gate-keeping procedure .................................................................... 71 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title: A randomized, 24 weeks, active-controlled, open-label, 2-arm multicenter study 
comparing the efficacy and safety of iGlarLixi to IDegAsp in Chinese type 2 diabetes mellitus 
participants insufficiently controlled with oral antidiabetic drug(s) 
Brief title: iGlarLixi vs IDegAsp in Chinese participants after OAD(s) 
Rationale: Premixed insulins are widely used in China (1) either as initial injectable therapy or as 
insulin treatment advancement. It is therefore meaningful to generate data showing the benefit of 
iGlarLixi over premixed insulins in different populations of people with T2DM. Fixed-ratio 
combinations (FRCs) of basal insulin and GLP-1 RAs can provide a novel alternative to premix 
insulin for therapy advancement. The SoliMix study showed that once daily iGlaLixi, is an 
efficacious and well-tolerated regimen that is simpler for the participant, providing better 
glycemic control with less hypoglycemia compared with the twice-daily premix insulin analog 
Biasp 30 as an alternative for advancing therapy in people with Type 2 diabetes previously 
suboptimaly controlled with basal insulin plus OADs (2). Given the high use of premix insulin as 
first injectable therapy in China (3) it is also very important to compare iGlarLixi and premix 
insulins in Chinese people with T2DM insufficiently controlled with OADs. IDegAsp is arising as 
preferred option for mixed insulin formulations and as such is considered as key comparator for 
new data generation. 
Thus, the proposed study will be a prospective, randomized, controlled trial to assess the efficacy 
and safety of iGlarLixi vs IDegAsp in people with T2DM inadequately controlled on metformin 
with or without a second OAD. 
Objectives and endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To demonstrate the non-inferiority of iGlarLixi 
versus IDegAsp on glycated hemoglobin A1c (HbA1c) 
change from baseline to Week 24 
• 
Change in HbA1c from baseline to Week 24 
Key secondary efficacy                                              
 
• 
To demonstrate superior therapeutic effect of iGlarLixi 
versus IDegAsp on HbA1c and body weight change, 
proportion of participants at HbA1c target, proportion 
of participants at target without weight gain and/no 
hypo after 24 weeks of treatment 
• 
2a Change in HbA1c from baseline to Week 24 
• 
2b Change in body weight from baseline to Week 24 
• 
2c Proportion of participants to reach HbA1c<7% at 
Week 24 
• 
2d Proportion of participants reaching HbA1c targets 
<7% without body weight gain at Week 24 
• 
2e Proportion of participants reaching Hba1c <7% 
with no body weight gain and no hypoglycemia 
(defined as ADA Level 1, 2 or 3) 
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Objectives 
Endpoints 
 
Other secondary  
 
• 
To further assess the therapeutic effect of iGlarLixi in 
comparison with IDegAsp on other glycemic control 
parameters after 24 weeks of treatment 
• 
To assess total insulin dose and percentage of 
participants requiring rescue therapy over the  
24 weeks treatment 
 
• 
Change in Fasting plasma glucose from baseline to 
Week 24 
• 
Change in 7-point self-monitored plasma glucose 
(SMPG) profile from baseline to eek 24 (each time 
point and average daily value) 
• 
Proportion of participants reaching Hba1c target <7% 
with no hypoglycemia (defined as ADA level 1, 2 or 3)  
• 
Proportions of participants reaching HbA1c target  
<7% with no clinically relevant hypoglycaemia 
(defined as ADA level 2 or 3)  
• 
Total insulin dose in each group at Week 24 
• 
Percentage of participants requiring rescue therapy 
during the 24-week treatment period 
• 
Change in fasting C-peptide from baseline to  
Week 24 
Secondary Safety  
 
• 
To assess safety and tolerability of iGlarLixi versus 
IDegAsp  
 
• 
Incidence and Event rates of hypoglycemia (Any, 
ADA classification level 1, 2, and 3) 
• 
Adverse events (AEs), Serious adverse events 
(SAEs), adverse events of special interest (AESIs), 
and AEs leading to treatment discontinuation, vital 
signs and safety laboratory values 
 
Overall design: 
• Open-label, 1:1 randomized, active-controlled, 2 treatment-arm, 24-week treatment 
duration, parallel-group, multicenter Phase 3 study comparing iGlarLixi to IDegAsp. 
• The randomization will be stratified by value of screening HbA1c (<8%, ≥8%), and by use 
at screening of metformin alone or metformin +SGLT2 (Yes/No). Participants with Type 2 
diabetes mellitus (T2DM) diagnosed for at least 1 year before the screening visit will be 
eligible to participate in the study, if they satisfy the inclusion and exclusion criteria. 
Brief summary:  
This is a parallel-group treatment, Phase 3, randomized, 2-arm study to assess the efficacy and 
safety of iGlarLixi to IDegAsp in Chinese T2DM participants insufficiently controlled with oral 
antidiabetic drug(s).  
Study details include: 
• Study duration per participant: approximately up to 27 weeks 
• Treatment duration: 24 weeks 
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• Visit frequency: after screening (an on-site visit), on-site or phone call visit every 1 week 
from randomization till Week 4, every 2 weeks till Week 12 and then every 3 weeks till 
Week 24 (End of Treatment). There will be 14 visits including 7 phone call and 7 on-site 
visits in total during screening and treatment periods. There will be a safety follow-up by a 
phone call visit (End of Study) in 3 days after the last dose of the treatment. 
• Health measurement/Observation: change in HbA1c as the primary endpoint. 
• Intervention name: iGlarLixi and IDegAsp 
• Participant sex: male and female  
• Participant age range: adults at least 18 years of age 
• Condition/disease: Type 2 diabetes mellitus  
• Study hypothesis: Compared to IDegAsp, iGlarLixi will demonstrate a similar therapeutic 
effect on glycemic control assessed by change in HbA1c from baseline to Week 24 in the 
study participants.   
Number of participants: 
Approximately 580 participants will be enrolled, and 290 participants will be randomized to each 
treatment group.  
Note: Enrolled participants are all participants from screened participants who have been allocated 
to an intervention regardless of whether the intervention was received or not.  
Intervention groups and duration: 
Study intervention(s) 
Investigational medicinal product(s) 
iGlarLixi 
• Formulation: iGlarLixi will be supplied as a sterile aqueous solution in 2 different pen-
injectors with 2 different ratios (100 U/mL insulin glargine with 100 or 50 μg/mL 
lixisenatide depending on the pen-injector). iGlarLixi must not be mixed with other 
insulins nor diluted. 
• Administration device: iGlarLixi will be self-administered with a pen-injector device.  
There will be 2 pen-injectors with different insulin glargine/lixisenatide fixed ratios which 
allow insulin glargine titration from 5 U/day to 40 U/day while limiting lixisenatide dose 
to a maximum of 20 μg/day: 
- 
1:1 Pen: pen-injector with 3 mL of a sterile aqueous solution of 100 U/mL insulin 
glargine and 100 μg/mL lixisenatide (1 unit of insulin glargine per 1 μg lixisenatide). 
This pen-injector is to be used for the iGlarLixi treatment initiation and administration 
of daily iGlarLixi doses between 5 and 20 dose steps (5 U insulin glargine / 5 μg 
lixisenatide and 20 U insulin glargine / 20 μg lixisenatide) in increments of 1 dose 
step. 
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- 
2:1 Pen: pen-injector with 3 mL of a sterile aqueous solution of 100 U/mL insulin 
glargine and 50 μg/mL lixisenatide (2 units of insulin glargine per 1 μg lixisenatide). 
This pen-injector is to be used for administration of daily iGlarLixi doses between 21 
and 40 dose steps (21 U insulin glargine / 10.5 μg lixisenatide and 40 U insulin 
glargine / 20 μg lixisenatide) in increments of 1 dose step. 
iGlarLixi pen-injectors will be provided to participants randomized to the iGlarLixi group 
at randomization visit and thereafter. 
• Route(s) of administration: subcutaneous (SC) injection 
• Dose regimen:  
iGlarLixi will be self-administered once daily in the morning in the hour (0 to 60 minutes) 
before the first meal. 
• Starting dose  
iGlarLixi is to be initiated with the 1:1 Pen. The starting dose is 5 to 10 dose steps (5 to 10 U 
insulin glargine/5 to 10 µg lixisenatide) based on investigator’s clinical judgment.  
• Dose adjustment 
After the first week, doses will be titrated once a week according to the dose adjustment 
algorithm to achieve glycemic target of fasting SMPG ≥80 and ≤100 mg/dL (≥4.4 and  
≤5.6 mmol/L) while avoiding hypoglycemia. Thereafter, until the end of the treatment, the 
dose will be adjusted as necessary to maintain this fasting SMPG target. A total daily dose 
greater than 40 dose steps (40 U insulin glargine / 20 μg lixisenatide) is not allowed.  
IDegAsp (Ryzodeg® 70/30) 
• Formulation: IDegAsp will be supplied as a sterile aqueous solution in a Ryzodeg 70/30 
FlexTouch. IDegAsp pen must not be mixed with other insulins nor diluted.  
• Pen-injector device: IDegAsp will be self-administered with FlexTouch®. The IDegAsp 
pen contains 3 mL of a sterile aqueous solution of 100 U/mL insulin Degludec and insulin 
Aspart with a ratio of 70:30.  
• Route(s) of administration: subcutaneous (SC) injection 
• Dose regimen: 
IDegAsp will be self-administered once daily prior to the largest meal of the day according to 
the locally approved label. The injection time will be determined at the discretion of 
participants and Investigators on the day of randomization and should remain about the same 
until the end of the treatment period. 
• Starting dose: 
The recommended starting daily dose is 5 U -10 U based on Investigator’s clinical judgement.  
• Dose adjustment:  
After the first week, dose will be adjusted weekly following same treat to target principle as 
for iGlarLixi.  The titration algorithm recommended for iGlarLixi can be considered as 
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reference or titration can follow clinical practice as per investigator´s discretion. Thereafter, 
until the end of the treatment the dose will be adjusted as necessary to maintain this fasting 
SMPG target.  No dose cap will be set to the upper limit. 
Non-investigational medicinal products (NIMP) 
Background therapy metformin ± SGLT-2 inhibitor and rescue therapy are considered as non-
investigational medicinal products (NIMPs).  
Route(s) of administration: Oral administration for metformin and SGLT-2 inhibitor.  
Dose regimen: Background treatments metformin ± SGLT-2 inhibitor will be administered orally 
according to the locally approved label. Metformin will be reimbursed by the Sponsor. A SU, a 
glinide, an alpha-GI, or a DPP-4 inhibitor, if previously taken, will be stopped at the 
randomization visit. Metformin is mandatory background therapy. Daily metformin dose will be 
maintained until the end of the treatment unless there is a specific safety issue related to this 
treatment. SGLT-2 inhibitors, if previously taken, should be continued at stable dose throughout 
the treatment period unless there is a specific safety issue related to this treatment. 
• Formulation: consistent with local labelling 
Posttrial access to study medication: Not applicable 
Duration of study intervention:  
The total duration of study participation for each participant is up to 27 weeks which includes 
upto 2 weeks of screening, 24 weeks of treatment period and 3 days of follow up period. 
Statistical considerations: 
Sample size determination: a total sample size of 580 participants (randomization ratio 1:1, ie,  
290 per intervention group) will be determined to demonstrate noninferiority of iGlarLixi versus 
IDegAsp in HbA1c reduction at Week 24 with 90% power and 2-sided significance level of 0.05 
based on the following assumptions on the primary endpoint: 
• True mean difference of zero between iGlarLixi and IDegAsp 
• Common standard deviation of 1.05% 
• Non-inferiority margin on the mean difference of 0.3% 
• Dropout rate of 10% 
Analysis populations: the efficacy analyses will be performed in the intent-to-treat (ITT) 
population, comprising all randomized participants. Participants will be analyzed according to the 
treatment group allocated by randomization. The non-inferiority analysis will also be performed 
in the per-protocol population, defined as participants from ITT who completed 24 weeks of 
randomized treatment and have no major or critical protocol deviation that can potentially affect 
efficacy analysis. 
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Safety data will be analyzed in the safety population, defined as all randomized participants who 
take at least 1 dose of study intervention; participants will be analyzed according to the 
intervention they actually received. 
Primary analysis:  
The primary estimand of change in HbA1c from baseline to Week 24 will be analyzed under the 
policy strategy measurements after treatment discontinuation and initiation of rescue medication, 
regardless of the occurrence of the intercurrent event. 
The primary analysis will be based on an ANCOVA model in the ITT population, with missing 
data imputed by multiple imputations using missingness patterns based on treatment completion, 
and under the missing at random (MAR) assumption within each pattern.  
Within each imputed dataset, the change in HbA1c from baseline to Week 24 will be analyzed 
using ANCOVA with treatment group and previous OADs as fixed effects, and baseline HbA1c 
value as continuous covariate. The results obtained from analyzing the datasets will be combined 
using Rubin’s rule to draw inference. The non-inferiority will be assessed using the upper bound 
of the 2-sided 95% confidence interval (CI). If the upper bound of the 95% CI is less than 0.3%, 
the non-inferiority of iGlarLixi versus IDegAsp will be claimed. 
Analysis of secondary endpoints: 
Continuous secondary endpoints will be analyzed using the similar ANCOVA model as the 
primary endpoint, adjusting for treatment groups, randomization strata and appropriate baseline 
covariates. Categorical endpoints will be analyzed using logistic regression model adjusting for 
treatment groups, randomization strata and appropriate baseline covariates. Summaries will be 
prepared for safety and tolerability findings. 
Multiplicity adjustment: to control overall type 1 error at 0.05 level (2-sided), a gate-keeping 
procedure will be used. Two families of hypothesis testing will be established: family 1 of 
primary and family 2 of key secondary hypotheses. For the primary endpoint (change from 
baseline to Week 24 in HbA1c), no multiplicity adjustment is needed to control the Type I error 
since only one comparison of iGlarLixi versus IDegAsp will be performed. 
If the primary endpoint is statistically significant at the 2-sided 0.05 level, a hierarchical testing 
procedure will be performed to test the key secondary efficacy endpoints.  
For other secondary hypotheses, no multiplicity adjustment will be applied. 
Data Monitoring/Other committee: No 
 
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1.2 
SCHEMA  
 
Figure 1 - Graphical study design  
  
 
 
 
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l 
Urine pregnancy test in female of childbearing potential only will be performed at study sites (local). 
m Participants must be in fasting status, not have any food and drinks (except for water) for at least 8 hours.  
n Fasting C-peptide sample at Visit 14/Week 24 should be only collected for participants who have C-peptide samples collected at Visit 2/Week0. 
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; D = day; ECG = electrocardiogram; eCRF = electronic case report form; eGFR = estimated 
glomerular filtration rate; FPG = fasting plasma glucose; FSH = follicle stimulating hormone; G-GT = gamma-glutamyl transpeptidase; HbA1c = glycated hemoglobin A1c;; IMP = investigational medicinal product; IRT 
= interactive response technology; RBC = red blood cell; SAE= serious adverse event; SMPG = self-monitored plasma glucose; V = Visit; WBC = white blood cell. 
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2 
INTRODUCTION  
iGlarLixi is a fixed-ratio combination of insulin glargine 100 u/mL (Lantus®) and the GLP-1 RA 
lixisenatide that is developed for treatment of T2DM. 
2.1 
STUDY RATIONALE  
Premixed insulins are widely used in China (1) either as initial injectable therapy or as insulin 
treatment advancement. It is therefore meaningful to generate data showing the benefit of 
iGlarLixi over premixed insulins in different populations of people with T2DM. Fixed-ratio 
combinations (FRCs) of basal insulin and GLP-1 RAs can provide a novel alternative to premix 
insulin for therapy advancement. The SoliMix study showed that once daily iGlarLixi, is an 
efficacious and well-tolerated regimen that is simpler for the participant, providing better 
glycemic control with less hypoglycemia compared with the twice-daily premix insulin analog 
Biasp 30 as an alternative for advancing therapy in people with type 2 diabetes previously 
suboptimally controlled with basal insulin plus OADs (2). Given the high use of premix insulins 
as first injectable therapy in China (3) it is also very important to compare iGlarLixi and premix 
insulins in Chinese people with T2DM insufficiently controlled with OADs. IDegAsp is arising as 
preferred option for mixed insulin formulations and as such is considered as key comparator for 
new data generation. 
Thus, the proposed study will be a prospective, randomized, controlled trial conducted in China to 
assess the efficacy and safety of iGlarLixi vs IDegAsp in people with T2DM inadequately 
controlled on metformin with or without a second OAD. 
2.2 
BACKGROUND  
Despite novel therapeutic options, many people with type 2 diabetes (T2D) do not achieve their 
individualized HbA1c targets. Close to 50% of participants with type 2 diabetes treated in routine 
practice using any type of therapy do not maintain an A1C value <7.0%, and ∼22% have an A1C 
value >8.0% (3).  
Given the progressive nature of T2D, many individuals un-controlled with multiple oral agents 
will require advancement to injectable therapy using either a glucagon-like peptide-1 receptor 
agonist (GLP-1 RA), recently recommended as a first option, or traditionally a basal insulin (4).  
Premix insulins remain frequently used in several countries including China, either as initial 
injectable therapy or as insulin treatment advancement (1). Premix insulin injections can 
potentially provide significant glycemic improvements but at the expense of increased 
hypoglycemia and weight gain, which may affect treatment adherence (5). Real-world evidence 
suggests that glycemic control often remains suboptimal with premix insulins (5).  
Fixed-ratio combinations (FRCs) of basal insulin and GLP-1 RAs can provide a novel alternative 
to premix insulin for therapy advancement. iGlarLixi combines two different glucose-lowering 
agents with complementary mechanisms of action. Insulin glargine is a long-acting basal insulin 
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that targets mainly FPG levels by mimicking physiologic insulin secretion to provide peakless 
insulin levels over a 24-hour period. Lixisenatide is a once-daily GLP-1 receptor agonist that 
increases insulin levels and decreases glucagon secretion in a glucose-dependent manner, 
minimizing the risk of treatment-related hypoglycemia. Lixisenatide also slows gastric emptying, 
thereby diminishing PPG excursions (6). The development of the fixed-ratio combination of 
insulin glargine and lixisenatide follows a participant-centric treatment approach. With iGlarLixi, 
reaching HbA1c targets is a result of both titration of insulin glargine to fasting glucose targets 
and a concomitant increase of the lixisenatide dose with a corresponding improvement in PPG 
control.   
Efficacy and Safety of iGlarLixi compared to basal insulin and GLP-1RA have been 
comprehensively assessed in global trials Lixilan-O, LixiLan-L and LixiLan-G (7, 8, 9). Similar 
trials have also been conducted in Japanese participants (10, 11, 12). All these studies have shown 
that iGlarLixi has superior efficacy in HbA1c reduction compared to basal insulin and GLP-1RAs, 
with no additional hypoglycemic risk and significantly less weight gain compared to basal insulin, 
and less gastrointestinal side effects compared to GLP-1RAs. 
 In China, phase III studies of iGlarLixi were recently conducted in T2DM participants 
inadequately controlled with OAD(s) and in participants inadequately controlled with basal 
insulin ± OADs. Data is expected to be released by end of 2021 -2022. 
IGlarlixi is approved in around 70 countries, among them in the United States (2016), Europe 
(2017) and Japan (2020). Approval in China is expected by 2022 (13, 14, 15). 
The simplified treatment regimen, high efficacy with weight neutrality and the absence of 
increased risk of hypoglycemia shown with iGlarLixi are likely to have positive impacts on 
treatment adherence. 
Fixed-ratio combinations (FRCs) of basal insulin and GLP-1 RAs can provide a novel alternative 
to premix insulin for therapy advancement. It is therefore meaningful to generate data showing the 
benefit of iGlarLixi over premixed insulins in different populations of people with T2DM. The 
SoliMix study showed that once daily iGlaLixi, is an efficacious and well-tolerated regimen that 
is simpler for the participant, providing better glycemic control with less hypoglycemia compared 
with the twice-daily premix insulin analog Biasp 30 as an alternative for advancing therapy in 
people with type 2 diabetes previously sub optimally controlled with basal insulin plus OADs (2). 
Up to date there is no direct data comparing a FRC to a premix insulin formulation in participants 
sub optimally controlled on OADs. 
Premix insulins are widely used as first injectable therapy in China. Thus, the proposed study will 
be a prospective, randomized, controlled trial conducted in China to assess the efficacy and safety 
of iGlarLixi vs IDegAsp in people with T2DM inadequately controlled on metformin with or 
without a second OAD. 
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2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Risk assessment  
Table 1 - Risk assessment  
Potential risk of 
clinical significance 
Summary of data/rationale 
for risk 
Mitigation strategy 
Study intervention:  
Hypersensitivity  to any of its 
ingredient  
Hypoglycemia caused by the study 
interventions 
Overdose due to medication errors 
Injection site reactions 
GI AEs, including nausea, diarrhea, 
and vomiting caused by iGlarLixi 
(lixisenatide) 
Acute pancreatitis 
Thyroid medullary cell cancer 
 
For details about data and 
rational of the risks, please 
refer to the current version 
of Investigator’s Brochure, 
Section 7.   
 
Participants with known allergy to GLP-1 RA or insulin 
products will be excluded.  investigator will educate the 
participants to seek immediate medical attention if 
suspected event with symptoms and signs.  
Participants will be monitored for hypoglycaemia through 
SMPG and to be educated how to treat hypoglycemia at 
home or seek to medical attention as needed.  
Participants will be well trained in self -injection before the 
1st dosing and at the time when a participant needs to shift 
injection pen from 1:1 to 2:1 pen (iGlarLixi). In addition, 
there will be more training opportunities in case any 
injection issue is observed at the onsite visits. The 
occurrence of dosing error could be efficiently minimized.  
Participants will be educated to change injection location 
(abdominal wall, thighs or upper arms) at each time of 
injection to avoid the injection site skin reaction.  
The GLP-1 class effect of GI reactions will be reduced with 
low starting dose (5 µg/lixisenatide). With the titration 
procedure ie, dose increase every week, the participants 
may tolerate better to higher doses (up to 20 µg).   
Patients with amylase and/or lipase >3 times the upper limit 
of normal (ULN) will be excluded from participation in this 
study. Pancreatic enzymes will be monitored during the 
study. Participants are instructed to seek medical attention 
and report any symptoms of abdominal pain to the 
investigator.  
C-cell hormone calcitonin is measured at screening and 
patients with calcitonin ≥20 pg/mL (5.9 pmol/L) will be 
excluded from participation in the study. 
 
Study procedures: Not 
applicable 
 
 
Other: Not applicable 
 
 
 
2.3.2 Benefit assessment  
• Potential benefit of receiving study intervention known to improve glycemic control 
during the study duration 
• Contributing to the process of developing new therapies in an area of treatment of T2DM 
• Medical evaluations/assessments associated with study procedures [eg, physical exam, 
ECG, glycemic assessments etc]. 
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2.3.3 Overall benefit: risk conclusion  
The investigational medicinal products (IMPs) administered in this study (iGlarLixi and IDegAsp) 
have demonstrated glucose lowering properties and are both approved for the treatment of adult 
participants with T2DM. iGlarLixi has been approved in more than 70 countries worldwide 
including the United States, the European Union, and Japan and is under review in several other 
countries (including China). Given the safety profile observed during development and confirmed 
by post-marketing data, iGlarLixi is considered to be well tolerated and reflective of the 
individual components, with no new risk identified for the population to be included in this study. 
In addition, treatment with both iGlarLixi and premixed IDegAsp is in line with current approved 
label indications. Therefore, the risk for participants participating in this study, using daily doses 
of iGlarLixi up to 40 U of insulin glargine/20 μg of lixisenatide is considered acceptable. All 
participants entering this study will receive treatment with iGlarLixi or IDegAsp on top of 
metformin or metformin + SGLT2i. In addition, all participants will benefit from close 
management of their T2DM. Rescue therapy is planned and described in the clinical study 
protocol for participants whose glycemia remains poorly controlled. Given the expected 
improvement of metabolic control and the additional measures to improve diabetes management, 
these benefits are considered to outweigh the potential risk associated with the iGlarLixi and 
premixed insulin. Therefore, the benefit-risk ratio for participants participating in this study is 
considered favorable. 
 
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3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary  
 
• 
To demonstrate the non-inferiority of iGlarLixi 
versus IDegAsp on glycated hemoglobin A1c 
(HbA1c) change from baseline to Week 24 
• 
Change in HbA1c from baseline to Week 24 
Secondary efficacy                                                 
 
• 
To demonstrate superior therapeutic effect of 
iGlarLixi versus IDegAsp on HbA1c and body 
weight change, proportion of participants at HbA1c 
target, proportion of participants at target without 
weight gain and/no hypo after 24 weeks of 
treatment 
• 
2a Change in HbA1c from baseline to Week 24 
• 
2b Change in body weight from baseline to Week 24 
• 
2c Proportion of participants to reach HbA1c<7% at 
week 24 
• 
2d Proportion of participants reaching HbA1c targets 
<7% without body weight gain at Week 24 
• 
2e Proportion of participants reaching Hba1c <7% with 
no body weight gain and no hypoglycemia (defined as 
ADA level 1,2 or 3) 
Other secondary  
• 
To further assess the therapeutic effect of iGlarLixi 
in comparison with IDegAsp on other glycemic 
control parameters after 24 weeks of treatment  
• 
To assess total insulin dose and percentage of 
participants requiring rescue therapy over the 24 
weeks treatment 
 
 
• 
Change in Fasting plasma glucose from baseline to 
Week 24 
• 
Change in 7-point self-monitored plasma glucose 
(SMPG) profile from baseline to Week 24 (each time 
point and average daily value) 
• 
Proportion of participants reaching Hba1c target <7% 
with no hypoglycemia (defined as ADA level 1, 2 or 3)  
• 
Proportions of participants reaching HbA1c target <7% 
with no clinically relevant hypoglycemia (defined as ADA 
level 2 or 3)  
• 
Total insulin dose in each group at Week 24 
• 
Percentage of participants requiring rescue therapy 
during the 24-week treatment period 
• 
Change in fasting C-peptide from baseline to Week 24 
Secondary Safety  
• 
To assess safety and tolerability of iGlarLixi versus 
IDegAsp  
 
 
• 
Incidence and Event rates of hypoglycemia (Any, ADA 
1-2-3) 
• 
AEs, SAEs, AESIs, and AEs leading to treatment 
discontinuation, vital signs and safety laboratory values 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
The primary efficacy variable is HbA1c values which reflects the glycemic history of the previous 
120 days and is thus an index of mean glycemia, documenting glycemic control over the past 2 to 
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3 months. HbA1c has also been shown to correlate with the development of long-term 
complications of diabetes, and reduction of HbA1c is known to reduce the risk of long-term 
microvascular complications. Therefore, HbA1c is considered an appropriate primary endpoint for 
assessing the effect of a treatment on glycemic control. In addition to the analysis of the change 
from baseline in HbA1c, the responder analysis allows the clinical relevance of the reduction 
observed in HbA1c to be demonstrated. The duration of study treatment is considered to be 
sufficient for achieving stable conditions with IMP after dose titration and for enabling an 
adequate assessment of time dependent changes in HbA1c and the concomitant risk of 
hypoglycemia. 
The problem of weight gain in T2DM is widely recognized. Consequently, iatrogenic weight gain 
is not only unwelcome, but represents an important clinical issue that can become a barrier to the 
successful management of glycemic control. Body weight control is one of the reasons to choose a 
GLP-1 RA instead of rapid-acting insulin to intensify basal insulin therapy in this overweight or 
obese type 2 diabetes population. Taking into account the major impact of insulin-related body 
weight gain, it is appropriate to include body weight change as secondary efficacy endpoint. 
Insulins target primarily, although not exclusively, fasting hyperglycemia, therefore, assessment 
of fasting glucose is relevant in this study. The 7-point SMPG profiles are also considered as a 
valuable parameter for monitoring the overall glycemic control throughout the day. ß-cell function 
will be assessed by fasting C-peptide at baseline and Week 24. The glycemic biomarker (HbA1c) 
will be further evaluated based on the baseline fasting C-peptide levels and therefore to provide 
evidence that iGlarLixi is effective regardless of baseline ß-cell function in patients with T2DM 
suboptimal controlled with OADs. The effect of iGlarLxi in preservation of ß-cell function could 
also be evaluated via the change in fasting C-peptide from baseline to Week 24 (16). 
Composite outcomes such as decrease in HbA1c not associated with body weight gain and/or with 
hypoglycemia events are also of interest in the management of T2DM and will be investigated in 
this study. Along with HbA1c, other glycemic measures such as FPG and SMPG would be 
assessed as secondary endpoints in this study. 
The duration of study treatment is considered to be sufficient for achieving stable conditions with 
IMP and for enabling an adequate assessment of time-dependent changes in HbA1c and the 
concomitant risk of hypoglycemia. 
Safety will be evaluated by standard clinical measurements. The study interventions administered 
in this study are approved with well-established safety profiles; additionally, routine post-baseline 
laboratory testing will be performed. Specific safety parameters of interest for a glucose lowering 
agent such as hypoglycemia and known GLP-1 AR class side effect of GI AEs will also be 
assessed. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
• Open-label, 1:1 randomized, active-controlled, 2 treatment-arm, 24-week treatment 
duration, parallel-group, multicenter phase 3 study 
• Participants with type 2 diabetes mellitus (T2DM) treated with metformin ± one additional 
OAD would be recruited in this study. 
• The randomization will be stratified by value of screening HbA1c (<8%, ≥8%), and by use 
at screening of metformin alone or metformin +SGLT2 (Yes/No). The overall objective of 
this last stratification group is to ensure that participants who will need to discontinue their 
second OAD are well balanced between groups 
• Total duration of study participation for each participant is up to 27 weeks. 
• This study comprises of 3 periods: 
- 
An up-to 2-week screening period during which: a sulfonylurea (SU), a glinide, an 
alpha-glucosidase inhibitor (alpha-GI), or a dipeptidyl-peptidase-4 (DPP-4) inhibitor, 
if previously taken, will be discontinued. Sodium-glucose co-transporter 2 (SGLT-2) 
inhibitor, if previously taken, will be kept at the stable dose; metformin treatment will 
maintain at the stable dose (at least 1000 mg/day or a maximal tolerated dose). 
- 
A 24-week, open-label randomized treatment period with iGlarLixi or IDegAsp, both 
on top of metformin ± SGLT-2 inhibitor. 
- 
A 3-day post-treatment safety follow-up period. 
• Screening is from signed informed consent to randomization  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
• IDegAsp 70/30 (Ryzodeg) is arising as one of the preferred options as co-formulation of 
basal and prandial insulin and so generating this data vs IDegAsp is of clinical relevance. 
• Randomized, controlled study design is widely considered the best and most rigorous way 
of investigating interventional medicine 
• Given the high use of premixed insulins as initial injectable therapy in China, it is of 
special interest to compare iGlarLixi and IDegAsp in Chinese people with T2DM 
insufficiently controlled with OADs 
• Improvement in HbA1c is a standard surrogate outcome measure recognized by the 
medical community and Health Authorities as an appropriate primary endpoint for 
assessing the effect of anti-diabetic treatments on glycemic control. 
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4.3 
JUSTIFICATION FOR DOSE  
Study intervention is discussed in Section 6 with details of starting dose and dose justification 
during the treatment period.     
4.4 
DURATION OF STUDY PARTICIPATION  
4.4.1 Duration of study participation for each participant  
The maximum study duration per participant will be approximately 27 weeks (comprised of a 
screening period of up to 2 weeks, a 24-week open-label randomized treatment period, and a 3-
day post-treatment safety follow-up period). 
4.4.2 Determination of end of clinical trial (all participants)  
The end of the study is defined as being the “last participant last visit” planned with the protocol, 
including follow-up visit. 
The sponsor can terminate the Trial prematurely based on any unforeseen developments.  
 
 
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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 of age inclusive, at the time of signing the informed consent. 
Type of participant and disease characteristics 
I 02. Participants who are diagnosed with T2DM for at least 1 year before the screening visit 
I 03. Participants who are treated for at least 3 months prior to the screening visit with a stable 
dose of metformin (at least 1000 mg/day or the maximum tolerated dose) alone or in 
combination with a second oral antidiabetic treatment that can be a sulfonylurea (SU), a 
glinide, an alpha-glucosidase inhibitor (alpha-GI), a dipeptidyl-peptidase-4 (DPP-4) 
inhibitor or a sodium-glucose co-transporter 2 (SGLT-2) inhibitor  
I 04. HbA1c at screening visit: 
• between 7.5% and 11%, both inclusive, for participants previously treated with metformin 
alone or + SGLT-2 inhibitor, or 
• between 7.0% and 10%, both inclusive, for participants previously treated with metformin 
+ a second oral antidiabetic treatment other than SGLT-2 inhibitor. 
I 05. Participants who are overtly healthy as determined by medical evaluation including 
medical history, physical examination, laboratory tests, and cardiac monitoring.  
Weight 
I 06. Body mass index (BMI) <40 kg/m² at screening 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 07. Male or female, including females of childbearing potential who agree to use contraception 
during the study duration 
Informed Consent 
I 08. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol.  
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participant who has a severe renal function impairment with an estimated glomerular 
filtration rate (eGFR) <30 mL/min/1.73m2  
E 02. Pregnant or breast-feeding woman. 
E 03. Woman of childbearing potential not protected by highly effective contraceptive method of 
birth control and/or who is unwilling or unable to be tested for pregnancy 
E 04. Conditions/situations such as: 
• Participant with short life expectancy. 
• Participant with conditions/concomitant diseases making him/her not evaluable for the 
primary efficacy endpoint (eg, hemoglobinopathy or hemolytic anemia, receipt of blood or 
plasma products within 3 months prior to screening). 
• Participant with conditions/concomitant diseases precluding his/her safe participation in 
this study (eg, active malignant tumor, major systemic diseases, presence of clinically 
significant diabetic retinopathy or presence of macular edema likely to require laser 
treatment within the study period). 
• Uncooperative or any condition that could make the participant potentially non-compliant 
to the study procedures (eg, participant unable or unwilling to do self-injections or blood 
glucose monitoring using the Sponsor-provided blood glucometer at home). 
Prior/concomitant therapy 
E 05. Previous treatment with insulin (except for short-term treatment ≤14 days due to 
intercurrent illness at the discretion of the Investigator) within 1 year prior to screening. 
E 06. Use of oral or injectable glucose-lowering agents other than those stated in the inclusion 
criteria within 3 months prior to screening. 
E 07. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 
1 week or more within 3 months prior to screening. 
E 08. Use of weight loss drugs within 3 months prior to screening. 
E 09. History of discontinuation of a previous treatment with GLP-1 RAs due to 
safety/tolerability reasons or lack of efficacy. 
E 10. Use of any investigational drug other than specified in this protocol within 1 month or 
5 half-lives, whichever is longer, prior to screening. 
Other exclusions 
E 11. Laboratory findings tested at the screening visit: 
• Amylase and/or lipase >3 times the upper limit of normal (ULN) laboratory range. 
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 ULN. 
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• Total bilirubin >1.5 ULN (except in case of Gilbert’s syndrome). 
• Calcitonin ≥20 pg/mL (5.9 pmol/L). 
• Hemoglobin <10.5 g/dL and/or neutrophils <1500/mm3 and/or platelets <100 000/mm3. 
• Positive urine pregnancy test in female of childbearing potential. 
E 12. Contraindication to metformin and/or SGLT-2 inhibitor use, for those who were taking it 
prior to the study, according to local labeling, warning/precaution of use (when 
appropriate) as displayed in the respective National regulation 
E 13. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized  
E 14. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures 
E 15. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with section 1.61 of the ICH-GCP Ordinance E6) 
E 16. Any specific situation during study implementation/course that may raise ethics 
considerations 
E 17. Sensitivity to any of the study interventions (insulin or, or components thereof, or drug or 
other allergy that, in the opinion of the Investigator, contraindicates participation in the 
study  
E 18. Participants who withdraw consent at randomization or are loss to follow up at 
randomization visit. 
5.3 
LIFESTYLE CONSIDERATIONS  
Lifestyle and diet therapy provided before the time of screening is to be continued during the 
study. Dietary and lifestyle counseling will be given by a healthcare professional on the day of 
randomization and as needed during the study, which should be consistent with international or 
local guidelines for participants with T2DM (with regard to the distribution of calories among 
carbohydrates, proteins, and fats, exercise, etc.). 
Compliance with the diet and lifestyle counseling will be assessed in case of insufficient glucose 
control. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
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Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE). 
A participant should not be randomized more than once. In cases where original screen failure 
was due to reasons expected to change during rescreening and based upon the Investigator’s 
clinical judgment, the participant can be rescreened one time for this study. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Appendix 6 (Section 10.6: Contingency measures for a regional or national emergency that is 
declared by a governmental agency) should be considered for 
screening/enrollment/randomization/administration of study intervention.  
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
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. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 3 - Overview of study interventions administered  
Intervention label 
Intervention label 1 
Intervention label 2 
Non-Interventional 
Intervention name 
iGlarLixi 
IDegAsp 
Metformin ± SGLT-2 inhibitor 
Type  
Drug 
Drug 
Drug 
Dose formulation 
Pen injector 
Pen injector 
Tablet 
Unit dose strength(s) 
2 types of SoloStar pens with 2 
different ratios of 1:1 or 2:1  
(100 U/mL insulin glargine with 
100 or 50 μg/mL lixisenatide). 
Each pen injector contains 3 ml 
of iGlarLixi solution. 
Ryzodeg 70/30 FlexTouch® 
which contains 3 ml of  
100 U/ml of insulin Degludec 
and insulin Aspart with a ratio 
of 70:30. 
 
Dosage level(s) 
  
 
 
 
 
 
 
 
 
 
 
  
Dosing time:  
Once daily in the hour (0 to  
60 minutes) before the first 
meal. 
 
Starting dose: 
Initiated with the 1:1 Pen at a 
dose of 5-10 dose steps (5-10 U 
insulin glargine / 5 -10 μg 
lixisenatide) per Investigator’s 
judgment. 
 
Dose modification: 
Once a week titration according 
to the algorithm described in 
Section 6.1.4   
 
 
Dosing time:  
Once daily before the largest 
meal. Time determined at the 
discretion of participants and 
Investigators at randomization 
and to remain unchanged 
during the treatment 
Starting dose: 
5-10 U per Investigator’s 
judgment. 
 
Dose modification: 
Once a week titration 
according to investigator´s 
discretion, or refer to the 
algorithm described in  
Section 6.1.4  
 
Metformin ± SGLT-2 inhibitor 
will be administered orally 
according to the locally 
approved label.  
 
Daily dose of metformin ± 
SGLT2 inhibitor (if previously 
taken) will be continued and 
maintained at the stable dose 
until the end of the treatment 
unless there is a specific 
safety issue related to this 
treatment.  
 
An SU, a glinide, an alpha-GI, 
or a DPP-4 inhibitor, if 
previously taken, will be 
stopped prior to 
randomization. 
 
Route of 
administration 
Self- administration via SC 
injection 
Self-administration via SC 
injection 
Oral administration  
Use 
Experimental 
Active comparator 
Background intervention 
IMP or NIMP 
IMP  
IMP  
NIMP 
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Packaging and 
labeling 
Study Intervention will be 
provided in kit. Each kit will be 
labeled as required per country 
requirement. 
Study Intervention will be 
provided in kit. Each kit will be 
labeled as required per 
country requirement. 
 
 
Table 4 - Arms and associated interventions  
Arm name 
1 
2 
Associated interventions 
(intervention label[s]) 
iGlarLixi  
IDegAsp  
 
6.1.1 Devices:  
Injectors:  
iGlarLixi will be self-administered with a pen-injector.  
There will be 2 pen-injectors with different insulin glargine/lixisenatide fixed ratios which allow 
insulin glargine titration from 5 U/day to 40 U/day while limiting lixisenatide dose to a maximum 
of 20 μg/day: 
• 1:1 Pen: pen-injector with 3 mL of a sterile aqueous solution of 100 U/mL insulin glargine 
and 100 μg/mL lixisenatide (1 unit of insulin glargine per 1 μg lixisenatide). This pen-
injector is to be used for the iGlarLixi treatment initiation and administration of daily 
iGlarLixi doses between 5 and 20 dose steps (5 U insulin glargine / 5 μg lixisenatide- 20 U 
insulin glargine / 20 μg lixisenatide) in increments of 1 dose step 
• 2:1 Pen: pen-injector with 3 mL of a sterile aqueous solution of 100 U/mL insulin glargine 
and 50 μg/mL lixisenatide (2 units of insulin glargine per 1 μg lixisenatide). This pen-
injector is to be used for administration of daily iGlarLixi doses between 21 and 40 dose 
steps (21 U insulin glargine / 10.5 μg lixisenatide and 40 U insulin glargine / 20 μg 
lixisenatide) in increments of 1 dose steps. 
iGlarLixi pen-injectors will be provided to participants randomized to the iGlarLixi group at 
randomization visit and thereafter. 
IDegAsp (Insulin Degludec and Insulin Aspart Injection) will be supplied as a sterile aqueous 
solution in a Ryzodeg 70/30 FlexTouch. IDegAsp pen must not be mixed with other insulins nor 
diluted.  
The IDegAsp pen contains 3 mL of a sterile aqueous solution of 100 U/mL insulin Degludec and 
insulin Aspart with a ratio of 70:30.  
All device deficiencies (including malfunction, use error and inadequate labelling) shall be 
detected, documented, and reported by the Investigator throughout the clinical investigation (see 
Section 8.3.8) and appropriately managed by the Sponsor. 
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6.1.2 Training for injection devices  
Handling procedures of the pen-injectors administration technique will be provided in specific 
instructional pen-injectors leaflets. The participants will be trained on how to use the relevant pen 
injectors and needles correctly, how to store it, and how to change the needle by the study staff 
and provided with an instruction leaflet at randomization visit (V2, Day 1), for the pen-injector 
devices listed below. 
At V2, depending on the randomized treatment group, participants will be trained on: 
• 1:1 pen injector and 2:1 pen injector for participants randomized to receive iGlarLixi 
• Ryzodeg 70/30 FlexTouch® for participants randomized to receive IDegAsp 
Training will be repeated as often as deemed necessary by study site staff during the treatment 
period. Additional training is needed if participants need to switch from 1:1 Pen to 2:1 Pen. The 
pen-injectors and leaflet that the participant will need to use during the treatment period will be 
dispensed according to the visit. Each participant is supplied with the appropriate number of pen-
injectors according to the dispensing scheme indicated in the study flowchart. 
Pen-injectors should never be shared with others, even if the needle is changed. Participants must 
always use a new needle for each injection to help ensure sterility and prevent blocked needles. 
Reuse or share needles with another person is not allowed. Participants must remove needles from 
pen-injectors after each injection completion. 
Pen device-related issues (malfunctions) must be reported to the Sponsor via the procedure for 
product technical complaint (PTC), using the respective PTC form, which is described in a 
separate manual. See Section 8.3.8 for guidelines for reporting PTC." 
6.1.3 Dosage schedule  
Injection time 
iGlarLixi 
iGlarLixi will be self-administered once daily in the morning in the hour (0 to 60 minutes) before 
the first meal using the pen-injector.  
IDegAsp: 
IDegAsp will be self-administered once daily before the largest meal of the day using Ryzodeg 
70/30 FlexTouch® pen. The injection time will be determined at the discretion of participants and 
Investigators on the day of randomization and should remain about the same until the end of the 
treatment period. 
Injection site 
The study intervention should be administered by deep SC injection, alternating between the left 
and right anterolateral and left and right posterolateral abdominal wall or thighs or upper arms. 
Within a given area, location should be changed (rotated) at each time to prevent injection site 
skin reactions. 
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6.1.4 Starting dose and dose modification  
6.1.4.1 iGlarLixi  
Starting dose: 
iGlarLixi is to be initiated with the 1:1 Pen. The recommended starting daily dose is 5 dose steps 
(5 U insulin glargine / 5 μg lixisenatide). A higher starting daily dose up to 10 dose steps (10 U 
insulin glargine / 10 μg lixisenatide) may be allowed in some cases according to the investigator’s 
clinical judgment that a higher starting dose of iGlarLixi is considered necessary.  
A starting daily dose greater than 10 dose steps (10 U insulin glargine / 10 μg lixisenatide) is not 
allowed, in order not to exceed the recommended starting dose of lixisenatide which is 10 μg. 
Dose adjustment: 
• After the first week, doses will be titrated once a week according to the dose adjustment 
algorithm described in Table 5 to achieve glycemic target of fasting SMPG ≥80 and 
≤100 mg/dL (≥4.4 and ≤5.6 mmol/L) while avoiding hypoglycemia. 
• Thereafter, until the end of the treatment period, the dose will be adjusted as necessary to 
maintain this fasting SMPG target. A total daily dose greater than 40 dose steps (40 U 
insulin glargine / 20 μg lixisenatide) is not allowed. Doses may be modified at any time for 
hypoglycemia.  
Dose modification will be based on a median of fasting SMPG values from the last 
3 measurements, which may include the value measured on the day of titration, measured by 
the participant using glucometers and accessories supplied by the Sponsor for this study. 
Table 5 - Dose adjustment algorithm for iGlarLixi  
Median of fasting SMPG values from the last 3 measurements, which may 
include the value measured on the day of titration 
iGlarLixi dose adjustments (dose step/day) 
>140 mg/dL (>7.8 mmol/L) 
+ 4 
>100 and ≤140 mg/dL (>5.6 and ≤7.8 mmol/L) 
+ 2 
Glycemic target: ≥80 and ≤100 mg/dL (≥4.4 and ≤5.6 mmol/L) 
No change 
≥60 and <80 mg/dL (≥3.3 and <4.4 mmol/L) 
- 2 
<60 mg/dL (<3.3 mmol/L) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or one severe hypoglycemic episode (requiring 
assistance) documented in the preceding week 
- 2 to -4 or at the discretion of the Investigator 
or medically qualified designee 
 
Median refers to intermediate SMPG value (the value between the lowest and the highest SMPG 
values when the values are ranked in a growing order). 
Note: Choice of pen-injector for iGlarLixi: 
• If the participant needs a total daily iGlarLixi dose of 5 to 20 dose steps, use the 1:1 Pen 
(100 U/mL insulin glargine with 100 μg/mL lixisenatide).  
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• If the participant needs a total daily iGlarLixi dose of 21 to 40 dose steps, use the 2:1 Pen 
(100 U/mL insulin glargine with 50 μg/mL lixisenatide).  
Daily doses of iGlarLixi higher than 40 dose steps (40 U insulin glargine / 20 μg lixisenatide) 
must not be administered. In case a dose >40 dose steps iGlarLixi is needed to maintain HbA1c 
below predefined threshold value for rescue, the dose must be kept at 40 dose steps and a rescue 
therapy should be introduced (see Section 6.8.4 for rescue therapy). 
6.1.4.2 IDegAsp:  
Starting dose: 
The recommended starting daily dose is 5 U. A higher starting daily dose up to 10 U may be 
allowed in some cases if according to clinical judgment the investigator believes that a higher 
starting dose might be necessary. A starting daily dose greater than 10 U is not allowed. 
Dose modification: 
After the first week, dose will be adjusted weekly to reach and maintain glycemic target of fasting 
SMPG ≥80 and ≤100 mg/dL (≥4.4 and ≤5.6 mmol/L) while avoiding hypoglycemia.  Titration 
should be based on median of fasting SMPG of 3 consecutive days measurements. According to 
their best clinical judgement, investigators can either follow the algorithm they usually use in their 
daily medical practice or the recommended algorithm below which is similar as used for iGlarlixi  
Table 6 - Dose adjustment algorithm for IDegAsp  
Median of fasting SMPG values from the last 3 measurements, which may 
include the value measured on the day of titration 
IDegAsp dose adjustments (U/day) 
>140 mg/dL (>7.8 mmol/L) 
+ 4 
>100 and ≤140 mg/dL (>5.6 and ≤7.8 mmol/L) 
+ 2 
Glycemic target: ≥80 and ≤100 mg/dL (≥4.4 and ≤5.6 mmol/L) 
No change 
≥60 and <80 mg/dL (≥3.3 and <4.4 mmol/L) 
- 2 
<60 mg/dL (<3.3 mmol/L) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or one severe hypoglycemic episode (requiring 
assistance) documented in the preceding week 
- 2 to -4 or at the discretion of the Investigator 
or medically qualified designee 
 
Median refers to intermediate SMPG value (the value between the lowest and the highest SMPG 
values when the values are ranked in a growing order). 
• Attention for dose modification (iGlarLixi and IDegAsp): iGlarLixi or IDegAsp dose 
titration may be withheld for a week or reduced in a participant who experiences two or 
more episodes of level 1 and/or level 2 hypoglycemia or one episode of level 3 
hypoglycemia (requiring assistance from others to treat the hypoglycemic event) 
• Participants who experienced hypoglycemia as a result of a missed meal, unusual exercise, 
or alcohol use will be counseled on the correction of those behaviors and may not need to 
have their insulin dose decreased. 
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• Investigators are allowed to modulate or stop titration or temporarily reduce dosage if they 
believe further titration would be hazardous to the participant (eg, due to age, comorbid 
conditions, individual participant considerations, other than hypoglycemia). In such a case 
the reason for the exceptions should be recorded in the source document. 
Good clinical judgment is to be exercised in dose titration for investigators to identify any barriers 
for participants’ titration compliance, eg., diet and exercise, alcohol consumption, and any 
concomitant illness.  Participants should be familiarized with the titration schedule so that they 
would be able to monitor the titration with the assistance of the investigator or medically qualified 
designee.  Investigators and qualified designees are encouraged to communicate with participants 
during the dose titration. More frequent contact via telecommunications eg, phone call, text 
message, WeChat etc can be added between visits if needed.   
6.2 
STUDY INTERVENTION PACKAGING AND LABELING  
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
The appropriate number of kits will be dispensed to cover up to the next dispensing visit (see the 
study flowchart in Section 1.3). Storage conditions and use-by-end date are part of the label text. 
Treatment kit labels will indicate the treatment number (used for treatment allocation and reported 
in the eCRF). The participant number, visit number, and date of dispensation will be entered 
manually by the site staff on the treatment box label prior to dispensing. 
In case of emergency only, for scheduled or unscheduled visits, the IMP might be supplied from 
the site to the participant via a Sponsor-approved courier company where allowed by local 
regulations. Direct-To-Patient (DTP) remains an option and the participant/investigator can refuse 
this option. 
6.3 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP/NIMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc.) must be promptly notified to 
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the Sponsor. Some deficiencies may be recorded through a complaint procedure (see  
Section 8.3.8). 
A potential defect in the quality of IMP/NIMP/device may be subject to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor, in order to recall the IMP/NIMP/device and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP/device to a third party (except for 
DTP shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP/NIMP/device to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP/device in any other manner. 
6.4 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
• The randomized intervention kit number list is generated centrally by Sanofi. 
• The IMPs are packaged in accordance with this list. 
• An interactive response technology (IRT) will generate the participant randomization list 
and allocates the intervention number and the corresponding intervention kits to the 
participants according to it.  
• All participants will be centrally assigned to randomized study intervention using an IRT. 
Before the study is initiated, the telephone number and call-in directions for the IVRS 
and/or the log in information and directions for the IWRS will be provided to each site. 
• Study intervention will be dispensed at the study visits summarized in the SoA.  
• Returned study intervention should not be re-dispensed to the participants. 
• The randomization will be stratified by value of screening HbA1c (<8%, ≥8%), and by use 
at screening of metformin alone or metformin +SGLT2 (Yes/No). 
• The overall objective of this last stratification group is to ensure that participants who will 
need to discontinue their second OAD are well balanced between groups. Definition of a 
randomized participant: a participant from screened population who has been allocated to 
a randomized intervention regardless of whether the intervention was received or not.  
• A participant cannot be randomized more than once in the study. 
• This is an open-label study because of the existing differences in the type and features of 
pens used to administer the iGlarLixi and IDegAsp. To compensate for the lack of 
blinding, the Investigator and the Sponsor will not have access to the data of the primary 
efficacy parameters (HbA1c, objectively collected and measured at a central laboratory) 
obtained after baseline visit until the end of the study. 
However, the study team may review the data for the primary efficacy parameter in 
descriptive statistics with the name of the IMP treatment masked during data review 
meetings. 
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6.5 
STUDY INTERVENTION COMPLIANCE  
• IMP accountability: 
- 
Intervention units are returned by the participant at each on-site visit. In case of DTP 
process, the intervention units can be returned by the carrier (if defined in the contract) 
- 
The Investigator counts the units remaining in the returned packs, and fills in the 
Intervention Log Form 
- 
The Investigator records the dosing information on the appropriate page(s) of the 
eCRF. 
- 
Also, a diary will be completed by the participant at each IMP administration. 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP which he/she has retrieved and intervention log forms 
- 
Proper placement of tear-off label for accounting purposes 
- 
For SC injections, participants will be given training during the randomization period 
to ensure that the participant accepts the route of administration (participant will not be 
randomized if not comfortable with SC injections). 
Compliance with study intervention will be assessed at each visit. Compliance will be assessed by 
direct questioning, counting of returned units in the pen devices during the site visits and 
documented in the source documents and relevant form. Deviation(s) from the prescribed dosage 
regimen should be recorded. 
A record of the quantity of study intervention dispensed to and administered by each participant 
must be maintained and reconciled with study intervention and compliance records.  Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
There will be no access to study intervention or any additional care provided after the end of the 
study. 
6.7 
MANAGEMENT OF OVERDOSE  
For this study, an overdose is defined as: 
• For iGlarLixi: any dose corresponding to a lixisenatide daily dose greater than 40 μg (ie, 
>40 U [40 U insulin glargine / 40 μg lixisenatide] for 1:1 Pen, >80 U [80 U insulin 
glargine / 40 μg lixisenatide] for 2:1 Pen) 
• For IDegAsp: any dose administration which, in the Investigator’s opinion based on 
clinical judgment, is considered significantly greater than the prescribed dose of insulin, 
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• An overdose with metformin is defined as any dose greater than 2-fold above the 
recommended/planned or prescribed dose administrated per day within this study. 
In the event of an overdose, the Investigator should: 
• Contact the Sponsor immediately. 
• Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities until study 
intervention can no longer be detected systemically. 
• Document appropriately in the CRF. 
6.8 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
6.8.1 Background therapy  
Background treatments metformin ± SGLT-2 inhibitor are considered as NIMPs and will be 
administered orally according to local labeling. Metformin will be supplied or reimbursed by the 
Sponsor. An SU, a glinide, an alpha-GI, or a DPP-4 inhibitor, if previously taken, will be stopped 
before or on the randomization day (V2) for the participants who are eligible for randomization. 
Metformin is mandatory background therapy. Daily metformin dose (at least 1000 mg or the 
maximum tolerated dose) should remain unchanged until the end of treatment period unless there 
is a specific safety issue related to this treatment. 
SGLT-2 inhibitors, if previously taken, should be continued at the stable dose throughout the 
treatment period unless there is a specific safety issue related to this treatment. 
The dose of metformin and SGLT-2 inhibitors is to be reported in the eCRF. 
6.8.2 Allowed concomitant therapy  
Any therapies or medications other than prohibited concomitant therapy in addition to the study 
intervention should be kept to a minimum during the study. However, if these are considered 
necessary for the participant’s welfare and are unlikely to interfere with the study intervention, 
they may be given at the discretion of the Investigator, with a stable dose (when possible). 
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In the iGlarLixi treatment group, for oral medicinal products that are particularly dependent on 
threshold concentrations for efficacy, such as antibiotics, statins and oral contraceptives, 
participants should be advised to take those medicinal products at least 1 hour before or 11 hours 
after study intervention injection. Gastro-resistant formulations containing substances sensitive to 
stomach degradation should also be administered 1 hour before or 11 hours after injection of 
iGlarLixi. 
Specific treatments, which are ongoing before the study and/or prescribed or changed during the 
study, must be recorded in the eCRF and source data. 
6.8.3 Prohibited concomitant therapy  
The following drugs are not permitted during the screening period and the 24-week randomized 
open-label treatment period: 
• Any glucose-lowering agents other than the study interventions, authorized background 
antidiabetic therapy (metformin ± SGLT-2 inhibitor) and rescue therapy, if necessary. 
• Note: Short time use (≤14 days) of short/rapid-acting insulin due to acute illness or surgery 
(eg, infectious disease) is allowed. 
• Systemic glucocorticoids for more than 14days (topical or inhaled applications are 
allowed). 
• Body weight loss drugs which is defined as prescription medications with indication to 
treat overweight or obesity. 
• Using any study interventional drugs other than those specified in this protocol. 
After the last administration of study interventions during the study period, any antidiabetic 
treatments are permitted, as deemed necessary by the Investigator. 
6.8.4 Rescue medicine  
The date and time of rescue medication administration as well as the name and dosage regimen of 
the rescue medication must be recorded. 
Routine central laboratory alerts on HbA1c are required to ensure that glycemic parameter results 
remain under predefined threshold value. In case HbA1c is above threshold (HbA1C > 8% at 
Week 12 or later on), the investigator will receive an alert issued by the central laboratory and 
should ensure that no reasonable explanation exists for insufficient glucose control and in 
particular that the study treatment is appropriately titrated according to the titration algorithm (up 
to a maximum of 40 dose steps [40 U insulin glargine / 20 μg lixisenatide] for iGlarLixi group; no 
upper limit for IDegAsp group), compliance to diet and lifestyle is appropriate, and there is no 
intercurrent disease, which may jeopardize glycemic control (eg, infectious disease) 
If any of the above can reasonably explain insufficient glycemic control, the Investigator should 
take appropriate actions and retest the central lab HbA1C in 4 weeks at next visit or an 
unscheduled visit whichever suitable.  
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If the repeated HbA1c remains above 8% despite appropriate corrective actions or none of the 
above-mentioned reasons can be found and managed, a rescue therapy can be considered.  
• For iGlarLixi group, rescue therapy can be considered if a daily dose >40 dose steps is 
necessary to decrease HbA1c below the threshold, or if any safety concerns (repeated 
hypoglycemia, severe gastrointestinal AE, etc) prevent up titration to reach 40 dose steps 
according to the Investigator’s judgment.  
• In both iGlarLixi and IDegAsp treatment groups, it is recommended to add one 
rapid/short-acting insulin; this should be started as a single daily administration to be 
given at a meal of the day as appropriately at the investigator’s discretion. 
No other GLP-1 RA or DPP-4 inhibitor or basal insulin, including pre-mixed insulin, should be 
used as rescue medication in either of the treatment groups. 
Once rescue medication is considered as necessary as per the investigator’s medical decision, the 
participant should be scheduled for a Pre-rescue onsite visit. Before initiating rescue therapy, all 
assessments (except 7-point SMPG) planned at the end of treatment visit are to be performed at 
the pre-rescue visit. After these assessments are completed and rescue therapy initiated, the 
participant will remain in the study and continue to administer the study treatment (including 
background therapies). The planned visits and assessments should be performed until the last 
scheduled visit. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
The study intervention should be continued whenever possible. In case the study intervention is 
stopped, it should be determined whether the stop can be made temporarily; permanent study 
intervention discontinuation should be a last resort. Any study intervention discontinuation must 
be fully documented in the eCRF. In any case, the participant should remain in the study as long 
as possible. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Permanent discontinuation  
• In general, Pregnancy will lead to permanent intervention discontinuation. 
• Stopping rules described in Appendix 10.5 (Section 10.5) should be applied, if applicable  
• Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation (please specify, eg after 24 hours) before making a decision of permanent 
discontinuation of the IMP for the concerned participant. 
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for end of study visit. See the SoA for data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to be 
completed. 
Handling of participants after permanent intervention discontinuation 
Participants will be followed-up 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-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in the algorithm or in the presence of abnormal 
liver chemistries not meeting protocol-specified stopping rules if the Investigator believes that it is 
in best interest of the participant. 
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7.1.3 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Appendix 6, Section 10.6: Contingency measures for a regional or 
national emergency that is declared by a governmental agency). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
CRF or eCRF.  
It is in the interest of the participant to monitor their blood glucose as per the protocol requirement 
during the temporary discontinuation period, therefore regular determination of SMPG is to be 
performed and documented. For all temporary treatment discontinuations regardless if related to 
an AE or other reasons, the duration should be recorded by the Investigator in the appropriate 
pages of the eCRF when considered as confirmed. Use of any other antihyperglycemic medication 
during the time of temporary treatment discontinuation is recorded as concomitant medication 
with the name and doses recorded in the eCRF. 
7.1.4 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 AE was unlikely 
and if the selection criteria for the study are still met. 
For a regional or national emergency declared by a governmental agency that is an 
epidemic/pandemic (eg COVID-19), the following text should also be considered and added to 
Appendix 6 (Section 10.6: Contingency measures for a regional or national emergency that is 
declared by a governmental agency) if applicable: During a regional or national emergency 
declared by a governmental agency, re-initiation of IMP can only occur once the Investigator has 
determined, according to his/her best judgement, that the contribution of the IMP(s) to the 
occurrence of the epidemic event (eg, COVID-19) was unlikely. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 6 (Section 10.6: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
Maximal duration of IMP temporary discontinuation to allow IMP restart: 
• Up to 4 weeks if before Week 12 
• Up to 2 Weeks if after Week 12 and before Week 21 
• No re-initiation should be done from Week 21 
The investigator may prescribe the re-starting IMP dose at the last dose given before the 
temporary discontinuation or at an appropriate lower dose based on the investigator’s medical 
judgment after a careful assessment on the participant’s glycemic status and the tolerability of the 
IMP. 
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Type of antidiabetic treatments that can be used during the temporary IMP discontinuation should 
be referenced to the respective Rescue therapy: 
• No other GLP-1 RA, basal insulin (including pre-mixed insulin) or DPP-4 inhibitor should 
be used. 
7.1.4.1 Study intervention restart or rechallenge after liver stopping criteria met  
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study is not allowed. 
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant with 
study intervention unless: 
• Sponsor approval is granted 
• Ethics and/or IRB approval is obtained, if required, and 
• Separate consent for intervention restart/rechallenge is signed by the participant 
NOTE: If study intervention was interrupted for suspected intervention-induced liver injury, 
the participant should be informed of the risk of death, liver transplantation, hospitalization, 
and jaundice and re-consented before resumption of dosing. 
If Sponsor approval to restart/rechallenge participant with study intervention is not granted, then 
participant must permanently discontinue study intervention and may continue in the study for 
protocol-specified follow up assessments. 
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, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed. 
• 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. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
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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 study withdrawals should be recorded by the Investigator in the appropriate 
screens of the e-CRF and in the participant’s medical records. In the medical record, at least the 
date of the withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. The statistical analysis plan (SAP) 
will specify how these participants lost to follow-up for their primary endpoints will be 
considered. 
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 (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
• Site personnel, or an independent third party will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study intervention. Public sources may be searched for vital status 
information.  If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1, 
(Section 10.1).  
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, 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.  
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 200 mL.  
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.  
8.1 
EFFICACY ASSESSMENTS  
Planned time points for all efficacy and/or immunogenicity assessments are provided in the SoA. 
8.1.1 HbA1c, FPG and fasting C-peptide measurement  
For the eligibility and efficacy assessments of the study, HbA1c, FPG and fasting C-peptide are 
measured by a Chinese national certified central laboratory. Please refer to the flowchart in SoA.  
8.1.2 Body weight  
Body weight should be obtained with the participant wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study and 
calibrated on a regular basis as recommended by the manufacturer. 
The use of balance scales is recommended; if digital scales are used, testing with standard weights 
is of particular importance. The floor surface on which the scale rests must be hard and should not 
be carpeted or covered with other soft material. The scale should be balanced with both weights at 
zero and the balance bar aligned. The participant should stand in the center of the platform as 
standing off-center may affect measurement. The weights are moved until the beam balances (the 
arrows are aligned). The weight is read and recorded in the eCRF and source data. Self-reported 
weights are not acceptable; participants must not read the scales themselves. 
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8.1.3 Self-monitored plasma glucose (SMPG) measurements, glucometer, participant 
diary and training  
Study participants will be supplied with a glucometer, the corresponding supplies (lancets, test 
strips, etc.), a leaflet, and with diaries at Visit 1 (Week -2) in order to perform self-measurement 
of plasma glucose and its recording. Participants will be trained how to use the glucometer. 
The glucometers should be calibrated according to instructions given in the package leaflet. To 
ensure the quality and data validity of glucometers, site staff should train participants on how to 
use control solution to run the control test according to glucometer manual, especially when a new 
container of test strips is opened; for each on site visit, site staff should check the date/time setting 
of glucometers and also run a control test. Appropriate documentation should be maintained 
Participants will be instructed to bring their glucometers and participant diaries with them to each 
site visit. 
8.1.3.1 Fasting SMPG:  
Fasting SMPG will be used by the Investigator and participants if appropriate to titrate and adjust 
iGlarLixi or IDegAsp dose and to monitor glycemic control. The fasting SMPG should be 
measured by the participant before the first meal and before the administration of the glucose-
lowering agents (IMP or background OAD) once a day from Visit 2 (Week 0, Day 1) to Visit 10 
(Week 12), and then at least 3 days per week to the end of treatment Visit 14 (Week 24). The 
Investigator may decide to request more frequent SMPG if considered necessary for the 
participant. 
Study participants will be instructed to document SMPG values in their diary books. Investigators 
and site staffs will review and validate the SMPG and the IMP doses in the diary records.  During 
the treatment period, (Day 1 up to Week 24), only 3 fasting SMPG values per week should be 
recorded in the eCRF: 
• In any week, the 3 fasting SMPG values that are used for IMP dose modification which 
may include the value on the day of titration.  
• If no IMP dose modification occurs, from Day 1 up to Week 12, the 3 fasting SMPG 
measured in the first 3 days of the week, (preferably 3 consecutive days, eg: Mon-Tues-
Wednesday). The same rule is applicable for documentation of fasting SMPG after  
Week 12 if more than 3 days’ SMPG are measured by the participants.  
8.1.3.2 Seven-point SMPG Profile:  
The 7-point SMPG profile should be measured at the following 7-points: pre-prandial (before 
starting a meal) and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two hours 
postprandial (breakfast, lunch and dinner) is defined as 2 hours after the start of the meal. 
The participants are requested to perform 7-point SMPG profile measurement over a single 24-
hour period on 2 different days in the week prior to Visit 2 (Week 0, Day 1), Visit 10 (Week 12), 
and Visit 14 (Week 24). All SMPG values measured on these days will be recorded in diary and 
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entered into the eCRF. On the 7-point profile days, information on times of meals, each of SMPG 
measurement and injection time with doses of IMP should be recorded in the participant diary and 
entered in the eCRF. 
7-Point SMPG is not required for assessments at pre-rescue and premature IMP discontinuation 
visits.  
8.1.3.3 Self-monitored plasma glucose during episodes of hypoglycemia:  
Whenever the participant feels hypoglycemic symptoms, plasma glucose should be measured by 
the participant (or others, if applicable), if possible. Participants should be instructed to measure 
plasma glucose levels prior to the administration of glucose or carbohydrate intake whenever 
symptoms due to hypoglycemia is suspected, unless safety considerations necessitate immediate 
glucose/carbohydrate rescue prior to confirmation. 
The SMPG values are to be entered in the participant diary and entered in the eCRF.  
Further SMPG: The Investigator may decide to request more frequent SMPG if considered 
necessary for the participant. The SMPG values are to be entered in the participant diary. 
8.1.3.4 Diary  
Instruction on how to complete the participant diary on a daily basis will be provided by site staff. 
At each on site visit: 
• The study site staff reviews the participant diary. 
• SMPG values stored in the glucometer memory will be downloaded, printed out, dated, 
signed and filed into the participant file.  
This information will help the Investigator to assess treatment effects, adjust insulin doses and 
compliance.  
Note: The SMPG values recorded into the diary, which have to be entered in the eCRF, have to be 
checked for consistency with the information downloaded from the glucometer. In case of 
inconsistency, the reason for inconsistency has to be documented. If needed, the resulting action 
(eg, training of the participant on correct documentation of the values) is also to be documented. 
The confirmed values will be entered into eCRF by the Investigator or designee based on the 
glucometer output values.  
The participant diary includes but not limited to the following information:  
• Time and dose of IMP (iGlarLixi or IDegAsp) injections.  
• Missed IMP injection (including start date and end date).  
• Time and value of fasting SMPG measurements.  
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• Time of start of meals and SMPG measurements as well as plasma glucose values on the 
day of the 7-point profile.  
• Potential changes in metformin treatment and/or SGLT2 inhibitor (if appropriate).  
• Adverse events, including signs and symptoms suggesting occurrence of hypoglycemia 
and local injection site reactions, if any.  
• Any problems with the pen-injector.  
• Any concomitant medications including prescription and over-the counter drugs. 
8.2 
SAFETY ASSESSMENTS  
This section presents safety assessments other than AEs which are presented in Section 8.3.  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A physical examination will include, at a minimum, assessments of the [Cardiovascular, 
Respiratory, Gastrointestinal and Neurological] systems. Height (at V1) and weight will 
also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous and ongoing 
illnesses and related to AE during the study. 
8.2.2 Vital signs  
• Blood pressure (mmHg) should be measured when the participant is quiet and seated and 
with their arm outstretched in line with mid-sternum and supported. Measurement should 
be taken under standardized conditions, approximately at the same time of the day, on the 
same arm, with the same device (after the participant has rested comfortably for at least 
five minutes) and the values are to be recorded in the eCRF. Both systolic blood pressure 
and diastolic blood pressure should be recorded.  
• Determination of the arm for blood pressure measurements: At screening visit (V1, Week -
2) of the screening period, blood pressure has to be measured on both of the arms after 
5 minutes in seated position and then again after two minutes in both arms in seated 
position. The arm with the higher diastolic pressure will be determined at this visit, 
identifying the reference arm for future measurements throughout the study. The highest 
value will be recorded in the eCRF (all blood pressure values are to be recorded in the 
source data).  
• Devices for blood pressure measurement should be regularly recalibrated according to 
manufacturers’ instructions.  
• Heart rate (bpm) will be measured at the time of the measurement of blood pressure. 
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8.2.3 Electrocardiograms  
• 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc 
intervals. 
• The investigator should assess the ECG results as normal, abnormal and clinically 
significant (Y/N) if abnormal. The assessment will be documented in the eCRF. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency.  
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, 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 or within 3 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator. 
- 
If clinically significant 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 tests, 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 tests 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. 
8.2.5 Pregnancy testing  
• The timepoints for pregnancy testing in WOCBP is defined in the SoA.  
• The pregnancy testing would be done by local urine test at study sites. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and serious adverse events (SAEs) can be found in Appendix 3  
(Section 10.3). The definition of AESI is provided in Section 8.3.6. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs that are serious, considered related to the study intervention or study procedures, or 
that caused the participant to discontinue the study intervention. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the follow-up 
visit at the time points specified in the SoA (Section 1.3). 
All SAEs and AESI will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
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 AEs of 
special interest, 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 provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
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relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• SAEs that are considered expected will be specified in the reference safety information 
(IB).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any 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. It is the responsibility of the 
Sponsor to assess whether an event meets the criteria for a SUSAR, and therefore, is 
expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until end of study. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant /pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant /pregnant 
female partner and the neonate and the information will be forwarded to the Sponsor. 
• 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 8.3.5. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, 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. 
8.3.6 Adverse event of special interest  
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 by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them.  
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The following are considered Adverse events of special interest: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP.  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. 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 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant (not based on systematic 
pills count) and defined as per Section 6.7.  
• Increase in alanine transaminase (ALT) more than 3 times the ULN 
8.3.7 Hypoglycemia  
Hypoglycemia (all, level 1, level 2 and level 3 hypoglycemia) will be assessed starting from 
randomization (Day 1) and continue until 3 days after the last dose of IMP.  
During the study, participants are instructed to document the presence of hypoglycemic episodes 
in their study diary. The hypoglycemia will be reported in the specific eCRF page with onset date 
and time, symptoms and/or signs, the SMPG value if available, and the treatment.  
Note: If the event fulfills SAE criteria, hypoglycemia will also be reported as an SAE. 
Hypoglycemia is categorized according to the ADA 2021 recommendation for hypoglycemia 
classification (17): 
• Level 1 hypoglycemia is defined as a measurable glucose concentration <70 mg/dL  
(3.9 mmol/L) but ≥54 mg/dL (3.0 mmol/L). Because many people with diabetes 
demonstrate impaired counterregulatory responses to hypoglycemia and/or experience 
hypoglycemia unawareness, a measured glucose level <70 mg/dL (3.9 mmol/L) is 
considered clinically important (independent of the severity of acute hypoglycemic 
symptoms).  
• Level 2 hypoglycemia (defined as a blood glucose concentration <54 mg/dL [3.0 
mmol/L]) is the threshold at which neuroglycopenic symptoms begin to occur and requires 
immediate action to resolve the hypoglycemic event. 
• Level 3 hypoglycemia is defined as a severe event characterized by altered mental and/or 
physical functioning that requires assistance from another person for recovery. 
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Note that “requires assistance” means that the participant could not help himself or herself. 
Assisting a participant out of kindness, when assistance is not required, should not be considered a 
“requires assistance” incident. 
8.3.8 Guidelines for reporting product complaints  
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within 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 
STUDY PROCEDURES  
The visit schedule and procedures/assessments are listed in the Study Flow Chart in Section 1.3. 
This section provides details for procedures/assessments.  
This is an outpatient study and consists of 8 on-site visits and 7 phone-call visits. In addition, 
optional phone call visits to monitor IMP titration should be scheduled whenever considered 
necessary by the Investigator.  
Participants must be fasting for on-site visits (except Visit 1/ Week 0 and Visit 4/Week 2). The 
fasting condition is defined as an overnight fast no less than 8 hours that consisted of no food or 
liquid intake, other than water. The participant should be seen in the morning, at approximately 
the same time, as far as possible.  
Note: If the participant is not fasting at the visits specified above, the blood sample will not be 
collected and a new appointment should be given to the participant for the following day if 
possible, with instruction to be fasted.  
8.4.1 Screening period (Week -2 to Week 0) and Visit 1  
The screening period is up to 2 weeks from screening visit (V1, Week -2) to randomization (V2, 
Week 0); it can be exceptionally extended up to one additional week.  
Only participants who meet the inclusion criteria as noted in Section 5.1 may be screened. It will 
be the Investigator’s responsibility to confirm the diagnosis of T2DM. The background OAD(s) 
should be continued without dose and type change during the screening period.  
If any of the laboratory parameters are not available 2 weeks after screening visit (eg, sample 
material damaged during transport etc), a retest can be performed. If this is the case (and 
exceptionally in other situations if justified according to the Investigator’s assessment), the 
screening period can be extended up to one additional week, ie, randomization visit (V2, Day 1) 
can be scheduled no later than 3 weeks after screening visit (V1, Week -2).  
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Participants can be re-screened one time before randomization in case of non-evaluable exclusion 
criteria or in case where original screen failure is due to reasons expected to change at rescreening 
and based upon the Investigator’s clinical judgment. Re-screened participants will be subject to 
the screening visit procedures/assessments including new informed consent signed and allocation 
of a new participant number. 
For the complete list and contents of procedures/assessments scheduled for the visit, please refer 
to the Study Flow Chart in Section 1.3 and for detailed description of assessments to Section 8.1, 
8.2 and 8.3.  
Informed consent: 
The participant will receive verbal information concerning the aims and methods of the study, its 
constraints and risks and the study duration at Visit 1 (screening visit). Written information will 
be provided to the participant and must be signed by the participant and Investigator prior to any 
investigations.  
Demography, medical history, and alcohol and smoking habits 
Demography, diabetes and medical/surgical history, allergy history, alcohol and smoking habits, 
and medications Demography data such as birth date and gender will be collected. Collection of 
diabetes history will include documentation of duration of diabetes, history of microvascular 
complications (retinopathy, neuropathy, and nephropathy), and history of gestational diabetes if 
applicable. General medical/surgical history will be recorded. Data for alcohol habits during the 
last 12 months before screening visit and smoking habits will be collected. Check of previous 
and/or current medication refers to documentation of medication including glucose-lowering 
agents and over-the-counter medications. In women of child-bearing potential, the contraceptive 
method(s) must be documented. 
IRT contact  
IRT will be contacted for notification of screening and participant number allocation. Please note 
that it is important to have the IRT contact before any blood sample is drawn because the 
participant number is given by IRT and it must be reported on the laboratory requisition forms.  
Glucometer, participant diary dispensation and training  
See Section 8.1.3.  
7-Point SMPG 
Participants who meet the selection criteria and will return to the study site for Visit 2 should be 
reminded to perform the 7-point SMPG in two different dates in the week prior to the next visit 
(Visit 2). 
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8.4.2 Open-label randomized treatment period (Week 0 to Week 24)  
Patients meeting all inclusion criteria and with no exclusion criteria at the end of the screening 
period are eligible to be enrolled into the open-label randomized treatment period.  
The duration of the open-label treatment period is 24 weeks from baseline visit (V2, Week 0) to 
the end of treatment visit (V14, Week 24). Each participant self-administers IMP once daily 
during the open-label treatment period (Section 6). 
8.4.2.1 Randomization visit (V2, Week 0, Day 1)  
For the complete list and contents of procedures/assessments scheduled for the visit, please refer 
to the Study Flow Chart in Section 1.3 and for detailed description of assessments to Section 8.1, 
8.2 and 8.3.  
At this visit, the participant must return to the investigational site in the morning in fasting status, 
i.e., not having any food or drinks (except for water) for at least 8 hours, not having administered 
metformin and the second OAD (if appropriate) at home. 
Patients will visit the site with the blood glucometer and the diary. 
Diet and lifestyle counseling  
Please see Section 5.3.  
Compliance check  
Compliance check includes compliance to background OAD metformin and/or SGLT2 inhibitor 
(if appropriate) and use of glucometer, review of daily of the 7-point SMPG profile and 
participant diary. If the participant is not compliant enough with the study procedures, the training 
will be repeated by the site staff.  
Any OAD other than metformin and/or SGLT2 inhibitor (if appropriate) will be discontinued on 
the day of randomization. 
IRT contact  
After the baseline assessments are completed and eligibility confirmed, the Investigator contacts 
IRT for randomization. The treatment group (ie, iGlarLixi or IDegAsp) is notified by IRT.  
Training on self-injection devices and dispensation of IMP Patients randomized to either 
treatment group (iGlarLixi or IDegAsp) are instructed by the study staff how to use properly the 
relevant pen-injector and to store it. Instructions on self-injection technique are also given. 
Relevant injection pen-injector with the instruction leaflet is dispensed. Training on relevant pen-
injector might be repeated if necessary, during the study.    
See Section 6 for starting dose and dose adjustment of IM 
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8.4.2.2 Phone call visits (Visits 3, 5, 7, 9, 11 and 13):  
The participant is called by the Investigator or qualified designee at a scheduled time. If the call 
has been completed by site staff other than the Investigator, the Investigator has to be consulted if 
AE/SAE is suspected and informed in case AE/SAE occurred. In case of an AE, the participant 
may be asked to come to the investigational site, as appropriate. A phone call visit can optionally 
be performed as a clinical visit in case of confirmed hypoglycemia/AE or other reasons.  
During the phone call, the following questions are to be asked:  
• Did you experience any new medical event, disease or symptom since the last visit?  
• Did you experience any changes in a pre-existing medical condition, disease or symptom 
since the last visit?  
• Did you miss, change, take or add any medications (including OAD if appropriate) since 
the last visit 
• Did you experience any hypoglycemic events or symptoms?  
• Did you experience any possible allergic symptoms, or skin reactions?  
• Do you feel comfortable handling the diary, glucometer and IMP injection device or do 
you need any more explanation?  
• Did you adjust IMP since last visit, including missing injection? If appropriate, what is 
your IMP dose?  
• Did you measure any fasting SMPG value < 80 or >100 mg/dL (< 4.4 or > 5.6 mmol/L)? 
• The phone visits will also include:  
• Adjustment of the dose of IMP ( iGlarLixi or IDegAsp) to continue treatment toward the 
target fasting SMPG ≥80 and ≤100 mg/dL (≥4.4 and ≤5.6 mmol/L).  
• Recording of AE and hypoglycemia events (if any).  
• Recording of the use or change of any concomitant medication.  
• The participant will be instructed to:  
• Perform required SMPG measurements.  
• Complete the diary on a daily basis.  
• Self-inject once daily IMP at the dose prescribed by the Investigator. 
• Contact the site in case of occurrence of AE, record the event in the participant diary and 
return to the site as deemed appropriate. An appointment for subsequent visits (on-site 
visit or phone call visit) will be given, and patients are reminded to come in fasting if 
planned at next on-site visit and to bring their glucometer, diary, and IMPs. 
8.4.2.3 Onsite visits (Visits, 4, 6, 8, 10, and 12)  
For the complete list and contents of procedures/assessments scheduled for the visit, please refer 
to the Study Flow Chart in Section 1.3 and for detailed description of assessments to Section 8.1, 
8.2 and 8.3.  
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For all onsite visits (except Visit 4/Week 2), participants are instructed to return to the site in the 
morning in fasting condition with the glucometer, the diary, the used, in-use and unused IMPs.  
The IMP iGlarLixi or IDegAsp (if appropriate) and the OAD metformin and SGLT2 inhibitor (if 
appropriate) will be administrated at the investigational site after the fasting blood sample has 
been drawn.  
Compliance check  
Compliance check includes compliance to IMP and metformin treatment and SGLT2 inhibitor (if 
appropriate) and use of glucometer, review of fasting SMPG values, and the 7-point SMPG 
profile and participant diary. If the participant is not compliant enough with the study, the training 
will be repeated by the site staff.  
The questions listed for phone call visits will also be asked, checked, and discussed with 
participants at onsite visits.  
Upon completion of each on-site visit, an appointment for the next visit (on-site visit or phone call 
visit) will be made 
8.4.2.4 Final on-treatment assessment/end of treatment visit (V14, Week 24)  
For the complete list and contents of procedures/assessments scheduled for the visit, please refer 
to the Study Flow Chart in Section 1.3 and for detailed description of assessments to Section 8.1, 
8.2 and 8.3.  
The same procedures/assessments including IRT contact as planned at V14 (Week 24) have to be 
performed in case of prematurely permanent treatment discontinuation.  
The IRT has to be contacted in order to register the end of treatment.  
An appointment for the post-treatment follow-up phone call visit will be made. 
8.4.3 Post-treatment follow-up phone call visit (V15)  
Following the last injection of IMP (iGlarLixi or IDegAsp) either as scheduled or prematurely, a 
post-treatment follow-up phone call visit is performed 3 (-1/+3) days after the end of treatment 
visit for patients who completed the study or withdrew from the study at the time of the open label 
IMP discontinuation.  
The post-treatment follow-up phone call visit is not performed for patients who prematurely 
discontinued the open-label IMP treatment and stay in the study.  
This visit can be a phone call visit, or an on-site visit in case of ongoing or new AE during the 
posttreatment period, if necessary. The participant is called by the Investigator or medically 
qualified designee at certain, previously agreed time point.  
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During the phone call, the following questions are to be asked:  
• Did you experience any new medical event, disease or symptom since the last visit?  
• Did you experience any changes in a pre-existing medical condition, disease or symptom 
since the last visit?  
• Did you change, take or add any medications since the last visit?  
• Did you experience any hypoglycemic symptoms or events?  
All reports of hypoglycemic events (if any) or any AEs are recorded. The use or change of any 
concomitant medications, including rescue therapy, is recorded.  
Interactive response technology (IRT) is contacted for notification of the end of study. 
8.5 
PHARMACOKINETICS  
Not applicable 
8.6 
GENETICS AND/OR PHARMACOGENOMICS  
Genetics are not evaluated in this study. 
8.7 
BIOMARKERS  
Biomarkers are not evaluated in this study. 
8.8 
IMMUNOGENICITY ASSESSMENTS  
Not applicable 
8.9 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable 
8.10 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
No biological samples will be collected for future research in this study. 
Relating data for future research will be stored for up to 25 years after the end of the study. 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
SAMPLE SIZE DETERMINATION  
A total sample size of 580 participants (randomization ratio 1:1, ie, 290 per intervention group) 
will be determined to demonstrate noninferiority of iGlarLixi versus IDegAsp in HbA1c reduction 
at Week 24 with 90% power and 2-sided significance level of 0.05 based on the following 
assumptions on the primary endpoint: 
• True mean difference of zero between iGlarLixi and IDegAsp 
• Common standard deviation of 1.05% 
• Non-inferiority margin on the mean difference of 0.3% 
• Dropout rate of 10% 
Calculations were made based on two sample t-test using SAS® (Version 9.4). 
9.2 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined:  
Table 7 - Populations for analyses  
Population 
Description 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the treatment 
allocated by randomization. 
Per-protocol (PP) 
All participants from ITT population who have completed 24 weeks of randomized 
treatment and did not start any rescue therapy before end of the 24-week randomized 
treatment period and have no major or critical protocol deviation that can potentially 
affect efficacy analysis. The protocol deviations for PP exclusion will be defined in the 
SAP and identified before database lock. 
Safety 
All randomized participants who take at least 1 dose of study intervention. 
Participants will be analyzed according to the intervention they actually received. 
 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population.  The safety experience associated with any 
later randomization will be reported separately. 
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9.3 
STATISTICAL ANALYSES  
The statistical analysis plan will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 
9.3.1 General considerations  
The baseline value is defined as the last available value before the first injection of open label 
IMP. For participants randomized but not treated, the baseline value is defined as the last 
available value before randomization. 
Continuous data will be summarized by treatment group using the number of observations 
available (N), mean, SD, minimum, median, and maximum. 
Categorical data will be summarized by treatment group using count and percentage. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from baseline) by scheduled visits will be provided on observed cases, ie, inclusion of only 
participants having non-missing assessments at a specific visit. 
Unless otherwise specified, analyses will be performed by treatment group for baseline, 
demographics characteristics, prior and concomitant medications. 
9.3.2 Analyses of primary endpoint  
The primary endpoint is change from baseline to Week 24 in HbA1c. Three estimands addressing 
different aspects of the trial objective as defined below. 
 
Estimand 
Population 
Strategy for accounting for 
intercurrent events 
Endpoint 
Population level 
summary 
Primary 
estimand 
All randomized 
participants 
Treatment policy strategy for both 
intercurrent events:  
• 
Treatment discontinuation 
• 
Initiation of rescue 
medication 
Change from 
baseline to  
Week 24 in 
HbA1c* 
LS Means difference 
between treatments 
Secondary 
estimand 
All randomized 
participants 
Hypothetical strategy for both 
intercurrent events:  
• 
Treatment discontinuation 
• 
Initiation of rescue 
medication 
Change from 
baseline to  
Week 24 in 
HbA1c* 
LS means difference 
between treatments 
Secondary 
estimand 
Per Protocol  
No intercurrent event expected as 
participants with treatment 
discontinuation or rescue medication 
will be excluded from PP population 
Change from 
baseline to  
Week 24 in 
HbA1c* 
LS means difference 
between treatments 
*For noninferiority testing. 
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Primary analysis for the primary estimand 
Under treatment policy strategy, measurements after treatment discontinuation and initiation of 
rescue medication will not be considered as missing data. 
The primary statistical analysis will be an ANCOVA performed on the ITT population with 
missing data imputed by multiple imputations using missingness patterns based on treatment 
completion, and under the missing at random (MAR) assumption within each pattern.  
• For participants completing the 24-week treatment period, the missing HbA1c values will 
be imputed using data from other participants completing the treatment. 
• For participants discontinuing prematurely the treatment, the missing HbA1c values will 
be imputed using data from participants also discontinuing treatment but having their 
HbA1c assessment (retrieved dropouts). In case there are not enough observed Week 24 
data post treatment discontinuation, return-to-baseline (RTB) approach will be used for 
imputation; missing HbA1c values at Week 24 will be imputed from a normal distribution 
with the expected value set to the participant’s baseline value and standard deviation based 
on the baseline value by treatment group. 
Missing HbA1c values will be imputed 1000 times to generate 1000 datasets with complete 
HbA1c values using SAS procedure for multiple imputation (PROC MI). The imputation model 
will include the treatment group, as fixed effect, and baseline HbA1c continuous value as 
covariate. The randomization strata of HbA1c can be removed from the model given that the 
baseline HbA1c continuous value is already in the model. 
For each of the 1000 imputed datasets, the change in HbA1c from baseline to Week 24 will be 
analyzed using an ANCOVA with treatment groups and previous OADs as fixed effects, and 
baseline HbA1c continuous value as covariate. The results obtained from analyzing the datasets 
will be combined using Rubin’s rule to draw inference. The non-inferiority will be assessed using 
the upper bound of the 2-sided 95% confidence interval (CI). If the upper bound of the 95% CI is 
less than 0.3%, the non-inferiority of iGlarLixi versus IDegAsp will be claimed. 
Sensitivity analyses of primary estimand 
The following sensitivity analyses will be performed for the primary estimand. 
• The primary endpoint will be analyzed using a mixed-effect model with repeated measures 
(MMRM), under the missing at random framework. The model will include treatment, 
previous OADs, visit, treatment-by-visit interaction as fixed effects, and baseline HbA1c 
value as continuous covariate. The randomization strata of HbA1c can be removed from 
the MMRM model given that the baseline HbA1c value is already in the model. The 
MMRM model will be implemented using SAS® (Version 9.4 or higher) MIXED 
procedure (PROC MIXED) with an unstructured correlation matrix to model the within-
participant errors. Parameters will be estimated using the restricted maximum likelihood 
method with the Newton-Raphson algorithm. Denominator degree of freedom will be 
estimated using the Kenward-Roger approximation by fitting values from post-
randomization scheduled visits. 
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Primary analysis for the secondary estimands 
Under hypothetical strategy, measurements after treatment discontinuation and/or initiation of 
rescue medication will be considered as missing data. 
A mixed-effect model with repeated measures (MMRM), under the missing at random 
framework, will be performed for both secondary estimands. The model will include treatment, 
previous OADs, visit, treatment-by-visit interaction as fixed effects, baseline HbA1c value as 
continuous covariate. The randomization strata of HbA1c can be removed from the MMRM 
model given that the baseline HbA1c continuous value is already in the model. The MMRM 
model will be implemented using SAS® (Version 9.4 or higher) MIXED procedure (PROC 
MIXED) with an unstructured correlation matrix to model the within-participant errors. 
Parameters will be estimated using the restricted maximum likelihood method with the Newton-
Raphson algorithm. Denominator degree of freedom will be estimated using the Kenward-Roger 
approximation by fitting values from post-randomization scheduled visits. 
For the per protocol estimand, the change in HbA1c from baseline to Week 24 will be analyzed 
using an ANCOVA with treatment group and previous OADs as fixed effects, and baseline 
HbA1c continuous value as covariate. Provided that patients with treatment discontinuation or 
rescue medication, as well of patients with missing assessment will be excluded from PP 
population, no missing data handling method is planned for this analysis. 
Subgroup analyses of the primary estimand 
Depending on the data availability, analyses will be performed on the primary endpoint to 
summarize the treatment effects across subgroups defined by the following baseline or screening 
factors: 
• Age group (<50, ≥50 to <65, ≥65 years). 
• Gender (Male, Female). 
• Baseline BMI level (<24, ≥24 to <28, ≥28 kg/m2). 
• Randomization strata screening HbA1c (<8%, ≥8%). 
• Randomization strata  treatment at screening with metformin alone or metformin +SGLT2 
(Yes/No). 
• Baseline fasting C-peptide level by quartiles.  
Other subgroup analyses may be explored and will be described in the SAP. 
Other sensitivity analyses may be explored. The detailed sensitivity analysis method will be 
described in the SAP. 
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9.3.3 Analyses of secondary endpoints  
9.3.3.1 Key secondary endpoints analysis  
See Section 3 for key secondary efficacy endpoints. Two estimands addressing different aspects 
of the trial objective as defined below. 
 
Estimand 
Population 
Strategy for accounting 
for intercurrent events 
Endpoint 
Population 
level 
summary 
Primary estimand 
All randomized 
participants 
Treatment policy strategy for 
both intercurrent events:  
• 
Treatment 
discontinuation 
• 
Initiation of rescue 
medication 
Change from baseline to 
Week 24 in: 
• 
HbA1c* 
• 
Body weight 
LS mean 
difference 
between 
treatments 
 
 
 
If a participant at Week 24 
achieves: 
• 
HbA1c < 7% 
• 
HbA1c < 7% and no 
body weight gain 
• 
HbA1c < 7% and no 
body weight gain 
and no 
hypoglycemia 
(defined as  ADA 
level 1. 2 or 3) 
Odds ratio 
between 
treatments 
Secondary estimand 
All randomized 
participants 
Hypothetical strategy for both 
intercurrent events:  
• 
Treatment 
discontinuation 
• 
Initiation of rescue 
medication 
Change from baseline to 
Week 24 in: 
• 
HbA1c* 
• 
Body weight 
LS mean 
difference 
between 
treatments 
*For superiority testing. 
Analyses of the secondary efficacy endpoints will be performed using the ITT. 
Descriptive statistics (Number, mean, SD, median, minimum, and maximum) will be provided by 
treatment for body weight at the scheduled visits. 
Change from baseline in body weight will be analyzed using the same approach as the primary 
endpoint (ANCOVA with MI or MMRM) to compare iGlarLixi with IDegAsp. The model will 
include treatment group, randomization strata of HbA1c and previous OAD and corresponding 
baseline for that endpoint. Details will be provided in the SAP. 
All categorical key secondary efficacy endpoints defined in Section 3 will be analyzed using a 
logistic regression model adjusting for treatment group, randomization strata of HbA1c and 
previous OADs, and appropriate baseline covariates. The proportion of participants in each 
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treatment group will be provided, as well as the odds ratio between groups with associated 2-sided 
CI at the specified significance level. For the categorical secondary endpoints in which HbA1c is 
assessed at Week 24, all values at Week 24 will be used to determine whether a participant is a 
responder or not, even if they are measured after IMP discontinuation or introduction of rescue 
therapy. If no assessment is available at Week 24, participants will be treated as non-responders. 
Details of the logistic model will be discussed in the SAP. 
9.3.3.2 Other secondary endpoints  
See Section 3 for other secondary efficacy endpoints. Unless otherwise specified, other secondary 
endpoints will be analyzed in the treatment policy framework using the ITT population.  
 
Population 
Strategy for accounting for 
intercurrent events 
Endpoint 
Population level 
summary 
All randomized 
participants 
Treatment policy strategy for both 
intercurrent events:  
• 
Treatment discontinuation 
• 
Initiation of rescue medication 
Change from baseline to 
Week 24 in: 
• 
FPG 
• 
7-point SMPG 
• 
Fasting C-
peptide 
LS mean difference between 
treatments 
 
 
If a participant at Week 24 
achieves: 
• 
HbA1c < 7% and 
no hypoglycemia 
(any 
hypoglycemia 
ADA level 1. 2 or 
3) 
• 
HbA1c < 7% and 
no clinically 
relevant 
hypoglycemia 
(any 
hypoglycemia 
ADA level 2 or 3) 
• 
Initiation of 
rescue 
medication 
Odds ratio between treatments 
Descriptive statistics (Number, mean, SD, median, minimum, and maximum) will be provided by 
treatment for FPG, 7-point SMPG and fasting C-peptide at the scheduled visits. Descriptive 
statistics (Number, mean, SD, median, minimum, and maximum) will be provided by treatment 
for total insulin dose. 
For continuous secondary endpoints, such as change from baseline in FPG, 7-point SMPG and 
fasting C-peptide, they will be analyzed using the same approach as the primary endpoint to 
compare iGlarLixi with IDegAsp. The model will include treatment group, randomization strata 
of HbA1c and the corresponding baseline for that endpoint. Details will be provided in the SAP. 
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Other secondary categorical efficacy endpoints defined in Section 3 will be analyzed using a 
logistic regression model same with the key secondary categorical endpoints. Details of the 
logistic model will be discussed in the SAP. 
9.3.4 Multiplicity adjustment  
Multiplicity adjustment: to control overall Type I error at 0.05 level (2-sided), a gate-keeping 
procedure will be used. Two families of hypothesis testing will be established: family 1 of 
primary and family 2 of key secondary hypotheses. For the primary endpoint (change from 
baseline to Week 24 in HbA1c), no multiplicity adjustment is needed to control the Type I error 
since only one comparison of iGlarLixi versus IDegAsp will be performed. 
If the primary endpoint is statistically significant at the 2-sided 0.05 level, a hierarchical testing 
procedure will be performed to test the following key secondary efficacy endpoints in the order 
specified in Figure 2.  
• Superiority in 2a and 2b will be test at the 2-sided 0.025 level each. 
• Only if 2a is statistically significant, 2c will be tested at the 2-sided 0.025 level. 
• 2d will be tested at the 2-sided 0.05 level if both 2b and 2c are statistically significant, or 
at the 2-sided 0.025 level if only one of them is statistically significant. 
• If 2d is statistically significant, 2e will be tested at the 2-sided 0.025 or 0.05 level based on 
the significant level passed from 2d. 
This gate-keeping procedure will only apply for the primary analysis of the primary estimand for 
each endpoint. For other secondary hypotheses, no multiplicity adjustment will be applied. 
 
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• The incidence of participants with at least one PCSA during the treatment-emergent period 
will be summarized regardless of the baseline level and according to the following 
baseline status categories: 
- 
Normal/missing 
- 
Abnormal according to PCSA criterion or criteria 
9.3.5.1 Adverse events  
General common rules for adverse events 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the time 
between the date of the informed consent and the first injection of open-label IMP. 
• TEAEs: AEs that developed, worsened or became serious during the time from the first 
injection of open-label IMP up to 3 days (1 day for hypoglycemia) after the last injection 
of IMP, regardless of initiation of rescue medication. The 3-day interval is chosen based 
on the half-life of the IMP (approximately 5 times the half-life of lixisenatide). 
• Post-treatment AEs: AEs that developed, worsened or became serious during the time 
from 4 days (2 days for hypoglycemia) after last injection of open-label IMP (after the on-
treatment period) to end of study. 
Analysis of all adverse events 
Adverse event incidence table will be sorted by System Organ Class (SOC) internationally agreed 
order and decreasing frequency of preferred term (PT) for the treatment group, the number (n) and 
percentage (%) of participants experiencing at least one TEAE. In case of equal frequencies of 
PTs within a SOC, the alphabetic order will be applied. Multiple occurrences of the same event in 
the same participant will be counted only once in the tables. The denominator for computation of 
percentages is the safety population within each treatment group. 
Summaries of all TEAEs in each treatment group may include: 
• The overview of AEs, summarizing number (n) and percentage (%) of participants with 
any 
• TEAE; 
•  Study drug related TEAE; 
•  Treatment emergent SAE; 
•  Study drug related treatment emergent SAE; 
•  Treatment emergent AESI 
• Study drug related treatment emergent AESI 
• TEAE leading to death; 
• Study drug related TEAE leading to death; 
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•  TEAE leading to permanent treatment discontinuation.  
• Study drug related TEAE leading to permanent treatment discontinuation. 
• The number (n) and percentage (%) of participants with at least one TEAE by primary 
SOC, HLGT, HLT, and PT; 
• Summary of TEAEs by maximal severity, presented by primary SOC and PT; 
•  Summary of TEAEs related to open-label IMP, presented by primary SOC and PT. 
A detailed listing of TEAE summaries will be provided in the SAP. 
Death and treatment emergent SAEs will be summarized and presented as number (n) and percent 
(%) of participants in each treatment group. 
9.3.5.2 Analyses of hypoglycemia  
Analyses of hypoglycemia will be performed, including any hypoglycemia, level 1 hypoglycemia, 
level 2 hypoglycemia, level 3 hypoglycemia, hypoglycemia occurred at any time of the day, 
hypoglycemia occurred nocturnally. 
The number (n) and incidence rate (%) of participants experiencing at least one specific 
hypoglycemic event will be summarized by treatment group. Each hypoglycemic endpoint will be 
analyzed using a logistic regression model adjusting for treatment group, randomization strata of 
HbA1c and previous OADs and appropriate baseline covariates. The proportion of participants in 
each treatment group will be provided, as well as the odds ratio between groups with associated 2-
sided 95% CI. 
The hypoglycemic event rate per participant year will be derived for each type of hypoglycemia 
and will be summarized by treatment group. A negative binomial model will be fitted in SAS to 
estimate the event rate. The number of hypoglycemic events is the response variable. The 
independent variables will be treatment group, randomization strata of HbA1c and previous 
OADs used as fixed effects and appropriate baseline covariates. The logarithm of the duration (in 
years) of open-label randomized treatment period as an offset variable to account for unequal 
follow-up time due to early withdrawal, rescue medication, etc. The ratio of hypoglycemic events 
rate, it’s 95% CI and p-value will be presented. The estimated mean hypoglycemic events in two 
groups along with their 95% CIs are presented from this model. 
The pattern of symptomatic hypoglycemia occurrence over time will also be assessed, if 
appropriate. 
9.3.5.3 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
For laboratory variables, vital signs and ECG variables, descriptive statistics for results and 
changes from baseline will be provided for each planned visit during the on-treatment period. The 
central laboratory measurements for safety parameters will be analyzed.    
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Analyses according to PCSA 
The number (n) and percentage (%) of participants with PCSA at any evaluation during the on-
treatment period will be summarized for each parameter within each treatment group. The 
summaries will include participants in the safety population who have at least one parameter to be 
analyzed during the on-treatment period. When the PCSA definition involves the change from the 
baseline value, participants need also to have a baseline value to be included in the summaries. 
Tabular and graphical methods may be used to present the results for parameters of interest. 
Listings will be provided with flags indicating the PCSA values. 
9.3.5.4 Study treatment duration and compliance  
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
The extent of study treatment exposure will be assessed by the duration of treatment exposure 
during the study. 
The duration of treatment exposure will be the total number of days of administration of the open-
label IMP, regardless of unplanned intermittent discontinuations. The duration of IMP exposure 
will be calculated as:(Date of the last open-label IMP injection – Date of the first open-label IMP 
injection) + 1. 
The number (n) and percentage (%) of participants randomized and exposed to the open-label 
IMP will be presented by categories of cumulative exposure for each treatment group in the safety 
population. The time periods of interest will be defined in the SAP. 
Descriptive statistics of duration of treatment exposure (number, mean, SD, minimum, median, 
and maximum) and cumulative exposure in participant-years will also be presented by treatment 
group in the safety population. 
Overall treatment compliance is defined as the actual number of days with IMP injection 
compared to the planned number of days with IMP injection during the open-label treatment 
period, up to treatment discontinuation. Compliance rate (%)=total number of days with IMP 
injection/ planned number of days with IMP injection*100. A given administration will be 
considered noncompliant if the participant did not take the planned dose of treatment as required 
by the protocol. For example, if participants miss one of the two injections in any day of the 
premixed insulin treatment, that day will be considered noncompliant. No imputation will be 
made for participants with missing or incomplete data.  
Treatment compliance will be summarized by treatment group using mean, SD, median, and range 
for the safety population. In addition, the percentage of participants who have <60%, ≥60% to 
<80%, ≥80% to ≤100%, and >100% compliance will be summarized by treatment group. 
9.4 
INTERIM ANALYSES  
No formal interim analysis for efficacy or safety is planned for this study. 
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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 the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• The protocol, protocol amendments, ICF, Investigator Brochure, [IDFU] 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.  
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation 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  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
• The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all applicable 
national, state, or regional laws and regulations in the country where the study is being 
conducted, and 
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• The finding reveals a substantial risk of a serious health condition or has reproductive 
importance, AND has analytical validity, AND has clinical validity.  
• The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted out of 
being notified and the finding has consequences for other individuals, eg, the finding 
relates to a communicable disease, Investigators should seek independent ethical advice 
before determining next steps. 
• In case the participant has decided to opt out, the Investigator must record in the site 
medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
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. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants or their legally authorized representative, and answer all questions regarding 
the study, including what happens to the participant when his/her participation ends (post-
trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Privacy and 
Data Protection requirements including those of the Global Data Protection Regulation 
(GDPR) and of the French law, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
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• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc.). 
• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative, where applicable.  
Participants who are rescreened are required to sign a new ICF. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 6 (Section 10.6: Contingency measures for a regional or national 
emergency that is declared by a governmental agency).  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
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. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
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• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or pre-
contractual relationship. They may be communicated to any company of the Sanofi group 
(“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
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• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the Transcelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other phamaceutical 
company members of the Transcelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the Transcelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to peer-
reviewed journals following internal company review for accuracy, fair balance and intellectual 
property. For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available 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.  
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
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by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• Guidance on completion of CRFs will be provided in the study “CRF completion 
instruction”. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
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10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the study “Monitoring 
guidelines”. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.8 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is considered the first act of recruitment of a participant and will be the 
study start date. 
Study/Site termination 
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 study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
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• For site termination: 
- 
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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.9 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in below Table 8 will be performed by the central laboratory.  
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 10.5 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 [(for instance, when participants with 
known acquired immunodeficiency syndrome (AIDS)-related illness or known HIV 
disease requiring antiviral treatments need to be excluded, an HIV serology testing at 
screening is mandatory for German participants)]. 
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Table 8 - Protocol-required laboratory tests  
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
• 
MCV 
 
• 
MCH 
 
• 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
• 
Neutrophils 
 
• 
Lymphocytes 
 
• 
Monocytes 
 
• 
Eosinophils 
 
• 
Basophils 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose [Indicate if fasting, or nonfasting] 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphataseb 
 
Total and direct bilirubin 
 
Total protein 
Amylase 
Lipase 
Calcitonin 
Pregnancy testing 
• 
Urine human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential)c  
Other screening tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of non-childbearing 
potential only) 
• 
All study-required laboratory tests will be performed by a central laboratory 
Other study specific tests 
• 
FPG, HbA1c, fasting C-peptide, SMPG 
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Laboratory tests 
Parameters 
NOTES: 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 [Liver Chemistry Stopping Criteria] 
and Appendix 5 (Section 10.5) [Liver and other safety: Suggested actions and follow-up assessments [and study intervention rechallenge 
guidelines]]. All events of [insert criteria related to ALT, bilirubin, INR etc] which may indicate severe liver injury (possible Hy’s Law) must be 
reported to [Sponsor] in an expedited manner (excluding studies of hepatic impairment or cirrhosis). 
b If alkaline phosphatase is elevated, consider fractionating.  
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant/participant’s parent(s)/LAR(s) who has signed the 
informed consent. Unsolicited AEs include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalization, or emergency room visit, or visit to/by a health care provider). The 
participants/ participant’s parent(s)/LAR(s) will be instructed to contact the site as soon as 
possible to report medically attended event(s), as well as any events that, though not 
medically attended, are of participant/ parental /LAR’s concern. Detailed information 
about reported unsolicited AEs will be collected by qualified site personnel and 
documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by 
participant/participant’s parent(s)/LAR(s) will be collected during interview with the 
participants/participant’s parent(s)/LAR(s) and by review of available medical records at 
the next visit. 
• Solicited AEs are predefined local [at the injection site] and systemic events for which the 
participant is specifically questioned, and which are noted by the participants in their 
diary. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
• 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 fulfill the definition of an AE or SAE.  
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
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10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (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 out 
participant 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 or significant 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) 
Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
g) Other situations: 
• Medical or scientific judgment should be exercised by the Investigator in deciding whether 
SAE reporting is appropriate in other situations such as significant medical events that 
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. 
• Note: The following list of medically important events is intended to serve as a guideline 
for determining which condition has to be considered as a medically important event. The 
list is not intended to be exhaustive:  
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- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm   
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × ULN  
- 
Suicide attempt or any event suggestive of suicidality  
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)  
- 
Bullous cutaneous eruptions   
10.3.3 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. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s 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’s 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: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental Activities of Daily Living (ADL). Instrumental ADL refers to preparing 
meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
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• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting self care 
ADL. Self care ADL refers to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden. 
“Severe” is a category used 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 that 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. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that 
the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
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. 
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• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sponsor with a copy of any post-mortem findings 
including histopathology.  
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• 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 (see next section) or to 
the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the “Investigator Site File”. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the “Investigator Site File”. 
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10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
Woman of childbearing potential (WOCBP): A woman is considered fertile following menarche 
and until becoming post-menopausal unless permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining study entry. 
Note:  Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
- 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
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 
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10.4.2 Contraception guidance  
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. The initial 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 for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring at 
>22 weeks gestational age) 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 AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS  
 
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Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs is met. 
 
Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting AEs is met. 
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ALT > 3 ULN
Monitor LFTs every 72 hours
ALT ≤ 5 ULN
ALT > 3 ULN &
Total Bilirubin > 2 ULN 
Permanent Discontinuation of IMP
ALT > 5 ULN 
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
COMPLETE the specific CRF forms 
for „ALT Increase” and inform the 
Monitoring Team within 24 hours
Confirm ALT > 3 ULN
Retest within 72 hours of initial sample*
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
INCREASE IN ALT
 
*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting. 
 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting AEs is met. 
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting AEs is met. 
 
 
  
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10.6 
APPENDIX 6: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Continuation of the study in the event of a regional or national emergency declared by a 
governmental agency: 
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below and in sections for an emergency that prevents 
access to the study site, to ensure the safety of the participants, to consider continuity of the 
clinical study conduct, protect trial integrity, and assist in maintaining compliance with Good 
Clinical Practice in Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained 
prior to the implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/randomization/administration of study intervention may be [temporarily 
delayed/halted. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study.   
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data.  
• If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local clinic or laboratory locations may be allowed. 
Informed consent: For a regional or national emergency declared by a governmental agency, 
contingency procedures may be implemented for the duration of the emergency. The participants 
or their legally authorized representative should be verbally informed prior to initiating any 
changes that are to be implemented for the duration of the emergency (eg. study visit 
delays/treatment extension, use of local labs). 
• Contingencies implemented due to emergency will be documented.  
 
 
 
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10.7 
APPENDIX 7: ABBREVIATIONS  
 
AEs: 
adverse events 
AESIs: 
adverse events of special interest 
DTP: 
direct-to-patient 
ICF: 
informed consent form 
IMPs: 
investigational medicinal products 
NIMPs: 
non-investigational medicinal products 
NMPA: 
National Medical Products Administration 
PCSA: 
potentially clinically significant abnormality 
SAEs: 
serious adverse events 
SMPG: 
self-monitored plasma glucose 
SUSAR: 
suspected unexpected serious adverse reaction 
 
10.8 
APPENDIX 8: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
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11 
REFERENCES  
1. He X, Chen L, Wang K, Wu H, Wu J. Insulin adherence and persistence among Chinese 
patients with type 2 diabetes: a retrospective database analysis. Patient Prefer Adherence. 
2017;11:237-45. 
2. Rosenstock J, Emral R, Sauque-Reyna L, et al. Advancing therapy in suboptimally controlled 
basal insulin-treated type 2 diabetes: clinical outcomes with iGlarLixi versus premix BIAsp 30 
in the SoliMix randomized controlled trial. Diabetes Care. 2021;dc210393. 
3. Ji L, Lu J, Guo X, Yang W, Weng J, Jia W, et al. Glycemic control among patients in China 
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4. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 
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5. McCrimmon RJ, Al Sifri S, Emral R, Mohan V, Sauque-Reyna L, Trescoli C, et al. Advancing 
therapy with iGlarLixi versus Premix 70/30 in basal insulin-treated type 2 diabetes: Design 
and baseline characteristics of the SoliMix randomised controlled trial. Diabetes Obes Metab. 
2021. 
6. Lorenz M, Pfeiffer C, Steinsträßer A, Reinhard H.A.B, Rütten H, Ruus P, Horowitz M et al. 
Effects of lixisenatide once daily on gastric emptying in type 2 diabetes — Relationship to 
postprandial glycemia. Regulatory Peptides 185 (2013) 1–8. 
7. Rosenstock J, Aronson R, Grunberger G, Hanefeld M, Piatti P, Serusclat P, et al. Benefits of 
LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus 
Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately 
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8. Aroda VR, Rosenstock J, Wysham C, Unger J, Bellido D, Gonzalez-Galvez G, et al. Efficacy 
and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus 
Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The 
LixiLan-L Randomized Trial. Diabetes Care. 2016;39(11):1972-80. 
9. Blonde L, Rosenstock J, Del Prato S, Henry R, Shehadeh N, Frias J, et al. Switching to 
iGlarLixi Versus Continuing Daily or Weekly GLP-1 RA in Type 2 Diabetes Inadequately 
Controlled by GLP-1 RA and Oral Antihyperglycemic Therapy: The LixiLan-G Randomized 
Clinical Trial. Diabetes Care. 2019;42(11):2108-16. 
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Safety of 1:1 Fixed-Ratio Combination of Insulin Glargine and Lixisenatide Versus 
Lixisenatide in Japanese Patients With Type 2 Diabetes Inadequately Controlled on Oral 
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Antidiabetic Drugs: The LixiLan JP-O1 Randomized Clinical Trial. Diabetes Care. 
2020;43(6):1249-1257. 
11. Terauchi Y, Nakama T, Spranger R, Amano A, Inoue T, Niemoeller E. Efficacy and safety of 
insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi 1:1) in Japanese patients with 
type 2 diabetes mellitus inadequately controlled on oral antidiabetic drugs: A randomized, 26-
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12. Kaneto H, Takami A, Spranger R, Amano A, Watanabe D, Niemoeller E. Efficacy and safety 
of insulin glargine/lixisenatide fixed-ratio combination (iGlarLixi) in Japanese patients with 
type 2 diabetes mellitus inadequately controlled on basal insulin and oral antidiabetic drugs: 
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filled pen) [summary of product characteristics]. Available from: 
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