Conditions: Type 2 Diabetes Mellitus
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 124
Healthy volunteers: no

Brief summary:
The purpose of the study was to demonstrate if iGlarLixi (Soliqua 100/33) would improve glycemic control (as measured by Time in Range) and glycemic variability in participants with very uncontrolled (HbA1c ≥ 9%) type 2 Diabetes Mellitus (T2DM) while on at least 2 oral antidiabetic drugs \[OADs\] with or without a glucagon-like peptide 1 receptor agonist \[GLP1 RA\]), as measured by continuous glucose monitoring (CGM).

The total study duration per participant was approximately 22 weeks. Three site visits, 3 site or home visits, and up to 13 phone contacts were scheduled.

* A screening period of up to 2 weeks
* A run-in period of up to 2 weeks, including the baseline period
* A 16-week, open-label treatment period
* A 2-week post-treatment safety follow-up period

Detailed description:

Arms:
arm 1: iGlarLixi (i.e., insulin glargine 100 Units/ml /lixisenatide 33 μg/mL) once daily for 16 weeks.

Interventions: intervention 1: Insulin glargine/Lixisenatide
Intervention descriptions: intervention 1: Solution for injection in a pre-filled pen by subcutaneous injection. Dose was individually titrated to achieve target fasting self-monitoring of plasma glucose (SMPG) of 80 to 100 milligrams per deciliter (mg/dL) (4.4 to 5.6 millimoles per liter \[mmol/L\]) while avoiding hypoglycemia.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
U1111-1261-7399 
A 16-Week, Multicenter, Prospective, Open-Label, Single-Arm, Phase 4 
Study to Evaluate the Effect of Soliqua™ 100/33 on the Percentage of Time 
in Range (TIR) from Continuous Glucose Monitoring (CGM) in 
Insulin-Naïve Patients With Very Uncontrolled Type 2 Diabetes Mellitus 
LPS16990 
Short Title 
Soli-CGM 
Sponsor: 
Sanofi US Services Inc. 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA 
Sponsor Contact: 
Medical Monitor: 
Version of Protocol: 
Date of Protocol:  
18 Aug 2021 
CONFIDENTIAL 
Any and all information presented in this document shall be treated as confidential and 
shall remain the exclusive property of Sanofi (or any of its affiliated companies). The use 
of such confidential information must be restricted to the recipient for the agreed purpose 
and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever, without the prior written consent of 
Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, 
partnership or other entity which at the date of communication or afterwards (i) controls 
directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting 
rights in such corporation, partnership or other entity. 
The study will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 
NCT05114590




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Protocol: LPS16990 (Original, Version 1.0) 
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Declaration of Investigator 
I have read and understood all sections of the protocol titled “A 16-Week, Multicenter, 
Prospective, Open-Label, Single-Arm, Phase 4 Study to Evaluate the Effect of 
Soliqua™ 100/33 on the Percentage of Time in Range (TIR) from Continuous Glucose 
Monitoring (CGM) in Insulin-Naïve Patients With Very Uncontrolled Type 2 Diabetes 
Mellitus” and the accompanying prescribing information, dated February 2019. 
I agree to supervise all aspects of the protocol and to conduct the clinical investigation in 
accordance with the Final Protocol Version 1.0, dated 18 Aug 2021; the International Council 
for Harmonisation harmonised tripartite guideline E6(R1): Good Clinical Practice; and all 
applicable government regulations. I will not make changes to the protocol before consulting 
with Sanofi US Services Inc. or implement protocol changes without institutional review 
board approval except to eliminate an immediate risk to participants. I agree to administer 
study drug only to participants under my personal supervision or the supervision of a 
sub-investigator. 
I will not supply the investigational drug to any person not authorized to receive it. 
Confidentiality will be protected. Participant identity will not be disclosed to third parties or 
appear in any study reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Sanofi US Services Inc. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................4 
List of Tables ..............................................................................................................................9 
List of Figures ............................................................................................................................9 
Protocol Synopsis.....................................................................................................................10 
List of Abbreviations................................................................................................................40 
1.
Introduction ......................................................................................................................43 
1.1 
Background Information .........................................................................................43 
1.2 
Rationale .................................................................................................................44 
1.3 
Benefit-Risk Assessment ........................................................................................46 
Study Objectives, Estimands, and Endpoints ...................................................................48 
2.1 
Primary Efficacy Objective, Estimands, and Endpoints .........................................48 
2.2 
Key Secondary Efficacy Objectives and Endpoints ...............................................49 
2.3 
Secondary, Other Efficacy, and Safety Objectives and Endpoints .........................49 
Investigational Plan ..........................................................................................................52 
3.1 
Study Design ...........................................................................................................52 
3.1.1 
Rationale of Study Design .......................................................................56 
3.1.2 
Duration of Study Participation for Each Participant ..............................56 
3.1.3 
End of Study Definition ...........................................................................58 
Selection of Study Population and Discontinuation/Withdrawal .....................................59 
4.1 
Inclusion Criteria ....................................................................................................59 
4.2 
Exclusion Criteria ...................................................................................................60 
4.3 
Screen Failure .........................................................................................................62 
4.4 
Discontinuation From Study Treatment and/or Withdrawal From the Study .........63 
4.4.1 
Discontinuation From Study Treatment ...................................................63 
4.4.1.1 
Permanent Discontinuation ......................................................................63 
4.4.1.2 
Temporary Discontinuation .....................................................................63 
4.4.2 
Lost to Follow-up.....................................................................................63 
4.4.3 
Handling of Withdrawals .........................................................................64 
4.4.4 
Replacements ...........................................................................................66 


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Study Treatments ..............................................................................................................67 
5.1 
Study Drug ..............................................................................................................67 
5.2 
Non-Investigational Medicinal Product ..................................................................67 
5.2.1 
Background OADs Related to Glycemic Management ...........................67 
5.2.2 
Appropriate Corrective Action/Rescue Therapy ......................................68 
5.3 
Storage and Dispensing...........................................................................................68 
5.4 
Method of Assigning Participants to Treatment Groups .........................................69 
5.5 
Treatments Administered ........................................................................................69 
5.5.1 
Dose Modifications ..................................................................................70 
5.6 
Identity of Investigational Product..........................................................................71 
5.7 
Management of Clinical Supplies ...........................................................................72 
5.7.1 
Study Drug Packaging and Storage .........................................................72 
5.7.2 
Study Drug Accountability ......................................................................72 
5.7.3 
Other Supplies..........................................................................................73 
5.7.3.1 
Blood Glucose Meter Kit .........................................................................73 
5.7.3.2 
CGM Device (FreeStyle Libre Pro Flash Glucose Monitoring System) .74 
5.8 
Overdose Management ...........................................................................................74 
5.8.1 
Treatment of Overdose ............................................................................75 
5.9 
Blinding...................................................................................................................75 
5.10 Treatment Accountability and Adherence ...............................................................75 
5.11 Concomitant Therapy ..............................................................................................76 
 
Study Assessments and Procedures ..................................................................................77 
6.1 
Study Visits .............................................................................................................77 
6.2 
Efficacy Assessments ..............................................................................................80 
6.2.1 
CGM Measures ........................................................................................80 
6.2.2 
MMTT-Derived β-Cell Function and PPG Measures ..............................82 
6.2.3 
Fasting SMPG ..........................................................................................83 
6.2.3.1 
SMPG During Symptomatic Hypoglycemia ...........................................83 
6.2.4 
FPG Measurements ..................................................................................84 
6.2.5 
HbA1c Measurements..............................................................................84 
6.2.6 
Assessment of Patient-Reported Outcome ..............................................84 
6.3 
Safety Assessments .................................................................................................85 


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6.3.1 
Physical Examination ..............................................................................85 
6.3.2 
Hypoglycemia Events ..............................................................................85 
6.3.3 
Clinical Safety Laboratory Assessments..................................................87 
6.3.4 
Vital Signs ................................................................................................89 
6.3.5 
Adverse Events ........................................................................................89 
6.3.5.1 
Suspected Unexpected Adverse Events ...................................................90 
6.3.5.2 
Adverse Events of Special Interest ..........................................................91 
6.3.5.3 
Pregnancy.................................................................................................92 
6.3.5.4 
Eliciting and Documenting AEs ..............................................................92 
6.3.5.5 
Reporting AEs ..........................................................................................93 
6.3.5.6 
Assessment of Severity ............................................................................93 
6.3.5.7 
Assessment of Causality ..........................................................................93 
6.3.5.8 
Follow-up of Participants Reporting AEs ................................................94 
6.3.6 
Safety Monitoring Committee .................................................................94 
6.3.7 
Guidelines for Reporting Product Complaints.........................................94 
6.4 
Outcomes Research Assessments ...........................................................................95 
6.5 
Sample Collections .................................................................................................95 
6.6 
Use of Biological Samples And Data For Future Research ....................................95 
6.6.1 
Assessment of β-Cell Function Indices ...................................................96 
 
Study-Specific Committees ..............................................................................................97 
 
Statistical Considerations .................................................................................................98 
8.1 
Estimands and Intercurrent Events .........................................................................98 
8.2 
Statistical Hypothesis ..............................................................................................99 
8.3 
Sample Size Determination.....................................................................................99 
8.4 
Analysis Sets .........................................................................................................100 
8.5 
Description of Subgroups to Be Analyzed ............................................................100 
8.6 
Accountability, Demographics, and Baseline Characteristics ..............................100 
8.6.1 
Adherence ..............................................................................................101 
8.7 
Statistical Analysis Methodology .........................................................................101 
8.7.1 
Overview of Statistical Methods: Estimation of Estimands and 
Sensitivity Analyses ...............................................................................103 
8.7.2 
Analysis of Primary Endpoint ...............................................................104 
8.7.2.1 
Main Estimation of Primary Estimand ..................................................104 


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8.7.2.2 
Sensitivity Analysis of Primary Endpoint ..............................................104 
8.7.2.3 
Supplementary Analysis of Primary Endpoint.......................................105 
8.7.3 
Analysis of Key Secondary Efficacy Endpoints ....................................105 
8.7.3.1 
Main Estimation of Key Secondary Estimand .......................................105 
8.7.3.2 
Sensitivity Analysis of Key Secondary Endpoints ................................105 
8.7.3.3 
Handling of Missing Data ......................................................................105 
8.7.4 
Analyses of Secondary Endpoints .........................................................106 
8.7.5 
Analyses of Other Efficacy Endpoints ...................................................107 
8.7.6 
Assessment of β-Cell Function Indices .................................................107 
8.7.7 
Analysis of PRO Endpoint .....................................................................107 
8.7.8 
Safety Analyses ......................................................................................107 
8.7.8.1 
Adverse Events ......................................................................................108 
8.7.8.2 
Hypoglycemia Events ............................................................................108 
8.8 
Data Quality Assurance.........................................................................................108 
8.8.1 
Data Management ..................................................................................109 
 
Ethics .............................................................................................................................. 111 
9.1 
Institutional Review Board ................................................................................... 111 
9.2 
Ethical Conduct of the Study ................................................................................ 111 
9.3 
Participant Information and Consent .................................................................... 111 
 Investigator’s Obligations .............................................................................................. 113 
10.1 Confidentiality ...................................................................................................... 113 
10.2 Data Protection...................................................................................................... 113 
10.3 Financial Disclosure and Obligations ................................................................... 116 
10.4 Investigator Documentation .................................................................................. 116 
10.5 Study Conduct ....................................................................................................... 117 
10.6 Adverse Events and Study Report Requirements ................................................. 117 
10.7 Investigator’s Final Report ................................................................................... 117 
 Study Management ......................................................................................................... 118 
11.1 Monitoring ............................................................................................................ 118 
11.1.1 
External Data Monitoring Committee ................................................... 118 
11.1.2 
Monitoring of the Study ......................................................................... 118 
11.1.3 
Inspection of Records ............................................................................ 118 


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11.2 Management of Protocol Amendments and Deviations........................................ 119 
11.2.1 
Modification of the Protocol .................................................................. 119 
11.2.2 
Protocol Deviations................................................................................ 119 
11.3 Study Termination ................................................................................................. 119 
11.4 Final Report ..........................................................................................................120 
11.5 Records Retention .................................................................................................120 
11.6 Publication Policy, Disclosure, and Clinical Study Registration ..........................121 
11.6.1 
Publication Policy and Disclosure .........................................................121 
11.6.2 
Clinical Study Registration ....................................................................121 
11.6.3 
Clinical Study Results Disclosure .........................................................121 
 Reference List.................................................................................................................123 
 Appendices .....................................................................................................................126 
13.1 Appendix: Schedule of Events ..............................................................................126 
13.2 Appendix: Diabetes Medication Satisfaction Tool ...............................................132 
13.3 Appendix: Participant eDiary Information ...........................................................136 
13.4 Appendix: Clinical Laboratory Tests ....................................................................137 
13.5 Appendix: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .............................................................................139 
13.5.1 
Definition of AEs ...................................................................................139 
13.5.2 
Definition of SAEs.................................................................................140 
13.5.3 
Recording and Follow-up of AEs and/or SAEs .....................................142 
13.5.4 
Reporting of SAEs .................................................................................144 
13.6 Appendix: Liver Safety .........................................................................................146 
13.7 Appendix: Contraceptive and Barrier Guidance ...................................................148 
13.8 Appendix: Source Documents ..............................................................................153 
13.9 Appendix: Eligibility and Analysis Criteria for CGM Measurements ..................155 


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List of Tables 
Table 2-1 
Primary Efficacy Objective, Estimand, and Endpoint .................................... 48 
Table 2-2 
Key Secondary Efficacy Objectives and Endpoints ....................................... 49 
Table 2-3 
Secondary, Other Efficacy, and Safety Objectives and Endpoints ................. 49 
Table 5-1 
Recommended Dose Adjustment Algorithm for Soliqua 100/33 ................... 71 
Table 6-1 
Criteria for CGM Device Reinsertion ............................................................. 81 
Table 8-1 
Estimand Framework ...................................................................................... 98 
Table 8-2 
Summary of Statistical Methods, Including Sensitivity Analyses ................ 103 
Table 13-1 
Schedule of Events ........................................................................................ 126 
Table 13-2 
Protocol-Required Safety Laboratory Assessments ...................................... 138 
Table 13-3 
Criteria for CGM Device Reinsertion ........................................................... 156 
List of Figures 
Figure 3–1 
Study Diagram ................................................................................................ 54 
Figure 6–1 
Criteria for CGM Device Reinsertion ............................................................. 81 
Figure 13–1 
Criteria for CGM Device Reinsertion ........................................................... 156 


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Protocol Synopsis 
Protocol Number: 
LPS16990 
Universal Trial 
Number: 
U1111-1261-7399 
Title: 
A 16-Week, Multicenter, Prospective, Open-Label, Single-Arm, 
Phase 4 Study to Evaluate the Effect of Soliqua™ 100/33 on the 
Percentage of Time in Range (TIR) from Continuous Glucose 
Monitoring (CGM) in Insulin-Naïve Patients With Very 
Uncontrolled Type 2 Diabetes Mellitus 
Short Title 
Soli-CGM 
Sponsor: 
Sanofi US Services Inc. 
55 Corporate Drive 
Bridgewater, NJ 08807 
USA 
Study Phase: 
Phase 4 
Study Sites: 
US only: Multicenter (Approximate number of sites: 15) 
Indication: 
Type 2 diabetes mellitus 
Rationale: 
Soliqua™ 100/33 is a fixed-ratio combination of insulin glargine 
U100 (100 units/mL) plus lixisenatide (33 μg/mL), a glucagon-like 
peptide 1 receptor agonist (GLP-1 RA; Soliqua 2019). The 
combination of a basal insulin and a GLP-1 RA addresses both 
fasting and postprandial hyperglycemia, thus ensuring more 
comprehensive glycemic control than basal insulin alone. The 
efficacy and safety of Soliqua 100/33 has been clearly established in 
randomized controlled clinical studies. In the LixiLan-O study, the 
glycated hemoglobin (HbA1c) of patients uncontrolled on oral 
antidiabetic drugs (OADs) who were treated with Soliqua 100/33 
decreased from 8.1% (baseline) to 6.5% (end of study) with the 
majority (74%) achieving the HbA1c target of <7% (Rosenstock 
et al 2016). The efficacy of Soliqua 100/33 was also demonstrated 
by a 2.9% HbA1c reduction from baseline, with 74% of patients 
achieving an HbA1c of <7%, in a subgroup of patients with type 2 
diabetes mellitus (T2DM) with baseline HbA1c ≥9% uncontrolled 
on OADs from the LixiLan-O study (Davies et al 2019). Similarly, 
patients uncontrolled on basal insulin in the LixiLan-L study 
demonstrated an HbA1c reduction from 8.1% to 6.9%, and most 
(55%) reached their target HbA1c of <7% (Aroda et al 2016). These 
results were achieved without weight gain and with fewer 
gastrointestinal (GI) side effects than with lixisenatide alone, likely 


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due to a more gradual titration of the GLP-1 RA dose (Rosenstock 
et al 2016; Davies et al 2019). 
Continuous glucose monitoring (CGM) provides a more complete 
picture of glycemic exposure and excursions than self-monitored 
blood glucose or HbA1c (Danne et al 2017). In the US, use of CGM 
is becoming mainstream, driven by improved sensor accuracy, 
convenience, ease of use, cost-effectiveness, and increased 
reimbursement. Continuous glucose monitoring facilitates improved 
glycemic control while reducing hypoglycemia risk (Danne et al 
2017; Battelino et al 2019) and is rapidly becoming standard of 
practice for many healthcare providers (HCPs) for management of 
patients with type 1 diabetes mellitus (T1DM) and insulin-treated 
T2DM. 
Time in range (TIR) is one of the metrics derived from CGM and is 
increasingly utilized to assess glycemic control. It can correlate with 
HbA1c values as well as the risk of diabetes-related complications 
(both microvascular and macrovascular). The International 
Consensus Report on “clinical targets for CGM interpretation” has 
identified “TIR” as a metric providing more actionable information 
than HbA1c and has defined targets for clinical use(Battelino et al 
2019). For example, in patients with uncomplicated T2DM whose 
HbA1c targets are <7%, the recommended TIR (for a target range of 
70-180 mg/dL) is >70% of the readings. 
Soliqua 100/33 is indicated as an adjunct to diet and exercise to 
improve glycemic control in adults with T2DM (Soliqua 2019). The 
2021 Standards of Medical Care in Diabetes from the American 
Diabetes Association (ADA; ADA 2021a; ADA 2021b) recommends 
the use of fixed-ratio combinations when the combination of 
individual components is indicated, such as when a GLP-1 RA is 
added to basal insulin or vice versa. The ADA 2021 Standards also 
recommend dual combination therapy in individuals with HbA1c 
values ≥1.5% from their glycemic target. Correlations of HbA1c and 
TIR indicate that CGM glucose readings of patients with an HbA1c 
≥9% are in range 40% of the time or less, compared with the 70% 
TIR associated with an HbA1c of 7% (Battelino et al 2019). 
Although there are currently no studies using CGM measurements 
to capture glycemic excursions and variability related to Soliqua 
100/33, a post hoc analysis demonstrated improvement in all 
measures of glycemic variability compared with its individual 
components (eg, lixisenatide or insulin glargine U100), assessed by 
7-point blood glucose profiles. These findings were attributable to 
Soliqua 100/33’s complementary mechanisms of action, which 


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demonstrate reductions in both fasting and postprandial 
hyperglycemia (Aronson et al 2019). 
The current study is intended to replicate these results using CGM 
to measure TIR and glycemic variability in a patient population with 
very uncontrolled T2DM (HbA1c ≥9%-13%), who are most likely 
to benefit from a fixed-ratio combination approach, such as Soliqua 
100/33. 
The primary objective of this study is to demonstrate an 
improvement in the percentage of TIR from baseline to the end of 
the study (16 weeks) in insulin-naïve patients with very 
uncontrolled (HbA1c ≥9%-13%) T2DM on 2+ OADs with or 
without GLP-1 RAs. 
Benefit-Risk 
Assessment 
Soliqua 100/33 has demonstrated superior glycemic efficacy in 
patients with T2DM uncontrolled on oral therapies, basal insulin, or 
GLP-1 RA (including weekly GLP-1 RA) with durable efficacy 
(52 weeks) compared with its individual components (insulin 
glargine U100 and lixisenatide), and recently premixed insulin 
analog (BIAsp 30) in those uncontrolled on basal insulin and oral 
therapies (Rosenstock et al 2021). Additionally, compared with 
insulin glargine U100 alone, patients on Soliqua 100/33 had weight 
neutrality with no increase in hypoglycemia events; compared with 
lixisenatide alone, they experienced fewer GI adverse events (AEs) 
(Aroda et al 2016; Rosenstock et al 2016; Blonde et al 2019). 
Soliqua 100/33 has also shown greater HbA1c reduction, less 
weight gain, and less hypoglycemia compared to a premixed insulin 
analog (BiAsp 70/30) in individuals not controlled on basal insulin 
therapy (Rosenstock et al 2021). No new risks have been identified 
for the population to be included in Study LPS16990. In this study, 
treatment with Soliqua 100/33 will be consistent with the current US 
Food and Drug Administration (FDA)-approved label indications 
(Soliqua 2019). During the titration period, the dose of Soliqua 
100/33 will be adjusted upwards or downwards by 2 to 4 units every 
week, or at the investigator’s discretion, based on the participant’s 
blood glucose monitoring results, with the objective of safely 
attaining a fasting self-measured plasma glucose (SMPG) value of 
80 to 100 mg/dL, as well as other glycemic goals, while minimizing 
the risk of hypoglycemia and hyperglycemia. The duration of the 
titration period and number of phone contacts to safely meet the 
study goals will also be at the discretion of the investigator. 
Therefore, the risk for patients participating in this study and using 
daily doses of Soliqua 100/33 up to a maximum of 60 units of 
insulin glargine and 20 μg of lixisenatide is considered acceptable. 


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All patients enrolled in this study will benefit from medical care and 
continuous monitoring of their glucose levels. 
The important identified risks for Soliqua 100/33 are hypoglycemia 
or hyperglycemia associated with alterations in the insulin dosing 
regimen, hypersensitivity reactions, overdose due to medication 
errors, injection site reactions, and GI AEs, including nausea, 
diarrhea, and vomiting. This study proposes a titration algorithm with 
titration targets that will closely follow the US label for 
Soliqua 100/33(Soliqua 2019), except in instances of hyper- or 
hypoglycemia, which require specific attention. All study 
participants will benefit from the safety monitoring planned during 
site visits as well as during the additional titration phone contacts. 
Given the expected improvement of glycemic control and the 
additional measures to improve diabetes management, the benefits 
are considered to outweigh any potential risks associated with 
Soliqua 100/33. Therefore, the benefit-risk ratio for patients 
participating in Study LPS16990 is considered favorable. 
 
Objectives and 
Endpoints: 
Objectives 
Endpoints 
To determine the effect of 
Soliqua 100/33 on indices of 
glycemic control and variability, 
as measured via CGM, from 
baseline to Week 16, in 
insulin-naïve patients with very 
uncontrolled (HbA1c ≥9%-13%) 
T2DM  
 
Efficacy Objectives 
 
Primary Objective 
Primary Endpoint 
• To demonstrate that in 
patients with T2DM failing to 
achieve glycemic control 
(HbA1c ≥9%-13%) on their 
current regimen of 2+ OADs 
with or without GLP-1 RAs, 
introduction of Soliqua 
100/33 exhibits superiority in 
terms of time spent in range 
(70-180 mg/dL) at Week 16 
compared with baseline, as 
measured by CGM  
 
• Change in the percentage of TIR 
(70-180 mg/dL) from baseline to 
Week 16 


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Key Secondary Objectives 
Key Secondary Endpoints 
• To evaluate the impact of 
Soliqua 100/33 on measures 
of glycemic control and 
variability in patients with 
T2DM 
• Change (%) from baseline to 
Week 16 in coefficient of 
variation (CV) 
• Change (mg/dL) from baseline 
to Week 16 in mean daily blood 
glucose 
• Change (mg/dL) from baseline 
to Week 16 in the maximum 
postprandial glucose (PPG) 
exposure in the 4 hours after the 
breakfast meal 
• Change (%) from baseline to 
Week 16 in time above range 
(TAR; >180 mg/dL) 
Secondary Objectives 
Secondary Endpoints 
• To evaluate the impact of 
Soliqua 100/33 on other 
measures of glycemic control 
and variability in patients 
with T2DM 
• Proportion (%) of patients 
achieving CV <36% 
• Change (%) from baseline to 
Week 16 in TIR (70-180 mg/dL) 
for specific time blocks 
(6 am-12 pm, 12 pm-6 pm, 
6 pm-12 am, and 12 am-6 am) 
• Proportion (%) of patients 
achieving Glucose Management 
Indicator (GMI) <7% and <9% 
at Week 16 
• Change from baseline to 
Week 16 in the 4-hour PPG area 
under the concentration versus 
time curve from 0 to 4 hours 
(AUC0-4h) after start of the 
breakfast meal, including time to 
reach maximum concentration 
(Tmax) 
• Proportion (%) of patients at 
Week 16 who spend 
<15 minutes/day at a glucose 
level <54 mg/dL 
 
 


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Other Efficacy Objectives 
• To evaluate the impact of 
Soliqua 100/33 on additional 
measures of glycemic control 
and variability in patients 
with T2DM 
Other Efficacy Endpoints and 
Analyses 
• Change (mg/dL) from baseline 
to Week 16 in mean of daily 
difference (MODD) of glucose 
levels 
• Change (%) from baseline to 
Week 16 in TAR (>250 mg/dL) 
• Change (%) from baseline to 
Week 16 in time below range 
(TBR; <70 mg/dL) 
• Correlation of change in the 
percentage of TIR 
(70-180 mg/dL) and least square 
(LS) mean change in 
patient-reported outcome (PRO) 
from baseline to Week 16 
• Correlation of percentage of TIR 
(70-180 mg/dL) and HbA1c 
percentage achieved at Week 16 
• Correlation of patients reaching 
60 units/day insulin glargine 
U100 and TIR >70% 
• Change in HbA1c percentage 
from baseline to Week 16 
PRO Objective 
• To assess patient-perceived 
treatment impact on 
health-related quality of life 
(HRQoL) and treatment 
satisfaction  
PRO Endpoint 
• Change from baseline to 
Week 16 in diabetes medication 
treatment satisfaction scores 
(total score and by subscales), 
using the Diabetes Medication 
Satisfaction Tool (DM-SAT) 
questionnaire 
Safety Objective 
Safety Endpoints 
• To assess the safety and 
tolerability of Soliqua 100/33 
Safety evaluations will include 
evaluation of the following (for 
16 weeks): 
• Overall hypoglycemia 
• Confirmed hypoglycemia  
o ADA Level 1: Measurable 
glucose concentration 


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<70 mg/dL (3.9 mmol/L) 
but ≥54 mg/dL (3.0 mmol/L) 
o ADA Level 2: Measurable 
glucose concentration 
<54 mg/dL (3.0 mmol/L) 
that needs immediate action 
o ADA Level 3: Severe event 
characterized by altered 
mental and/or physical 
functioning that requires 
assistance* from another 
person for recovery 
• AEs, serious adverse events 
(SAEs), and adverse events of 
special interest (AESIs) 
 
*Note that “requires assistance” means that the person could not help themselves. 
Assisting a person out of kindness, when assistance is not required, should not be 
considered a “requires assistance” incident. 
Study Population: 
Key Inclusion Criteria 
Each participant must meet all of the following criteria to be 
enrolled in this study: 
1. Is capable of understanding the written informed consent, 
provides signed written informed consent, is willing and able to 
complete the electronic diary (eDiary), and agrees to comply 
with protocol requirements (confirmed by the site staff 
performing the recruitment efforts). 
2. Is an adult ≥18 years of age. 
3. Has an HbA1c ≥9%-13% during the run-in period. 
4. Was diagnosed with T2DM at least 6 months before the baseline 
period. 
5. Has been treated with 2+ OADs with or without GLP-1 RAs 
with stable doses (for both) for 3 months before the screening 
period. 
6. Is willing and able to wear the CGM device continuously for 
14 days to capture CGM measures at baseline (from Visit 2 
[ie, the run-in period] until the next site visit at Visit 3.1) and 
again at the end of the treatment period [ie, from Visit 6 until the 
next site visit at Visit 7; Section 13.1). 
7. Is willing and able to prick fingers a minimum of 2 to 4 times 
per week, using sterile lancets provided with a manual blood 
glucose meter kit. 


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8. Is willing to discontinue daily (oral or injectable) or weekly 
GLP-1 RA or DPP-4i before administration of Soliqua 100/33. 
9. Is willing and able to inject Soliqua 100/33 and increase dose as 
needed to achieve SMPG target. 
Key Exclusion Criteria 
Participants meeting any of the following criteria will be excluded 
from the study: 
1. Has T1DM or any other types of diabetes, except T2DM. 
2. Is being treated with meglitinides (eg, nateglinide, repaglinide). 
3. Has a body mass index (BMI) >40 kg/m² during the screening 
period.* 
*Body weight and height will be recorded during the screening 
period for the calculation of BMI (metric: BMI = weight (kg)/height 
[m2]). 
4. Provides less than equivalent of 8 days of evaluable CGM data 
(not necessarily consecutive) over a 14-day period (eg, days of 
CGM device wear × % time CGM device active < 8; 
Section 6.2.1). 
5. Has any current or previous skin conditions, including (but not 
limited to) severe psoriasis, burns, eczema, scarring, and 
excessive tattoos, that would inhibit the proper wearing of the 
CGM device. 
6. Has a history of severe nausea and vomiting that resulted in 
subsequent discontinuation of GLP-1 RA. 
7. Has a known history or presence of clinically significant 
pancreatitis or gastroparesis. 
8. Has had an episode of severe hypoglycemia or hypoglycemia 
unawareness (defined as the onset of neuroglycopenia before the 
appearance of autonomic warning symptoms [for example, 
blurred vision, difficulty speaking, feeling faint, difficulty 
thinking, and confusion] or as the failure to sense a significant 
fall in blood glucose below normal levels) within the 6 months 
before the screening period. 
9. Has any clinically significant abnormality identified from the 
physical examination, vital sign measurements, or laboratory 
tests (eg, amylase, lipase, alanine aminotransferase [ALT] 
>3 × upper limit of normal [ULN], calcitonin ≥20 pg/mL, severe 
renal impairment [estimated glomerular filtration rate 
<30 ml/min/1.73m2] or end-stage renal disease) or visual 


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impairment at screening that, in the opinion of the investigator 
or any qualified designee, would make implementation of the 
protocol or interpretation of the study results difficult or would 
preclude safe participation in the study. 
10. Has personal or immediate family history of medullary thyroid 
cancer (MTC) or a genetic condition that predisposes the 
participant to MTC (eg, multiple endocrine neoplasia 
syndromes). 
11. Has current or known history of alcohol or drug abuse within 
6 months before the screening period. 
12. Has significant current (within past 2 months) or expected use of 
medications known to affect glycemia (eg, ≥5 mg/day 
prednisone). 
13. Uses substances known to interfere with CGM readings, such as 
aspirin-containing products (>650 mg/day of salicylic acid) or 
supplements containing vitamin C (>1000 mg/day of ascorbic 
acid) taken during the 14-day periods of CGM measure at 
baseline (ie, from Visit 2 to Visit 3.1) and end of the treatment 
period (ie, from Visit 6 to Visit 7). 
14. Has undergone previous treatment with any insulin (except for 
short-term treatment due to intercurrent illness, including 
gestational diabetes, at the discretion of the investigator). 
15. Is enrolled in another clinical study or has taken other 
investigational drug(s) within 1 month or 5 half-lives from 
screening, whichever is longer. 
16. Has a hypersensitivity to Soliqua 100/33, either of its active 
components (insulin glargine or lixisenatide), or any of its 
excipients that, in the opinion of the investigator, contraindicates 
participation in the study. 
17. Has used weight loss drugs (including over-the-counter and 
herbal medications) within 12 weeks before the screening visit. 
Study Design: 
This is a 16-week, multicenter, interventional, open-label, 
single-arm, Phase 4 study using blinded CGM (FreeStyle Libre Pro) 
to demonstrate improvement in the percentage of TIR from baseline 
in patients adding Soliqua 100/33 and treated for 16 weeks. The 
study will be conducted in approximately 100 patients whose T2DM 
is very uncontrolled on 2+ OADs with or without GLP-1 RAs (with 
stable doses for 3 months), as evident from a screening HbA1c of 
≥9%-13%. The study will attempt to represent the diversity of the 


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US patient population with T2DM through site recruitment 
efforts. 
All eligible participants will undergo 14 days of blinded continuous 
CGM monitoring at baseline (the run-in period) and a mixed-meal 
tolerance test (MMTT) while on baseline medications. Soliqua 
100/33 treatment will be initiated on Day 0 (Visit 3.2), after the 
MMTT (which is scheduled at Visit 3.1). Sulfonylurea (SU) doses 
should be down-titrated by 50% when starting Soliqua 100/33, and 
the last doses of daily dipeptidyl peptidase-4 inhibitor (DPP-4i) and 
daily GLP-1 RA (oral or injectable) should be administered on the 
morning of Day –1, the day before the first dose of Soliqua 100/33 
(Section 13.1).  
At Visit 3.1, participants on OADs or an oral or injectable GLP-1 
RA will be required to take their dose after blood sample for fasting 
plasma glucose (FPG) and HbA1c is collected and 30 minutes 
before administration of the meal during the MMTT (during which 
measures for both β-cell function and PPG analyses will be 
captured). Participants on a weekly GLP-1 RA should have their 
baseline MMTT conducted within 7 (± 3) days after their last dose 
and administer their last weekly GLP-1 RA dose 7 (± 2) days before 
the first dose of Soliqua 100/33.  
During the end of the treatment period (from Visit 6 to Visit 7), 
participants will again be required to undergo 14 days of blinded 
continuous CGM monitoring and a MMTT (only to derive PPG 
measures). Soliqua 100/33 should be administered 30 minutes 
before administration of the meal during the MMTT at Visit 7 
(during which only measures for PPG analyses will be captured). 
All participants will be allowed to continue their background OADs 
(except DPP-4i and SU, as previously described) at stable doses and 
regimens throughout the study period, unless they have to be 
stopped or modified for safety reasons.  
The study comprises the following periods: 
• A screening period of up to 2 weeks. 
• A run-in period of 2 weeks, including the baseline period. 
o At Visit 2, the CGM device will be applied to the back of the 
upper arm of the participant and baseline CGM data will be 
collected continuously for 14 days; the device will be 
removed at the subsequent site visit during the baseline 
period (ie, Visit 3.1), after the MMTT. 


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o During the baseline period, on Day –1 (Visit 3.1), 
participants will return to the site for the MMTT (for both 
β-cell function and PPG measures) and CGM removal and 
data download (after the MMTT). Dispensing of the 
Soliqua 100/33 pen and instruction on administration of 
Soliqua 100/33 will also take place during this visit. 
o Visit 3.2 (ie, Day 0) during the baseline period is the first 
day of Soliqua 100/33 administration and includes a phone 
contact to ALL participants to ensure that all administration 
procedures were successfully executed and to answer any 
questions. (Note: The first day of Soliqua 100/33 
administration [ie, Visit 3.2, Day 0] for participants on 
weekly GLP-1 RA will depend on their administration 
schedule and may not be the day immediately following 
Visit 3.1. Soliqua 100/33 administration for these 
participants should be 7 [± 2] days after their last weekly 
GLP-1 RA dose.) 
 A phone contact should also be made ONLY to 
participants on weekly GLP-1 RA on the day before 
Soliqua 100/33 initiation, to remind them of the next 
morning’s injection and to provide instructions for 
SoloStar pen use. The participants will provide their 
concomitant medication details to the site personnel over 
the phone.  
• A 16-week, open-label treatment period. 
o Visit 3.2 (ie, Day 0) is the first day of Soliqua 100/33 
administration and begins the open-label treatment period 
(with different initiation requirements based on weekly or 
daily GLP-1 RA use, as explained above). 
o The dose of Soliqua 100/33 will be adjusted during the 
titration period (ie, from Weeks 1 through 12; Visits 4.0 to 
5.4), at the investigator’s discretion, until the desired fasting 
SMPG value (80-100 mg/dL) is achieved 
(Table: Recommended Dose Adjustment Algorithm for 
Soliqua 100/33). 
o During Visits 4.0 to 4.6, weekly phone contacts for dose 
adjustments are to continue at the investigator’s discretion 
until the desired fasting SMPG value is achieved. 
o If the desired fasting SMPG value is not achieved in the first 
8 weeks of treatment, the investigator has the option to 
continue weekly dose titration phone contacts for an 


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additional 4 weeks (until Week 12; ie, from Visits 5.1 to 5.4) 
with the purpose of achieving glycemic targets. 
o At Visit 6, a blinded CGM device will again be applied to 
the back of the upper arm of the participant and CGM data 
will be collected continuously for 14 days; the device will be 
removed at the subsequent site visit (ie, Visit 7), after the 
MMTT (only to derive PPG measures). 
o At the end of the study (ie, Visit 7), participants should 
discuss with the investigator, in collaboration with their 
HCP, whether to remain on the Soliqua 100/33 treatment 
regimen or transition to an alternate antihyperglycemic 
therapy. 
• A 2-week post-treatment safety follow-up period after the last 
dose of Soliqua 100/33 (eg, treatment completion) or after 
premature/permanent treatment discontinuation from 
Soliqua 100/33. 
Estimated Study 
Duration: 
The total duration of the study will be approximately 22 weeks for 
each participant. Three site visits, 3 site or home visits, and up to 
13 phone contacts are scheduled. 
Participants will have the choice to have Visits 2, 5, and 6 
performed at the study site or at home. This choice is to be 
determined at the screening visit. Participants who opt for site visits 
should be encouraged not to change to home visits during the study 
period. However, if this is unavoidable, the home health provider 
and the sponsor-approved courier company for investigational 
medicinal product (IMP) shipment will need at least 72 hours’ 
notice from the investigator to arrange a home visit and 
direct-to-patient (DTP) IMP supply, if required. An unscheduled site 
or home visit can be planned during the treatment period for IMP 
Soliqua 100/33 resupply, if required. If DTP Soliqua 100/33 supply 
is required, the sponsor-approved courier company will need at least 
72 hours’ notice to collect Soliqua 100/33 treatment kits from a 
study site. The end of the study is defined as the date of the last visit 
of the last participant in the study. Although Sanofi has every 
intention of completing the study, Sanofi reserves the right to 
discontinue the study at any time for clinical or administrative 
reasons. 
Efficacy 
Assessments: 
The schedule of events (SoE) is provided in Section 13.1. 
The efficacy assessments are as follows: 
 


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• CGM measures. 
• MMTT-derived β-cell function and PPG measures. 
o Biomarkers of β-cell function (plasma glucose, insulin, and 
C-peptide) will be collected at baseline; whereas only 
plasma glucose will be collected at Visit 7. 
• Fasting SMPG. 
• FPG measurements. 
• HbA1c measurements (during the screening and run-in periods 
and at Visits 3.1 and 7). 
CGM Measures 
Blinded CGM will be performed for 14 continuous days during 
baseline (ie, from Visit 2 to Visit 3.1) and again for 14 days at the 
end of the treatment period (ie, from Visit 6 to Visit 7; Section 13.1). 
The baseline CGM measure will be captured before discontinuing 
the daily (oral or injectable) or weekly GLP-1 RA, DPP-4i, or 
down-titration of SU by 50%, and before initiation of Soliqua 
100/33 treatment. The blinded CGM device (FreeStyle Libre Pro) 
will be applied to the back of the upper arm of the participant and 
activated at Visit 2 (ie, the run-in period). Participants will be 
required to wear the device continuously for 14 days for baseline 
CGM data collection, with device removal and data download on 
Day –1 at their next site visit during the baseline period (ie, 
Visit 3.1), after collection of C-peptide, insulin, and plasma glucose 
data from the MMTT. Downloaded CGM data will be reviewed by 
the investigator to determine participants’ study eligibility. (Note: 
During the run-in period, CGM device reinsertion will be allowed 
for participants who do not meet the equivalent of at least 8 days of 
evaluable CGM data [not necessarily consecutive] over a 14-day 
period as a result of premature sensor failure [eg, days of CGM 
device wear × % time CGM device active < 8]; Table 6-1 and 
Figure 13–1.) Similarly, participants will be required to 
continuously wear the device for 14 days at the end of the treatment 
period from Weeks 14 to 16 (ie, Visit 6 to Visit 7) to collect CGM 
data, with device removal and data download on the fifteenth day 
after CGM placement (ie, Visit 7), after collection of only plasma 
glucose data from the MMTT. Downloaded CGM data will be 
verified by the investigator at the site to determine participants’ 
study completion. During the end of the treatment period, CGM 
device reinsertion will also be allowed for participants who do not 
meet the equivalent of at least 8 days of evaluable CGM data (not 


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necessarily consecutive) over a 14-day period as a result of 
premature sensor failure (eg, days of CGM device wear × % time 
CGM device active < 8; Table 6-1 and Figure 13–1), if data can be 
captured during the 14-day end of treatment window. (Note: The 
minimum requirement for evaluable CGM data is if at least 10 out 
of 14 days [not necessarily consecutive] have at least ≥80% of 
evaluable CGM data per 24-hour period during the run-in period as 
well as the end of the treatment period [ie, from Weeks 14 to 16]; 
Battelino et al 2020.) 
Participants with less than equivalent of 8 days of evaluable CGM 
data (not necessarily consecutive) of a 14-day period (eg, days of 
CGM device wear × % time CGM device active < 8) during the 
run-in period will be considered as screen failures. For participants 
who discontinue study treatment prematurely, the visit window can 
be extended by 14 days to collect the CGM data before they 
permanently discontinue the treatment. 
MMTT-Derived β-Cell Function and PPG Measures 
Participants will undergo the MMTT (while wearing the CGM 
device) to assess maximum PPG exposure in the 4-hour period after 
the breakfast meal (tested at a central laboratory) with biomarkers of 
β-cell function (plasma glucose, insulin, and C-peptide) measured at 
Visit 3.1 (ie, site visit during the baseline period). The baseline 
MMTT will be conducted before discontinuing the daily (oral or 
injectable) or weekly GLP-1 RA, DPP-4i, or down-titration of SU 
by 50%. Participants on OADs or an oral or injectable GLP-1 RA 
will be required to take their dose after the blood sample for FPG 
and HbA1c is collected and 30 minutes before administration of the 
meal during the MMTT (Visit 3.1). Participants who are on weekly 
GLP-1 RA should have their baseline MMTT conducted within 
7 (± 3) days after their last dose. During baseline (Visit 3.1), blood 
samples will be collected at the following time points: premeal 
(30 min) and just before administration of OADs or GLP-1 RA (oral 
or injectable) (baseline); time 0 (just before the meal), 10 min, 
20 min; and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal for 
plasma glucose, C-peptide, and insulin levels.  
At the end of the treatment period (Visit 7), participants will again 
undergo the MMTT (while wearing the CGM device; only to derive 
PPG measures). Soliqua 100/33 should be administered 30 minutes 
before administration of the meal during the MMTT at Visit 7. At 
the end of the treatment period (Visit 7), blood samples will be 
collected for plasma glucose levels, as follows: premeal (30 min) 
and just before administration of Soliqua 100/33; and time 0 (just 


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before the meal), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal. 
These values will be used for PPG analyses with the goal of 
deriving reduction in the maximum glucose exposure in the 4-hour 
period after the breakfast meal following Soliqua 100/33 
administration for 16 weeks compared with baseline. During both 
baseline and end-of-treatment assessments, removal of the CGM 
device and download of data will be done after completion of the 
MMTT (Section 13.1). 
The MMTT includes a standardized meal (ie, Boost Very High 
Calorie) that contains approximately 530 kcal and is composed of 
19% carbohydrates, 44% protein, and 33% fat. The composition and 
the quantity of the standardized meal must be identical throughout 
the study period. 
During the baseline period (ie, Visit 3.1), on the day of the MMTT, 
the participants must not eat any food or drink, except water, for at 
least 8 hours before the scheduled meal test (to be completed in the 
morning). At the end of the treatment period (ie, Visit 7), the MMTT 
will also be performed in a fasted state (eg, no consumption of any 
food or drink for at least 8 hours, except water, before the scheduled 
meal test), and participants will receive their Soliqua 100/33 dose at 
the site 30 minutes before the start of the test (ie, consumption of the 
meal and just after the first blood draw). 
For participants who discontinue study treatment prematurely, the 
visit window can be extended by 14 days to collect the CGM data, 
followed by the MMTT data, before they permanently discontinue 
the treatment. 
Fasting SMPG 
Participants will be supplied with a glucometer and an eDiary at the 
screening visit. Appropriate training will be provided to the 
participants related to proper use of the glucometer and eDiary 
completion. Fasting SMPG values (lowest values in conjunction 
with measurements from the previous 3 days) will be used to titrate 
and adjust Soliqua 100/33 doses and monitor glycemic control. The 
participants are required to measure fasting SMPG values before 
breakfast at least 3 to 4 times per week throughout the study period 
(to inform each dose adjustment) and record the results in the 
eDiary. During the titration period, fasting SMPG should be 
performed on each of the 3 to 4 days before each dose adjustment. 
(Note: Additional titration is at the discretion of the investigator 
with the goal of achieving glycemic targets while minimizing the 
risk of hypoglycemia and hyperglycemia.) 


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SMPG During Symptomatic Hypoglycemia 
Whenever participants experience hypoglycemia symptoms, they 
(or others, if applicable) should measure plasma glucose, if possible. 
Participants should be instructed to measure plasma glucose levels 
before carbohydrate intake/administration of glucose whenever 
symptomatic hypoglycemia is suspected, unless safety 
considerations necessitate immediate carbohydrate/glucose rescue 
before confirmation with the SMPG values. Participants must 
contact the investigator as soon as possible following hypoglycemia 
events for review and so that a decision regarding any necessary 
actions can be made. Participants should be instructed to measure 
plasma glucose levels again after the event resolves. 
FPG Measurements 
Blood samples will be collected to determine FPG at the time points 
specified in the SoE (Section 13.1) and will be measured at a central 
laboratory. For the scheduled site visits, participants are required to 
arrive fasting without administering the Soliqua 100/33 injection. 
Fasting is defined as no food intake in the 8 hours before blood 
sampling, except water. 
HbA1c Measurements 
Blood samples will be collected to measure HbA1c during the 
screening and run-in periods, and at Visit 3.1 (before administration 
of the meal) at the central laboratory, to determine study eligibility, 
and at the end of the 16-week treatment period (Visit 7), to 
determine change in glycemic control. 
Assessment of PRO 
Diabetes Medication Satisfaction Tool 
The assessment of treatment-related impact on participants’ 
health-related quality of life and their satisfaction with diabetes 
therapy will be assessed using the DM-SAT questionnaire 
(Anderson et al 2009) at the baseline visit before stopping or 
down-titration of baseline therapies and at the end of the treatment 
period (Section 13.1). The DM-SAT questionnaire (Section 13.2) is 
a 16-item measure with 4 subscales assessing wellbeing (3 items), 
medical control (3 items), lifestyle (5 items), and convenience 
(5 items). 
Participants will be requested to complete the DM-SAT 
questionnaire by themselves, independently from the investigator or 
site staff, and without any help from friends or relatives. For validity 
purposes, the questionnaire should be completed by participants in a 


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quiet place, at the start of the visit before any other study tests or 
procedures are performed or Soliqua 100/33 is administered. 
Safety 
Assessments: 
Safety will be evaluated by the frequency, severity, seriousness, and 
duration of any AEs. Hypoglycemia events, AEs, and SAEs, 
including AESIs, will be recorded at each site visit and phone 
contact throughout the study period. 
Any abnormal changes in vital signs, standard chemistry, and 
hematology will be assessed at Visit 1 (ie, screening period), 
Visit 3.1 (ie, before initiation of Soliqua 100/33 treatment), and 
Visit 7 (ie, end of the treatment period; Section 13.1). 
The safety assessments are as follows: 
• Physical examination. 
• Hypoglycemia events. 
• AEs and SAEs, including AESIs. 
• Vital signs (heart rate, systolic blood pressure [BP], and 
diastolic BP). 
• Clinical safety laboratory assessments (eg, clinical chemistry, 
calcitonin [screening only], hematology, urinalysis). 
Physical Examination 
A complete physical examination (including body weight) will be 
performed, per standard of care, in order to assess the health status 
of the participants at time points described in the SoE 
(Section 13.1). Height measurements in conjunction with body 
weight will be utilized to calculate BMI during the screening period. 
Hypoglycemia Events 
During the study, participants must be instructed to document any 
hypoglycemia events in their eDiary. Hypoglycemia will be reported 
in the specific hypoglycemia event information form in electronic 
case report form (eCRF) with onset date and time; symptoms and/or 
signs; the SMPG value, if available; and the treatment. A 
hypoglycemia event that fulfills the seriousness criteria will also be 
documented on the SAE form in the eCRF. Participants should be 
instructed to record their SMPG values in the eDiary after the event 
resolves. 
Hypoglycemia will be evaluated in accordance with the consensus 
report of a steering committee on levels of hypoglycemia 
(Agiostratidou et al 2017). These levels are consistent with the ADA 
standard of care 2021 recommendations (ADA 2021a). 


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The following are the categories of interest: 
• Overall hypoglycemia. 
• Confirmed hypoglycemia. 
o ADA Level 1: A measurable glucose concentration of 
<70 mg/dL (3.9 mmol/L) but ≥54 mg/dL (3.0 mmol/L). 
o ADA Level 2: A measurable glucose concentration of 
<54 mg/dL (3.0 mmol/L) that needs immediate action.  
o ADA Level 3: A severe event characterized by altered mental 
and/or physical functioning that requires assistance* from 
another person for recovery. 
*Note that “requires assistance” means that the person could not 
help themselves. Assisting a person out of kindness, when assistance 
is not required, should not be considered a “requires assistance” 
incident. 
Clinical symptoms that are related to a hypoglycemia episode can 
include (but are not necessarily limited to) increased sweating, 
nervousness, asthenia, tremor, dizziness, increased appetite, 
palpitations, headache, sleep disorder, confusion, seizures, 
unconsciousness, and coma (Agiostratidou et al 2017). 
Adverse Events and Serious Adverse Events, including Adverse 
Events of Special Interest 
All AEs (serious or nonserious) will be collected from the signing of 
the informed consent form (ICF) until the follow-up visit 
(Section 13.1). The definitions of AEs and SAEs are provided in the 
Section 13.5. 
AESI: 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. 
Adverse events of special interest may be added, modified, or 
removed during a study by protocol amendment. 
The following AEs will be considered AESIs in this study: 
• Pregnancy of a female participant enrolled in the study as well 
as pregnancy occurring in a female partner of a male participant 
enrolled in the study with IMP/non-investigational medicinal 
product (NIMP). 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP. 


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o An overdose (accidental or intentional) with the IMP/NIMP 
is an event suspected by the investigator or spontaneously 
reported by the participant and is defined as any dose 
administration that, in the investigator’s opinion based on 
clinical judgment, is considered significantly greater than the 
prescribed dose of insulin or is at least twice the intended 
dose within the intended therapeutic interval (for example, 
for a participant prescribed 60 units/20 µg Soliqua 100/33 
once a day, administration of ≥120 units of insulin glargine 
U100 with ≥40 μg of lixisenatide once a day would be 
considered an overdose), adjusted according to the tested 
drug. 
• Increase in ALT (>3 × ULN; Section 13.6). 
The investigator is responsible for reporting all AEs that are 
observed or reported during the study, regardless of their 
relationship to study drug or their clinical significance. The 
investigator remains responsible for following up on AEs that are 
serious, considered related to the study treatment or study 
procedures, or caused the participant to discontinue the 
Soliqua 100/33 treatment and/or the study. 
Vital Signs 
Vital signs will be recorded at the time points specified in the SoE 
(Section 13.1). 
Clinical Safety Laboratory Assessments 
All clinical safety laboratory assessments will be performed by a 
central laboratory. The investigator must review the laboratory 
report and document this review. The laboratory reports must be 
filed with the source documents. 
Clinically significant abnormal laboratory findings associated with 
the underlying disease or vital signs will not be considered 
clinically significant or be reported as AEs unless one of the 
following criteria is met: 
• Participant is symptomatic (and/or laboratory values or vital 
signs are clinically significant per the investigator’s discretion). 
• Participant requires either corrective treatment or consultation.  
• Participant requires Soliqua 100/33 treatment to be discontinued 
or modification of dosing. 
• Event fulfills a seriousness criterion. 
• Event meets the definition of an AESI (Section 6.3.5.2). 


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Pregnancy 
A urine pregnancy test will be performed at time points specified in 
the SoE (Section 13.1). Any female participant who becomes 
pregnant while participating in the study will be discontinued from 
study drug treatment. 
Study Visits 
The SoE is provided in Section 13.1. 
• The screening period (Visit 1) will encompass up to 2 weeks and 
includes obtaining informed consent, eligibility criteria, 
demographic assessment, review of medical/surgical history and 
current medications, physical examination (BMI calculation), 
dispensing of glucometer, HbA1c measurement, setting up the 
eDiary, recording of vital signs, and clinical chemistry, 
calcitonin, hematology, urinalysis, and pregnancy tests. 
• The run-in period (Visit 2) will encompass 2 weeks, including 
the baseline period, and includes HbA1c measurement and 
application of blinded CGM device (FreeStyle Libre Pro). 
o Visit 3.1 will be a site visit and includes assessment of 
eligibility criteria, MMTT, CGM device removal and data 
download (after the MMTT), CGM compliance assessment, 
evaluation of PPG and biomarkers of β-cell function 
(insulin, C-peptide, plasma glucose) during the MMTT, 
instructions for certain therapies (eg, DPP-4i, oral daily or 
weekly GLP-1 RA, and down-titration of SU by 50% when 
starting Soliqua 100/33), dispensing of Soliqua 100/33 and 
providing instruction for SoloStar™ pen use, HbA1c and 
FPG measurements, administration of the DM-SAT, 
recording of vital signs and body weight, and clinical 
chemistry, hematology, urinalysis, and pregnancy tests. 
o Visit 3.2 (ie, Day 0) during the baseline period is the first 
day of Soliqua 100/33 administration and includes a phone 
contact to ALL participants to ensure that all administration 
procedures were successfully executed and to answer any 
questions. (Note: The first day of Soliqua administration 
[ie, Visit 3.2, Day 0] for participants on weekly GLP-1 RA 
will depend on their administration schedule and may not be 
the day immediately following Visit 3.1. Soliqua 100/33 
administration for these participants should be 7 [± 2] days 
after their last weekly GLP-1 RA dose.) 
 A phone contact should also be made ONLY to 
participants on weekly GLP-1 RA on the day before 
Soliqua 100/33 initiation, to remind them of the next 


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morning’s injection and to provide instructions for 
SoloStar pen use. The participants will provide their 
concomitant medication details to the site personnel over 
the phone. 
• The treatment period will encompass up to 16 weeks (Visits 3.2 
through 7), and includes the following: 
o Visit 3.2 (ie, Day 0) is the first day of Soliqua 100/33 
administration and begins the open-label treatment period 
(with different initiation requirements based on weekly or 
daily GLP-1 RA use, as explained above). 
o Titration period (Visits 4.0 to 4.6, 5, and 5.1 to 5.4). 
 For Visits 4.0 to 4.6, titration of the Soliqua 100/33 dose 
will occur via phone contacts, but it can occur at the 
study site or at home for Visit 5. For Visits 5.1 through 
5.4, titration of Soliqua 100/33 dose will again occur via 
phone contacts. 
 During the titration period, participants will continue to 
make entries into their eDiary, administer Soliqua 
100/33, adjust the Soliqua 100/33 dose, and capture any 
product complaints. 
 Other than an unscheduled visit, dispensing of 
Soliqua 100/33 will occur at Visit 5, if required. A 
pregnancy test will also be conducted at Visit 5. 
o Visit 6: Application of blinded CGM device, assessment of 
Soliqua 100/33 adherence, and capturing of any product 
complaints. 
o Visit 7 (ie, end of the treatment period): Physical 
examination (including body weight), MMTT (only to derive 
PPG measures), removal of CGM device and download of 
data, assessment of Soliqua 100/33 adherence, HbA1c and 
FPG measurements, recording of the DM-SAT, vital signs, 
and clinical chemistry, hematology, urinalysis, and 
pregnancy tests. 
o At the end of the study (ie, Visit 7), participants should 
discuss with the investigator, in collaboration with their 
HCP, whether to remain on the Soliqua 100/33 treatment 
regimen or transition to an alternate antihyperglycemic 
therapy. 
• An unscheduled visit can be performed at any time during the 
treatment period and may include dispensing of Soliqua 100/33, 


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adjustment of Soliqua 100/33 dose, review of concomitant 
medications, and recording of hypoglycemia events and 
AEs/SAEs (including AESIs). 
• The follow-up safety period (Visit 8) will occur 2 weeks after 
the end of the treatment period. 
• Fasting SMPG values and those measures required to manage 
hypoglycemia events will occur from the run-in period (Visit 2) 
through the end of the treatment period (Visit 7). 
• Soliqua 100/33 dosing will occur from the end of the baseline 
period (Visit 3.2) through the end of the treatment period 
(Visit 7). 
• eDiary completion, recording of hypoglycemia events, and 
AEs/SAEs (including AESIs) will occur from the screening 
period (Visit 1) through the follow-up period (Visit 8), whereas 
review of concomitant medications will occur from the baseline 
period (Visit 3.1) through the follow-up period (Visit 8). 
Study Drug, 
Dosage, and Route 
of Administration: 
• Formulation: Soliqua 100/33 will be supplied as a sterile, 
non-pyrogenic, clear, colorless solution in SoloStar prefilled 
(disposable) pen for subcutaneous (SC) injection. The SoloStar 
pen is necessary for Soliqua 100/33 administration, and it is 
considered an integral part of the Soliqua 100/33 therapy. 
o The prefilled SoloStar disposable pen contains 3 mL of 
sterile solution containing 100 units/mL insulin glargine and 
33 μg/mL lixisenatide in a 3:1 ratio (ie, 3 units of insulin 
glargine to 1 μg lixisenatide), and it allows for 
administration of both ingredients simultaneously with doses 
ranging from 15 units/5 μg to 60 units/20 μg (insulin 
glargine U100/lixisenatide). 
o Soliqua pen instructions will be given to all participants at 
Visit 3.1. 
o A phone contact should be made to participants on weekly 
GLP-1 RA on the day before Soliqua 100/33 initiation, to 
remind them of the next morning’s injection and to provide 
instructions for SoloStar pen use. 
• Route of administration: SC injection using the SoloStar pen 
into the abdominal area, thigh, or upper arm. Injection sites 
should be rotated within the same region from one injection to 
the next to reduce the risk of lipodystrophy. 


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• Time of administration: Soliqua 100/33 should be 
self-administered once-daily in the morning approximately 
60 minutes before breakfast. 
o The first dose of Soliqua 100/33 will be administered on the 
morning of Day 0 (ie, Visit 3.2). This date should be 
7 [± 2] days after the last weekly GLP-1 RA dose or the 
morning following the last dose of DPP-4i, or daily GLP-1 
RA (oral or injectable) administration. 
Starting Dose 
• For all participants, the starting dose of Soliqua 100/33 will be 
15 units of insulin glargine (corresponding to 5 μg of 
lixisenatide). 
• The maximum daily dose of Soliqua 100/33 should not exceed 
60 units of insulin glargine (corresponding to 20 μg of 
lixisenatide). 
Dose Modifications 
The dose of Soliqua 100/33 will be adjusted with the aim of 
attaining a target fasting SMPG value of 80 to 100 mg/dL. The dose 
will be adjusted based on the lowest fasting SMPG values in 
conjunction with measurements from the previous 3 days 
throughout the study period. During the titration period (ie, Weeks 1 
through 12) fasting SMPG should be assessed on each of the 3 to 
4 days before each dose adjustment. During the titration period, the 
dose of Soliqua 100/33 should be adjusted upwards or downwards 
by 2 to 4 units every week (with additional titration also at the 
discretion of the investigator in accordance with the participant’s 
blood glucose monitoring results) with the goal of achieving a 
fasting SMPG value of 80 to 100 mg/dL, as well as other glycemic 
goals, while minimizing the risk of hypoglycemia and 
hyperglycemia. The duration of the titration period and number of 
phone contacts to safely meet the study goals will also be at the 
discretion of the investigator. 
As stated above, dose titration is at the discretion of the investigator. 
Study participants should be trained and retrained on an ongoing 
basis to establish proper understanding of titration procedures 
because very close communication between the participant and the 
study site is necessary to ensure adequate titration while minimizing 
the associated risks. Investigators may adjust or stop titration or 
temporarily reduce the dose if they believe further titration would 
result in participants experiencing any AEs (eg, hypoglycemia, 
AESIs). After the target fasting SMPG value has been achieved, the 


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dose of Soliqua 100/33 will be adjusted as necessary until the end of 
the study to maintain the target fasting SMPG value in accordance 
with the dose titration guidelines provided in the following table. If 
the desired fasting SMPG target is not achieved in the first 8 weeks 
of treatment, the investigator has the option to continue weekly dose 
titration phone contacts for an additional 4 weeks (until Week 12) 
for the purpose of achieving glycemic targets. 
Doses will be adjusted at least weekly, but additional titration may 
be considered at the investigator’s discretion. Participants are, 
therefore, required to record their fasting SMPG values before 
breakfast at least 3 to 4 times per week throughout the study period 
to inform each dose adjustment. 
Recommended Dose Adjustment Algorithm for Soliqua 100/33 
Median of Fasting SMPG Values 
(With Lowest Value Considered in 
Conjunction With Previous 
3 Measurements) 
Soliqua 100/33 Dosage 
Adjustment (Units/Week) 
>140 mg/dL (>7.8 mmol/L) 
+4 units  
>100 to ≤140 mg/dL (>5.5 to 
≤7.8 mmol/L)  
+2 units 
Glycemic target: 80 to 100 mg/dL 
(4.4–5.5 mmol/L), inclusive 
No change 
≥60 to <80 mg/dL (≥3.3 to 
<4.4 mmol/L)  
–2 units  
<60 mg/dL (<3.3 mmol/L) or 
occurrence of 2 (or more) 
symptomatic hypoglycemia events or 
1 severe hypoglycemia event 
(requiring assistance) documented in 
the preceding week 
–2 to –4 units or at the 
discretion of the investigator or 
any qualified designee 
Notes: Dose changes should also be based on the median SMPG values (with the 
lowest value considered in conjunction with the previous 3 measurements). If 
the lowest value from the previous 3 measurements is from 80 to 100 mg/dL 
and the other 2 values are well above 100 mg/dL, further titration may be 
implemented at the investigator’s discretion. If the lowest value is <70 mg/dL 
and the other 2 values are near 100 mg/dL, the investigator may stop or 
temporarily reduce the dose if, in their judgment, further titration would be 
hazardous. 
 
 
 


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NIMP and Concomitant Therapy 
Background OADs (eg, SU, biguanides, thiazolidinediones, 
α-glucosidase inhibitors, sodium-glucose co-transporter-2 [SGLT2] 
inhibitors, bile acid sequestrants, dopamine agonists) are permitted 
during the screening and treatment periods of the study, initiated and 
at stable doses for a minimum of 3 months before the screening 
period. Meglitinides will be prohibited (eg, repaglinide, 
nateglinide). 
Appropriate Corrective Action/Rescue Therapy 
Titration will be exceedingly important throughout the first 
12 weeks of this study and will require consistent reviews of fasting 
SMPG values, the daily insulin dose, and hypoglycemia events to 
identify participants whose Soliqua 100/33 dose is not being 
appropriately managed. 
If after Week 12 (ie, end of the titration period), the participant’s 
FPG level is >240 mg/dL with no reasonable explanation for severe 
hyperglycemia, such as intercurrent illnesses or nonadherence to 
instructed titration, the investigator should obtain an HbA1c 
measurement and decide whether rescue therapy is warranted. 
Devices 
Blood Glucose Meter Kit: Each study participant will be provided 
with a blood glucose meter kit, in order to perform SMPG 
assessments. The blood glucose meter kit will include a blood 
glucose meter, lancing device, test strips, sterile lancets, storage 
box, control solution, and instructions for use. 
CGM Device (FreeStyle Libre Pro Flash Glucose Monitoring 
System): The device will be applied to the back of the upper arm of 
each participant, and they will be required to wear it continuously 
for 14 days during CGM data collection both at baseline (during the 
run-in period) and for 2 weeks at the end of the treatment period 
(ie, Weeks 14 to 16). 
Management of 
Clinical Supplies 
Study Drug Packaging and Storage 
Packaging will be 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 (including pen needles as ancillary supplies) will be 
dispensed to provide participants with Soliqua 100/33 coverage up 
to the next site visit or phone contact with DTP Soliqua 100/33 
delivery (Section 13.1). Storage conditions and use-by-end date 
(ie, expiry date) are part of the Soliqua 100/33 label text. 


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Investigators or other authorized persons (eg, pharmacists, IMP 
managers) are responsible for storing Soliqua 100/33 in a secure and 
safe place in accordance with local regulations, labeling 
specifications, policies, and procedures. Control of Soliqua 100/33 
storage conditions, especially control of temperature 
(eg, refrigerated storage), and information on in-use stability and 
instructions for handling the Soliqua 100/33 should be managed 
according to the rules provided by the sponsor. 
Study Drug Accountability 
The investigator or other personnel designated by the investigator 
will maintain accurate records of receipt of study drug, including 
dates of receipt. In addition, accurate records will be kept regarding 
when and how much study drug is dispensed and used by each 
participant in the study. The investigator or other personnel 
designated by the investigator will also be responsible for 
controlling the site stocks of Soliqua 100/33 and requesting any 
resupply, as needed. 
All Soliqua 100/33 will be dispensed in accordance with the 
investigator’s oversight. It is also the investigator’s responsibility to 
ensure that an accurate recording of Soliqua 100/33 kits issued and 
returned is maintained. 
Any quality issue noticed with the receipt or use of Soliqua 100/33 
pen (deficiency in condition, appearance, documentation, labeling, 
expiration date, etc.) must be promptly reported to the sponsor. 
Under no circumstances will the investigator supply Soliqua 100/33 
pens to a third party (except for DTP shipment, for which a courier 
company has been approved by the sponsor), allow the Soliqua 
100/33 pen to be used other than as directed by this clinical study 
protocol, or dispose of the Soliqua 100/33 pen. 
Overdose 
Management 
An overdose (accidental or intentional) with the IMP/NIMP is an 
event suspected by the investigator or spontaneously reported by the 
participant and is defined as any dose administration that, in the 
investigator’s opinion based on clinical judgment, is considered 
significantly greater than the prescribed dose of insulin or is at least 
twice the intended dose within the intended therapeutic interval. 
Any overdose, with or without associated AEs, must be promptly 
reported in eCRFs by the sites, which will then be notified to the 
sponsor’s representative (ie, PPD Pharmacovigilance). Overdoses 
without signs or symptoms should be recorded as a standard 
overdose; any AEs associated with the overdose should be reported 
on the relevant AE/SAE sections in the eCRF. 


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Treatment of Overdose 
Insulin Glargine 
Excess insulin administration may cause hypoglycemia and 
hypokalemia. Mild episodes of hypoglycemia can usually be treated 
with oral carbohydrates. Adjustments in study drug dose, meal 
patterns, or exercise may be needed. 
More severe episodes of hypoglycemia with coma, seizure, or 
neurologic impairment may be treated with 
intramuscular/subcutaneous glucagon or concentrated intravenous 
glucose. After apparent clinical recovery from hypoglycemia, 
continued observation and additional carbohydrate intake may be 
necessary to avoid recurrence of hypoglycemia. Hypokalemia must 
be corrected appropriately. 
Lixisenatide 
During clinical studies, doses up to 30 µg of lixisenatide twice daily 
(3 times the daily recommended dose) were administered to patients 
with T2DM in a 13-week study. Increased incidence of GI disorders 
was observed (Soliqua 2019). 
In case of overdose, appropriate supportive treatment should be 
initiated according to the participant’s clinical signs and symptoms, 
and the Soliqua 100/33 dose should be reduced to the prescribed 
dose. 
Treatment 
Adherence 
The investigator or their delegate will track treatment 
accountability/adherence by comparing the treatment kit number 
captured in the electronic data collection (EDC) tool with the 
treatment/accountability log, eDiary information about daily doses, 
and number of treatment kits provided versus number of treatment 
kits returned (whether empty or unused). 
The monitor in charge of the study will check the data entered on 
the Soliqua 100/33 administration page of the eCRF by comparing 
them with the Soliqua 100/33 study drug that has been returned and 
the participant’s treatment log form. 
Sample Size: 
Sufficient participants will be screened from approximately 15 sites 
to include 100 patients, such that approximately 82 evaluable 
participants complete the study (anticipating that approximately 
15% of participants discontinue the study before Week 16). 
Determination of Sample Size 
The sample size is based on the primary objective to demonstrate 
the significant mean change (ie, increase) in the percentage of TIR 
(70‑180 mg/dL) from baseline to Week 16 with sufficient power. A 


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sample size of 82 patients will have 95% power to detect an 
absolute increase in TIR means of 10%, assuming a standard 
deviation (SD) of 25 for the change in TIR, with a two-sided type I 
error of 0.05. Anticipating a 15% loss to follow-up rate, 100 patients 
would need to be enrolled. 
Statistical 
Methods: 
Analysis Sets 
• Enrolled set: All eligible participants who are dispensed 
Soliqua 100/33 and sign the ICF. 
• Efficacy analysis set: All enrolled participants who receive 
≥1 dose of Soliqua 100/33 and have evaluable CGM data at 
baseline.  
• Safety set: All enrolled participants who receive ≥1 dose of 
Soliqua 100/33. 
General Statistical Methods 
In general, descriptive statistics of quantitative efficacy and safety 
parameters (result and change from baseline) by scheduled visits 
will be provided on observed cases (OC; ie, inclusion of only 
participants having non-missing assessments at a specific visit). The 
baseline value is defined as the last available value before the first 
injection of Soliqua 100/33. 
All efficacy analyses (primary, key secondary, secondary, and other 
efficacy endpoints) will be performed on the efficacy analysis set. 
Analysis of demographics, baseline characteristics, and prior and 
concomitant medications will be provided in detail in the statistical 
analysis plan (SAP). 
The extent of study treatment exposure and adherence will be 
assessed and summarized with dose frequency and duration of 
treatment. 
Continuous data will be summarized using number of observations 
available, mean, SD, quartile ranges, minimum, median, and 
maximum. Categorical data will be summarized using count and 
percentage. 
Primary Analysis 
Mean change in the percentage of TIR (70‑180 mg/dL) from 
baseline to Week 16 and its associated 95% confidence interval (CI). 
A one-sample t-test will be applied to test the significance of 
changes at Week 16 over baseline. A p-value <0.05 will be 
considered significant. 
 


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Key Secondary Analysis 
Mean changes for continuous outcomes (eg, CV, mean daily blood 
glucose, maximum PPG exposure in the 4 hours after the breakfast 
meal, TAR >180 mg/dL) will be presented at baseline and at the end 
of the treatment period (Week 16). Mean (SD) and associated 95% 
CI, as well as minimum, median, and maximum will be provided. 
Analysis of Secondary Endpoints 
• Mean changes for continuous outcomes will be presented at 
baseline and at the end of the treatment period (Week 16). Mean 
(SD) and associated 95% CI, as well as minimum, median, and 
maximum will be provided. 
• Binary outcomes will be summarized with proportions and 95% 
CI using the Clopper Pearson exact method. 
Analysis of Other Efficacy Endpoints 
• Mean changes for continuous outcomes will be presented at 
baseline and at the end of the treatment period (Week 16). Mean 
(SD) and associated 95% CI, as well as minimum, median, and 
maximum will be provided. 
• The correlation of TIR to PRO, HbA1c, and requirement for 
60 units/day of insulin glargine U100 (related to TIR >70%) at 
Week 16 will be assessed using Pearson correlation coefficient. 
Analysis of PRO Endpoint 
• Change in diabetes medication treatment-related impact and 
satisfaction, as measured by the DM-SAT, from baseline to 
Week 16 will be analyzed using the efficacy analysis set and 
described as mean (SD) and associated 95% CI as well as 
minimum, median, and maximum for overall score and by 
subscales. 
Safety Endpoints 
All safety and tolerability endpoints will be described by number, 
proportions, and the associated 95% CI for proportions. Adverse 
event incidence tables will be presented by system organ class 
(SOC; sorted by internationally agreed order), high-level group term 
(HLGT), high-level term (HLT), and preferred term (PT) sorted in 
alphabetical order with the number (n) and percentage of 
participants experiencing an AE. Participants with more than 1 AE 
episode will be counted only once. The denominator for 
computation of percentages will be the safety set. Hypoglycemia 
events will be counted with multiple episodes per participant, if 


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available, and the event rate per person-years will be reported 
overall and by level. 
Handling of Missing Data 
Missing data will be handled differently in accordance with the 
reasons for the missing data for both primary and key secondary 
endpoints. If the missing data are due to technical issues with the 
CGM device (ie, CGM data are not evaluable if at least 10 out of 
14 days [not necessarily consecutive] have <80% of evaluable CGM 
data per 24-hour period during the run-in period as well as the end 
of the treatment period [ie, from Weeks 14 to 16]), the participant 
will be excluded from the analysis (missing completely at random 
[MCAR] approach). For other reasons for missing measurements 
(eg, lost to follow-up, discontinued treatment), the baseline value 
carried forward (MCAR, conservative approach) is planned for both 
primary and key secondary analyses. 
Multiple Comparisons and Multiplicity 
A hierarchical testing procedure will be performed. Key secondary 
endpoints will be evaluated with a one-sample t-test to determine 
whether there is any change at Week 16 over baseline in succession 
in accordance with the hierarchy and as long as the endpoints 
continue to show statistical significance. If one test is nonsignificant 
(p >0.05), then the testing will be stopped (or consider all further 
tests to be only secondary, and no formal conclusions can be 
drawn).  
Study Committees: Scientific steering committee: No 
Adjudication committee: No 
Data monitoring committee: No 
Date of Protocol: 
18 Aug 2021 


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List of Abbreviations 
Abbreviation 
Definition 
ADA 
American Diabetes Association 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC0-4h 
area under the concentration versus time curve from time 0 to 4 hours 
BMI 
body mass index 
BOCF 
baseline observation carry forward  
BP 
blood pressure 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CGM 
continuous glucose monitoring 
CNIL 
Commission Nationale de l’Informatique et des Libertés 
CONSORT 
Consolidated Standards of Reporting Trials 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CV 
coefficient of variation 
DM-SAT 
Diabetes Medication Satisfaction Tool 
DPP-4i 
dipeptidyl peptidase-4 inhibitor 
DTP 
direct-to-patient 
EASD 
European Association for the Study of Diabetes 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data collection 
eDiary 
electronic diary 
EU 
European Union 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
GCP 
Good Clinical Practice 


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Abbreviation 
Definition 
GDPR 
General Data Protection Regulation 
GI 
gastrointestinal 
GLP-1 RA 
glucagon-like peptide 1 receptor agonist 
GMI 
Glucose Management Indicator 
HbA1c 
glycated hemoglobin 
HCP 
healthcare provider 
HLGT 
high-level group term 
HLT 
high-level term  
HRQoL 
health-related quality of life 
HRT 
hormonal replacement therapy 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IMP 
investigational medicinal product 
IR 
Investigator Registry 
IRB 
institutional review board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LAM 
lactational amenorrhea method 
LLOQ 
lower limit of quantification 
LS 
least square 
MCAR 
missing completely at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMTT 
mixed-meal tolerance test 
MNAR 
missing not at random 
MODD 
mean of daily difference 
MTC 
medullary thyroid cancer 
NIMP 
non-investigational medicinal product 
OAD 
oral antidiabetic drug 
OC 
observed cases 
OTC 
over-the-counter 
PPG 
postprandial glucose 


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Abbreviation 
Definition 
PRO 
patient-reported outcome 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SGLT2 
sodium-glucose co-transporter-2 
SIP 
Shared Investigator Platform 
SMPG 
self-measured plasma glucose 
SOC 
system organ class 
SU 
sulfonylurea 
SUSAR 
suspected unexpected serious adverse reaction 
Tmax 
time to reach maximum concentration 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TAR 
time above range 
TBR 
time below range 
TIR 
time in range 
ULN 
upper limit of normal 
WOCBP 
woman of childbearing potential 
WONCBP 
woman of non-childbearing potential 


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1. Introduction 
1.1 Background Information 
Diabetes represents a major health burden in the US and had a prevalence of 34.2 million 
people of all ages in 2018, which is expected to increase to 54 million by 2030. Despite 
notable advancements in drug discovery, 50% of patients still have a glycated hemoglobin 
(HbA1c) >7%, and 14% of patients have an HbA1c >9%, signifying poor glycemic control 
(Centers for Disease Control and Prevention [CDC 2020]; HEDIS Comprehensive Diabetes 
Care 2021). The 2021 American Diabetes Association (ADA)/European Association for the 
Study of Diabetes (EASD) consensus report recommends combination therapy with a basal 
insulin and a glucagon-like peptide-1 receptor agonist (GLP-1 RA) as one approach to 
glycemic control in patients with type 2 diabetes (T2DM) with HbA1c levels more than 1.5% 
above their target (Davies et al 2018; ADA 2021b). 
In 2017, the total US cost of diagnosed diabetes care was projected to be $237.3 billion 
(ADA 2018). Approximately 38% of these costs were attributed to hospital-related fees 
(eg, outpatient treatment [$12.1 billion], inpatient care [$69.7 billion], emergency department 
costs [$8.0 billion], and ambulance charges [$332.0 million]). Indirect costs associated with 
loss of productivity and these direct costs account for 73.1% of the total cost of diabetes 
(Anderson et al 2020). Patients with T2DM, who account for 90% of all US diabetes cases, 
are often hospitalized or treated in the emergency department for severe hyperglycemia or 
hypoglycemia. In particular, those patients with fluctuations of HbA1c and very low or very 
high mean HbA1c levels contribute significantly to these costs (Conn et al 2015; Cannon 
et al 2018; Critchley et al 2019). 
Traditional methods of measuring blood glucose have resulted in substandard glycemic 
control in many patients with T2DM (Stone et al 2013; Carls et al 2017). Measuring HbA1c 
provides a retrospective 3-month glucose average with little, if any, information on hypo- or 
hyperglycemia, which can subsequently lead to microvascular or macrovascular 
complications. Although self-measured plasma glucose (SMPG), when used within a 
structured testing program, has demonstrated improved glycemic control and quality of life 
in people with diabetes (both insulin-treated and noninsulin-treated), it cannot predict 
impending hyperglycemia, hypoglycemia, or alert for hypoglycemia, and therefore, 
alternative glucose measurement methods must be considered (Danne et al 2017). 


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Continuous glucose monitoring (CGM) can address many of the limitations of HbA1c testing 
and SMPG monitoring, and has contributed to rapid growth amongst specialists and patients 
in the US over the past few years. Randomized, controlled, clinical studies evaluating CGM 
use in insulin-requiring individuals have demonstrated improvements in HbA1c, glycemic 
variability, and increased time in target glycemic range as well as reductions in hypoglycemia 
events (Anderson et al 2020). Based on the benefits and utility of CGM, several national and 
international medical organizations have recommended CGM use for people with diabetes 
who require insulin therapy in type 1 diabetes mellitus (T1DM) and T2DM and/or those at 
risk for hypoglycemia. Glucose measures captured via CGM are also being considered as a 
required accompanying measure to HbA1c in clinical studies investigating new diabetes 
therapies for review and approval by the US Food and Drug Administration (FDA). 
However, utilization of CGM monitoring in primary care settings has remained low, in part, 
due to the new skills required to meaningfully and appropriately use the data collected. As 
the pandemic has propelled primary care into the virtual healthcare arena, the pandemic has 
also increased patient demand for CGM use. Primary care physicians have developed the 
skills required to improve telemedicine visits. Similarly, primary care will be forced to 
embrace the utility of continuously collected glucose data to improve the glycemic 
management and refine the self-care behaviors of their patients (Johnson and Kayne 2020). 
1.2 Rationale 
Soliqua™ 100/33 is a fixed-ratio combination of insulin glargine U100 (100 units/mL) plus 
lixisenatide (33 μg/mL), a GLP-1 RA (Soliqua 2019). The combination of a basal insulin and 
a GLP-1 RA addresses both fasting and postprandial hyperglycemia, thus ensuring more 
comprehensive glycemic control than basal insulin alone. The efficacy and safety of Soliqua 
100/33 has been clearly established in randomized controlled clinical studies. In the 
LixiLan-O study, the HbA1c of patients uncontrolled on oral antidiabetic drugs (OADs) who 
were treated with Soliqua 100/33 decreased from 8.1% (baseline) to 6.5% (end of study) with 
the majority (74%) achieving the HbA1c target of <7% (Rosenstock et al 2016). The efficacy 
of Soliqua 100/33 was also demonstrated by a 2.9% HbA1c reduction from baseline, with 
74% of patients achieving an HbA1c of <7%, in a subgroup of patients with T2DM with 
baseline HbA1c ≥9% uncontrolled on OADs from the LixiLan-O study (Davies et al 2019). 
Similarly, patients uncontrolled on basal insulin in the LixiLan-L study demonstrated an 
HbA1c reduction from 8.1% to 6.9%, and most (55%) reached their target HbA1c of <7% 
(Aroda et al 2016). These results were achieved without weight gain and with fewer 


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gastrointestinal (GI) side effects than with lixisenatide alone, likely due to a more gradual 
titration of the GLP-1 RA dose (Rosenstock et al 2016; Davies et al 2019). 
Continuous glucose monitoring provides a more complete picture of glycemic exposure and 
excursions than self-monitored blood glucose or HbA1c (Danne et al 2017). In the US, use of 
CGM is becoming mainstream, driven by improved sensor accuracy, convenience, ease of 
use, cost-effectiveness, and increased reimbursement. Continuous glucose monitoring 
facilitates improved glycemic control while reducing hypoglycemia risk (Danne et al 2017; 
Battelino et al 2019) and is rapidly becoming standard of practice for many healthcare 
providers (HCPs) for management of patients with T1DM and insulin-treated T2DM. 
Time in range (TIR) is one of the metrics derived from CGM and is increasingly utilized to 
assess glycemic control. It can correlate with HbA1c values as well as the risk of 
diabetes-related complications (both microvascular and macrovascular). The International 
Consensus Report on “clinical targets for CGM interpretation” has identified “TIR” as a 
metric providing more actionable information than HbA1c and has defined targets for clinical 
use (Battelino et al 2019). For example, in patients with uncomplicated T2DM whose HbA1c 
targets are <7%, the recommended TIR (for a target range of 70-180 mg/dL) is >70% of the 
readings. 
Soliqua 100/33 is indicated as an adjunct to diet and exercise to improve glycemic control in 
adults with T2DM (Soliqua 2019). The 2021 Standards of Medical Care in Diabetes from the 
ADA (ADA 2021a; ADA 2021b) recommends the use of fixed-ratio combinations when the 
combination of individual components is indicated, such as when a GLP-1 RA is added to 
basal insulin or vice versa. The ADA 2021 Standards also recommend dual combination 
therapy in individuals with HbA1c values ≥1.5% from their glycemic target (ADA 2021b). 
Correlations of HbA1c and TIR indicate that CGM glucose readings of patients with an 
HbA1c ≥9% are in range 40% of the time or less, compared with the 70% TIR associated 
with an HbA1c of 7% (Battelino et al 2019). Although there are currently no studies using 
CGM measurements to capture glycemic excursions and variability related to Soliqua 
100/33, a post hoc analysis demonstrated improvement in all measures of glycemic 
variability compared with its individual components (eg, lixisenatide or insulin glargine 
U100), assessed by 7-point blood glucose profiles. These findings were attributable to 
Soliqua 100/33’s complementary mechanisms of action, which demonstrate reductions in 
both fasting and postprandial hyperglycemia (Aronson et al 2019). 


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The current study is intended to replicate these results using CGM to measure TIR and 
glycemic variability in a patient population with very uncontrolled T2DM (HbA1c 
≥9%-13%), who are most likely to benefit from a fixed-ratio combination approach, such as 
Soliqua 100/33. 
The primary objective of this study is to demonstrate an improvement in the percentage of 
TIR from baseline to the end of the study (16 weeks) in insulin-naïve patients with very 
uncontrolled (HbA1c ≥9%-13%) T2DM on 2+ OADs with or without GLP-1 RAs. 
1.3 Benefit-Risk Assessment 
Soliqua 100/33 has demonstrated superior glycemic efficacy in patients with T2DM 
uncontrolled on oral therapies, basal insulin, or GLP-1 RA (including weekly GLP-1 RA) 
with durable efficacy (52 weeks) compared with its individual components (insulin glargine 
U100 and lixisenatide), and recently premixed insulin analog (BIAsp 30) in those 
uncontrolled on basal insulin and oral therapies (Rosenstock et al 2021). Additionally, 
compared with insulin glargine U100 alone, patients on Soliqua 100/33 had weight neutrality 
with no increase in hypoglycemia events; compared with lixisenatide alone, they experienced 
fewer GI adverse events (AEs) (Aroda et al 2016; Rosenstock et al 2016; Blonde et al 2019). 
Soliqua 100/33 has also shown greater HbA1c reduction, less weight gain, and less 
hypoglycemia compared to a premixed insulin analog (BiAsp 70/30) in individuals not 
controlled on basal insulin therapy (Rosenstock et al 2021). No new risks have been 
identified for the population to be included in Study LPS16990. In this study, treatment with 
Soliqua 100/33 will be consistent with the current US FDA-approved label indications 
(Soliqua 2019). During the titration period, the dose of Soliqua 100/33 will be adjusted 
upwards or downwards by 2 to 4 units every week, or at the investigator’s discretion, based 
on the participant’s blood glucose monitoring results, with the objective of safely attaining a 
fasting SMPG value of 80 to 100 mg/dL, as well as other glycemic goals, while minimizing 
the risk of hypoglycemia and hyperglycemia. The duration of the titration period and number 
of phone contacts to safely meet the study goals will also be at the discretion of the 
investigator. Therefore, the risk for patients participating in this study and using daily doses 
of Soliqua 100/33 up to a maximum of 60 units of insulin glargine and 20 μg of lixisenatide 
is considered acceptable. All patients enrolled in this study will benefit from medical care 
and continuous monitoring of their glucose levels. 


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The important identified risks for Soliqua 100/33 are hypoglycemia or hyperglycemia 
associated with alterations in the insulin dosing regimen, hypersensitivity reactions, overdose 
due to medication errors, injection site reactions, and GI AEs, including nausea, diarrhea, and 
vomiting. This study proposes a titration algorithm with titration targets that will closely 
follow the US label for Soliqua 100/33 (Soliqua 2019), except in instances of hyper- or 
hypoglycemia, which require specific attention. All study participants will benefit from the 
safety monitoring planned during site visits as well as during the additional titration phone 
contacts. 
Given the expected improvement of glycemic control and the additional measures to improve 
diabetes management, the benefits are considered to outweigh any potential risks associated 
with Soliqua 100/33. Therefore, the benefit-risk ratio for patients participating in 
Study LPS16990 is considered favorable. 


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 Study Objectives, Estimands, and Endpoints 
Objectives: 
To determine the effect of Soliqua 100/33 on indices of glycemic control and variability, as 
measured via CGM, from baseline to Week 16, in insulin-naïve patients with very 
uncontrolled (HbA1c ≥9%-13%) T2DM. 
2.1 Primary Efficacy Objective, Estimands, and Endpoints 
The primary efficacy objective, estimand, and endpoint are presented in Table 2-1. 
Table 2-1 
Primary Efficacy Objective, Estimand, and Endpoint 
Primary Objective 
Primary Estimand 
Description  
Primary Endpoint 
• To demonstrate that in 
patients with T2DM failing 
to achieve glycemic control 
(HbA1c ≥9%-13%) on 
their current regimen of 2+ 
OADs with or without 
GLP-1 RAs, introduction 
of Soliqua 100/33 exhibits 
superiority in terms of time 
spent in range 
(70-180 mg/dL) at Week 16 
compared with baseline, as 
measured by CGM  
• The primary estimand 
is the mean change in 
the percentage of TIR 
(70-180 mg/dL) from 
baseline to Week 16. 
The primary estimand 
will be estimated based 
on the efficacy analysis 
set using obtained 
measurements, 
regardless of 
intercurrent events 
• Change in the 
percentage of TIR 
(70-180 mg/dL) from 
baseline to Week 16 
Abbreviations: CGM, continuous glucose monitoring; GLP-1 RA, glucagon-like peptide 1 receptor agonist; 
HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug; T2DM, type 2 diabetes mellitus; TIR, time in 
range. 


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2.2 Key Secondary Efficacy Objectives and Endpoints 
The key secondary efficacy objectives and endpoints are presented in Table 2-2. 
Table 2-2 
Key Secondary Efficacy Objectives and Endpoints 
Key Secondary Objectives 
Key Secondary Endpoints 
• To evaluate the impact of Soliqua 
100/33 on measures of glycemic control 
and variability in patients with T2DM 
• Change (%) from baseline to Week 16 in 
CV 
• Change (mg/dL) from baseline to 
Week 16 in mean daily blood glucose 
• Change (mg/dL) from baseline to 
Week 16 in the maximum PPG exposure 
in the 4 hours after the breakfast meal 
• Change (%) from baseline to Week 16 in 
TAR (>180 mg/dL) 
Abbreviations: CV, coefficient of variation; PPG, postprandial glucose; T2DM, type 2 diabetes mellitus; 
TAR, time above range. 
2.3 Secondary, Other Efficacy, and Safety Objectives and Endpoints 
The secondary, other efficacy, and safety objectives and endpoints are presented in Table 2-3. 
Table 2-3 
Secondary, Other Efficacy, and Safety Objectives and Endpoints 
Objectives 
Endpoints 
Secondary 
 
• To evaluate the impact of Soliqua 
100/33 on other measures of glycemic 
control and variability in patients with 
T2DM 
• Proportion (%) of patients achieving CV 
<36% 
• Change (%) from baseline to Week 16 in 
TIR (70-180 mg/dL) for specific time 
blocks (6 am-12 pm, 12 pm-6 pm, 
6 pm-12 am, and 12 am-6 am) 
• Proportion (%) of patients achieving 
GMI <7% and <9% at Week 16 


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Objectives 
Endpoints 
• Change from baseline to Week 16 in the 
4-hour PPG AUC0-4h after start of the 
breakfast meal, including Tmax 
• Proportion (%) of patients at Week 16 
who spend <15 minutes/day at a glucose 
level <54 mg/dL 
Other Efficacy 
 
• To evaluate the impact of Soliqua 
100/33 on additional measures of 
glycemic control and variability in 
patients with T2DM 
• Change (mg/dL) from baseline to 
Week 16 in MODD of glucose levels 
• Change (%) from baseline to Week 16 in 
TAR (>250 mg/dL) 
• Change (%) from baseline to Week 16 in 
TBR (<70 mg/dL) 
• Correlation of change in the percentage 
of TIR (70-180 mg/dL) and LS mean 
change in PRO from baseline to 
Week 16 
• Correlation of percentage of TIR 
(70-180 mg/dL) and HbA1c percentage 
achieved at Week 16 
• Correlation of patients reaching 
60 units/day insulin glargine U100 and 
TIR >70% 
• Change in HbA1c percentage from 
baseline to Week 16 
PRO 
 
• To assess patient-perceived treatment 
impact on HRQoL and treatment 
satisfaction  
• Change from baseline to Week 16 in 
diabetes medication treatment 
satisfaction scores (total score and by 
subscales), using the DM-SAT 
questionnaire 


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Objectives 
Endpoints 
Safety 
 
• To assess the safety and tolerability of 
Soliqua 100/33 
Safety evaluations will include evaluation 
of the following (for 16 weeks): 
• Overall hypoglycemia 
• Confirmed hypoglycemia 
 
o ADA Level 1: Measurable glucose 
concentration <70 mg/dL 
(3.9 mmol/L) but ≥54 mg/dL 
(3.0 mmol/L) 
 
o ADA Level 2: Measurable glucose 
concentration <54 mg/dL 
(3.0 mmol/L) that needs immediate 
action 
 
o ADA Level 3: Severe event 
characterized by altered mental 
and/or physical functioning that 
requires assistance* from another 
person for recovery 
• AEs, SAEs, and AESIs 
Abbreviations: ADA, American Diabetes Association; AE, adverse event; AESI, adverse events of special 
interest; AUC0-4h, area under the concentration versus time curve from time 0 to 4 hours; CV, coefficient of 
variation; DM-SAT, Diabetes Medication Satisfaction Tool; GMI, Glucose Management Indicator; 
HbA1c, glycated hemoglobin; HRQoL, health-related quality of life; LS, least square; MODD, mean of 
daily difference; OAD, oral antidiabetic drugs; PPG, postprandial glucose; PRO, patient-reported outcome; 
SAE, serious adverse event; T2DM, type 2 diabetes mellitus; Tmax, time to reach maximum concentration; 
TAR, time above range; TBR, time below range; TIR, time in range. 
*Note that “requires assistance” means that the person could not help themselves. Assisting a person out of 
kindness, when assistance is not required, should not be considered a “requires assistance” incident. 


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 Investigational Plan 
3.1 Study Design 
This is a 16-week, multicenter, interventional, open-label, single-arm, Phase 4 study using 
blinded CGM (FreeStyle Libre Pro) to demonstrate improvement in the percentage of TIR 
from baseline in patients adding Soliqua 100/33 and treated for 16 weeks. The study will be 
conducted in approximately 100 patients whose T2DM is very uncontrolled on 2+ OADs 
with or without GLP-1 RAs (with stable doses for 3 months), as evident from a screening 
HbA1c of ≥9%-13%. The study will attempt to represent the diversity of the US patient 
population with T2DM through site recruitment efforts. 
All eligible participants will undergo 14 days of blinded continuous CGM monitoring at 
baseline (the run-in period) and a mixed-meal tolerance test (MMTT) while on baseline 
medications. Soliqua 100/33 treatment will be initiated on Day 0 (Visit 3.2), after the MMTT 
(which is scheduled at Visit 3.1; Figure 3–1). Sulfonylurea (SU) doses should be 
down-titrated by 50% when starting Soliqua 100/33, and the last doses of daily dipeptidyl 
peptidase-4 inhibitor (DPP-4i) and daily GLP-1 RA (oral or injectable) should be 
administered on the morning of Day –1, the day before the first dose of Soliqua 100/33.  
At Visit 3.1, participants on OADs or an oral or injectable GLP-1 RA will be required to take 
their dose after the blood sample for fasting plasma glucose (FPG) and HbA1c is collected 
and 30 minutes before administration of the meal during the MMTT (during which measures 
for both β-cell function and postprandial glucose [PPG] analyses will be captured). 
Participants on a weekly GLP-1 RA should have their baseline MMTT conducted within 
7 (± 3) days after their last dose and administer their last weekly GLP-1 RA dose 7 (± 2) days 
before the first dose of Soliqua 100/33. 
The dose of Soliqua 100/33 will be adjusted during the titration period (ie, from Weeks 1 
through 12; Visits 4.0 to 5.4), at the investigator’s discretion until the desired fasting SMPG 
value (80-100 mg/dL) is achieved.  
During the end of the treatment period (from Visit 6 to Visit 7), participants will again be 
required to undergo 14 days of blinded continuous CGM monitoring and a MMTT (only to 
derive PPG measures). Soliqua 100/33 should be administered 30 minutes before 


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administration of the meal during the MMTT at Visit 7 (during which only measures for PPG 
analyses will be captured).  
All participants will be allowed to continue their background OADs (except DPP-4i and SU, 
as previously described) at stable doses and regimens throughout the study period, unless 
they have to be stopped or modified for safety reasons. 
Adverse events, including adverse events of special interest (AESIs), will be assessed. 
Physical examination (including body weight), hypoglycemia events, clinical laboratory 
values, and vital signs will be measured to evaluate the safety of the study drug treatments 
(Section 13.1). 
The maximum study duration per participant will be 22 weeks. Three site visits, 3 site or 
home visits, and up to 13 phone contacts are scheduled. 
Participants will have the choice to have Visits 2, 5, and 6 performed at the study site or at 
home. This choice is to be determined at the screening visit. Participants who opt for site 
visits should be encouraged not to change to home visits during the study period. However, if 
this is unavoidable, the home health provider and the sponsor-approved courier company for 
investigational medicinal product (IMP) shipment will need at least 72 hours’ notice from the 
investigator to arrange a home visit and direct-to-patient (DTP) IMP supply, if required. An 
unscheduled site or home visit can be planned during the treatment period for IMP resupply, 
if required. If DTP Soliqua 100/33 supply is required, the sponsor-approved courier company 
will need at least 72 hours’ notice to collect Soliqua 100/33 treatment kits from a study site. 
 


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Figure 3–1 
Study Diagram 
 
Abbreviations: CGM, continuous glucose monitoring; DPP-4i, dipeptidyl peptidase-4 inhibitor; DTP, direct-to-patient; GLP-1 RA, glucagon-like peptide-1 
receptor agonist; HCP, healthcare provider; IMP, investigational medicinal product; MMTT, mixed-meal tolerance test; SMPG, self-measured plasma 
glucose; SU, sulfonylurea. 
Notes: During the run-in period, CGM device reinsertion will be allowed for participants who do not meet the equivalent of at least 8 days of evaluable CGM 
data (not necessarily consecutive) over a 14-day period as a result of premature sensor failure (eg, days of CGM device wear × % time CGM device 
active < 8; Section 6.2.1). 
During the end of the treatment period, CGM device reinsertion will also be allowed for participants who do not meet the equivalent of at least 8 days of 
evaluable CGM data (not necessarily consecutive) over a 14-day period as a result of premature sensor failure (eg, days of CGM device wear × % time CGM 
device active < 8), if data can be captured during the 14-day end-of-treatment window (Section 6.2.1). 
a An unscheduled visit can be planned anytime during the treatment period if IMP resupply is required. This can be a site visit or via phone contact with DTP IMP 
delivery. If DTP Soliqua 100/33 supply is required, the sponsor-approved courier company will need at least 72 hours’ notice to collect Soliqua 100/33 
treatment kits from a study site. 
b Participants on weekly GLP-1 RA should administer their last dose 7 (± 2) days before the first dose of Soliqua 100/33, whereas the last dose of daily DPP-4i 


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and daily GLP-1 RA (oral or injectable) should be administered on the morning of Day –1, the day before the first dose of Soliqua 100/33. 
c It is the first day of Soliqua 100/33 administration and includes a phone contact to ALL participants to ensure that all administration procedures were 
successfully executed and to answer any questions. The first day of Soliqua 100/33 administration (ie, Visit 3.2, Day 0) for participants on weekly GLP-1 RA 
will depend on their administration schedule and may not be the day immediately following Visit 3.1. Soliqua 100/33 administration for these participants 
should be 7 (± 2) days after their last weekly GLP-1 RA dose. A phone contact should be made to participants on weekly GLP-1 RA on the day before 
Soliqua 100/33 initiation, to remind them of the next morning’s injection and to provide instructions for SoloStar pen use. The participants will provide 
their concomitant medication details to the site personnel over the phone. 
d Doses of SU should be down-titrated by 50% when Soliqua 100/33 is started on Day 0. 
e Weekly phone contacts for dose adjustments are to continue at the investigator’s discretion until the desired fasting SMPG value is achieved. 
f If the desired fasting SMPG value is not achieved in the first 8 weeks of treatment; the investigator has the option to continue weekly dose titration phone 
contacts for an additional 4 weeks (until Week 12) for the purpose of achieving glycemic targets. 
g At the end of the study, participants should discuss with the investigator, in collaboration with their HCP, whether to continue on the Soliqua 100/33 treatment 
regimen or transition to an alternate antihyperglycemic therapy. 
h At baseline, the CGM device will be removed and the data will be downloaded on Day –1 at their next site visit (ie, Visit 3.1), after collection of C-peptide, 
insulin, and plasma glucose data from the MMTT. Downloaded CGM data will be reviewed by the investigator to determine participants’ study eligibility. 
NOTE: Participants on weekly GLP-1 RA should have their baseline MMTT conducted within 7 (± 3) days after their last dose. At the end of the treatment 
period, the CGM device will be removed and the data will be downloaded on the fifteenth day after CGM placement (ie, Visit 7; after collection of only 
plasma glucose data from the MMTT). Downloaded CGM data will be verified by the investigator at the site to determine participants’ study completion. 
 


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3.1.1 Rationale of Study Design 
This study is designed to demonstrate improvement in the percentage of TIR with 
Soliqua 100/33 in patients with very uncontrolled T2DM (HbA1c ≥9%-13%) after 3 months 
of stable treatment with 2+ OADs with or without additional GLP-1 RA therapy. 
Continuous glucose monitoring has significantly improved the ability to monitor glycemic 
variability throughout the day. Data from CGM can be critical in making daily treatment 
decisions and quantifying TIR, which provides more actionable information than HbA1c 
alone (Battelino et al 2019). Continuous glucose monitoring is a much-improved measure of 
TIR compared with SMPG (ie, hundreds of values to analyze versus a single measure in 
time), to truly understand glycemic variability in people with T2DM. 
In a previous post hoc analysis, treatment with Soliqua 100/33 improved measures of 
glycemic variability (ie, 7-point blood glucose data) in patients uncontrolled on either oral or 
insulin therapies more than its individual components (ie, lixisenatide or insulin glargine 
U100). This finding was attributed to the complementary reductions of both fasting and 
postprandial hyperglycemia (Aronson et al 2019). Clinicians frequently request CGM 
measures to better understand their patients’ TIR, time above range (TAR), and time below 
range (TBR). Hence, the current study is intended to replicate and enhance the results from 
the 7-point blood glucose study, but using CGM. Measures such as TIR, coefficient of 
variation (CV), TAR, TBR, and PPG will be collected in this patient population with very 
high HbA1c. This is the first CGM study performed with Soliqua 100/33 in patients with 
very uncontrolled T2DM (HbA1c ≥9%-13%) on oral therapies with or without GLP-1 RAs. 
3.1.2 Duration of Study Participation for Each Participant 
The study comprises the following periods (further detailed in the graphical study diagram 
[Figure 3–1] and the schedule of events [SoE; Section 13.1]): 
• A screening period of up to 2 weeks. 
• A run-in period of 2 weeks, including the baseline period. 
o At Visit 2, the CGM device will be applied to the back of the upper arm of the 
participant and baseline CGM data will be collected continuously for 14 days; the 


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device will be removed at the subsequent site visit during the baseline period 
(ie, Visit 3.1), after the MMTT. 
o During the baseline period, on Day –1 (Visit 3.1), participants will return to the site 
for the MMTT (for both β-cell function and PPG measures) and CGM removal and 
data download (after the MMTT). Dispensing of the Soliqua 100/33 pen and 
instruction on administration of Soliqua 100/33 will also take place during this visit. 
o Visit 3.2 (ie, Day 0) during the baseline period is the first day of Soliqua 100/33 
administration and includes a phone contact to ALL participants to ensure all 
administration procedures were successfully executed and to answer any questions. 
(Note: The first day of Soliqua 100/33 administration [ie, Visit 3.2, Day 0] for 
participants on weekly GLP-1 RA will depend on their administration schedule and 
may not be the day immediately following Visit 3.1. Soliqua 100/33 administration 
for these participants should be 7 [± 2] days after their last weekly GLP-1RA dose.) 
 A phone contact should also be made ONLY to participants on weekly GLP-1 
RA on the day before Soliqua 100/33 initiation, to remind them of the next 
morning’s injection and to provide instructions for SoloStar pen use. The 
participants will provide their concomitant medication details to the site personnel 
over the phone. 
• A 16-week open-label treatment period. 
o Visit 3.2 (ie, Day 0) is the first day of Soliqua 100/33 administration and begins the 
open-label treatment period (with different initiation requirements based on weekly or 
daily GLP-1 RA use, as explained above). 
o The dose of Soliqua 100/33 will be adjusted during the titration period (ie, from 
Weeks 1 through 12; Visits 4.0 to 5.4), at the investigator’s discretion, until the 
desired fasting SMPG value (80-100 mg/dL) is achieved (Table 5-1). 
o During Visits 4.0 to 4.6, weekly phone contacts for dose adjustments are to continue 
at the investigator’s discretion until the desired fasting SMPG value is achieved. 
o If the desired fasting SMPG value is not achieved in the first 8 weeks of treatment, 
the investigator has the option to continue weekly dose titration phone contacts for an 
additional 4 weeks (until Week 12; ie, from Visits 5.1 to 5.4) with the purpose of 
achieving glycemic targets. 


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o At Visit 6, a blinded CGM device will again be applied to the back of the upper arm 
of the participant, and CGM data will be collected continuously for 14 days; the 
device will be removed at the subsequent site visit (ie, Visit 7), after the MMTT (only 
to derive PPG measures). 
o At the end of the study (ie, Visit 7), participants should discuss with the investigator, 
in collaboration with their HCP, whether to continue on the Soliqua 100/33 treatment 
regimen, or transition to an alternate antihyperglycemic therapy. 
• A 2-week post-treatment safety follow-up period after the last dose of Soliqua 100/33 
(eg, treatment completion) or after premature/permanent treatment discontinuation from 
Soliqua 100/33. 
The total duration of the study will be approximately 22 weeks for each participant. 
A detailed description of the assessments performed during each study period and at each 
visit is provided in Section 13.1. 
3.1.3 End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 


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 Selection of Study Population and Discontinuation/Withdrawal 
One-hundred participants will be enrolled at approximately 15 sites in the US. Participants 
will be enrolled in the study only if they meet all of the inclusion criteria and none of the 
exclusion criteria. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
4.1 Inclusion Criteria 
Each participant must meet all of the following criteria to be enrolled in this study: 
1. Is capable of understanding the written informed consent, provides signed written 
informed consent, is willing and able to complete the electronic diary (eDiary), and 
agrees to comply with protocol requirements (confirmed by the site staff performing the 
recruitment efforts). 
2. Is an adult ≥18 years of age. 
3. Has an HbA1c ≥9%-13% during the run-in period. 
4. Was diagnosed with T2DM at least 6 months before the baseline period. 
5. Has been treated with 2+ OADs with or without GLP-1 RAs with stable doses (for both) 
for 3 months before the screening period. 
6. Is willing and able to wear the CGM device continuously for 14 days to capture CGM 
measures at baseline (from Visit 2 [ie, the run-in period] until the next site visit at 
Visit 3.1) and again at the end of the treatment period [ie, from Visit 6 until the next site 
visit at Visit 7; Section 13.1). 
7. Is willing and able to prick fingers a minimum of 2 to 4 times per week, using sterile 
lancets provided with a manual blood glucose meter kit. 
8. Is willing to discontinue daily (oral or injectable) or weekly GLP-1 RA or DPP-4i before 
administration of Soliqua 100/33. 


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9. Is willing and able to inject Soliqua 100/33 and increase dose as needed to achieve 
SMPG target. 
10. If female, is not pregnant or breastfeeding and one of the following conditions applies: 
o Is a woman of non-childbearing potential (WONCBP), as defined in contraceptive 
and barrier guidance (Section 13.7). 
o Is a woman of childbearing potential (WOCBP) and agrees to use a contraceptive 
method that is highly effective, with a failure rate of <1%, as described in 
contraceptive and barrier guidance (Section 13.7), during the study treatment period 
(to be effective before starting the study drug) and for at least 1 week after the last 
administration of study drug. 
 A WOCBP must have a negative urine pregnancy test at both screening and 
baseline visits. (Note: If a urine test cannot be confirmed as negative [eg, an 
ambiguous result], a serum pregnancy test is required. In such cases, the 
participant must be excluded from participation if the serum pregnancy result is 
positive.) 
4.2 Exclusion Criteria 
Participants meeting any of the following criteria will be excluded from the study: 
1. Has T1DM or any other types of diabetes except T2DM. 
2. Is being treated with meglitinides (eg, nateglinide, repaglinide). 
3. Has a body mass index (BMI) >40 kg/m² during the screening period.* 
*Body weight and height will be recorded during the screening period for the calculation of 
BMI (metric: BMI = weight (kg)/height [m2]). 
4. Provides less than equivalent of 8 days of evaluable CGM data (not necessarily 
consecutive) over a 14-day period (eg, days of CGM device wear × % time CGM device 
active < 8; Section 6.2.1). 


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5. Has any current or previous skin conditions, including (but not limited to) severe 
psoriasis, burns, eczema, scarring, and excessive tattoos, that would inhibit proper 
wearing of the CGM device. 
6. Has a history of severe nausea and vomiting that resulted in discontinuation of GLP-1 
RA. 
7. Has a known history or presence of clinically significant pancreatitis or gastroparesis. 
8. Has had an episode of severe hypoglycemia or hypoglycemia unawareness (defined as 
the onset of neuroglycopenia before the appearance of autonomic warning symptoms [for 
example, blurred vision, difficulty speaking, feeling faint, difficulty thinking, and 
confusion] or as the failure to sense a significant fall in blood glucose below normal 
levels) within the 6 months before the screening period. 
9. Has any clinically significant abnormality identified from the physical examination, vital 
sign measurements, or laboratory tests (eg, amylase, lipase, alanine aminotransferase 
[ALT] >3 × upper limit of normal [ULN], calcitonin ≥20 pg/mL, severe renal impairment 
[estimated glomerular filtration rate, <30mL/min/1.73m2], or end stage renal disease) or 
visual impairment at screening that, in the opinion of the investigator or any qualified 
designee, would make implementation of the protocol or interpretation of the study 
results difficult or would preclude safe participation in the study. 
10.  Has personal or immediate family history of medullary thyroid cancer (MTC) or a 
genetic condition that predisposes the participant to MTC (eg, multiple endocrine 
neoplasia syndromes). 
11. Has current or known history of alcohol or drug abuse within 6 months before the 
screening period. 
12. Has significant current (within past 2 months) or expected use of medications known to 
affect glycemia (eg, ≥5 mg/day prednisone). 
13. Uses substances known to interfere with CGM readings, such as aspirin-containing 
products (>650 mg/day of salicylic acid) or supplements containing vitamin C 
(>1000 mg/day of ascorbic acid) taken during the 14-day periods of CGM measure at 
baseline (ie, Visit 2 to Visit 3.1) and the end of the treatment period (ie, Visit 6 to Visit 7). 


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14. Has undergone previous treatment with any insulin (except for short-term treatment due 
to intercurrent illness, including gestational diabetes, at the discretion of the investigator). 
15. Is enrolled in another clinical study or has taken other investigational drug(s) within 
1 month or 5 half-lives from screening, whichever is longer. 
16. Is currently in an institution because of a regulatory or legal order (ie, is a prisoner or 
participant who is legally institutionalized). 
17. Is an employee or family member of the investigator or study site personnel. 
18. Is not suitable for participation, whatever the reason, as judged by the investigator, 
including medical or clinical conditions, or potentially is at risk of noncompliance to 
study procedures. 
19. Is involved in a specific situation during study implementation or the course of the study 
that may raise ethics considerations. 
20. Has a hypersensitivity to Soliqua 100/33, either of its active components (insulin glargine 
or lixisenatide), or any of its excipients that, in the opinion of the investigator, 
contraindicates participation in the study. 
21. Has used weight loss drugs (including over-the-counter [OTC] and herbal medications) 
within 12 weeks before the screening visit. 
4.3 Screen Failure 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled. A minimal set of screen failure information is required to 
ensure transparent reporting to meet Consolidated Standards of 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 events (SAEs). 
Participants who are screen failed may be rescreened based on a discussion between the 
medical monitor and the investigator. 


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4.4 Discontinuation From Study Treatment and/or Withdrawal From the 
Study 
4.4.1 Discontinuation From Study Treatment 
4.4.1.1 Permanent Discontinuation 
All efforts should be made to keep participants on treatment. 
In rare instances, it may be necessary for a participant to permanently discontinue study 
treatment. Before permanent discontinuation of treatment regardless of the reason or as soon 
as possible after the decision for discontinuation has been made, if possible, the participant 
will undergo all procedures planned for the last dosing day with Soliqua 100/33 and the 
follow-up visit (Section 13.1). 
All cases of permanent treatment discontinuation (Section 4.4.3) must be recorded by the 
investigator in the appropriate pages of the electronic case report form (eCRF) when 
confirmed. 
4.4.1.2 Temporary Discontinuation 
Temporary study drug discontinuation decided by the investigator corresponds to more than 
1 dose not administered to the participant. 
Temporary study drug discontinuation may be considered by the investigator because of 
suspected AEs or for other reasons. In case of study drug interruption due to an AE, 
reinitiating Soliqua 100/33 treatment at the appropriate dose will be done under close and 
appropriate clinical/and or laboratory monitoring if the investigator deems the relationship of 
the event to Soliqua 100/33 as unlikely and if the study inclusion criteria are still met. 
The duration of temporary study drug discontinuation should be recorded in the appropriate 
eDiary pages when confirmed. 
4.4.2 Lost to Follow-up 
A participant will be considered lost to follow-up if they repeatedly fail to return for 
scheduled visits and are unable to be contacted by the study site. 


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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. The participant should be counselled on the importance of maintaining the 
assigned visit schedule and asked whether they wish 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. The methods to contact the participants 
include 2 phone 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. 
If the participant continues to be unreachable, they will be considered to have withdrawn 
from the study. 
4.4.3 Handling of Withdrawals 
Participants are free to withdraw from the study or study treatment at any time upon request. 
Their participation in the study may be stopped at any time at the discretion of the 
investigator or at the request of the sponsor. 
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, they may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
Participants who discontinue study treatment or active participation in the study will no 
longer receive study drug. When a participant withdraws from the study, the reason(s) for 
withdrawal shall be recorded by the investigator on the relevant page of the eCRF. 


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A participant may withdraw from the study or study treatment under the circumstances 
(including, but not limited to) listed below: 
• The participant intends to become pregnant. 
• The participant may be withdrawn at the discretion of the investigator due to 
noncompliance or due to a safety concern. 
• The participant will be withdrawn if starting any drugs that interfere with glucose 
metabolism (eg, steroid doses equivalent to prednisone ≥5 mg/day). 
• The participant may be withdrawn if diagnosed with acute pancreatitis (defined as 
meeting 2 of the following 3 rules: typical abdominal pain; amylase/lipase >3 × ULN; 
and/or characteristic ultrasound, computed tomography, or magnetic resonance imaging 
findings). 
• If the fasting or the mean SMPG value during 3 consecutive days is >300 mg/dL, the 
investigator will schedule an unplanned visit as soon as possible to obtain confirmatory 
FPG and investigate the cause. If no apparent or intercurrent cause is detected, the 
participant may be withdrawn. 
• The participant has recurrent severe hypoglycemia or recurrent nocturnal hypoglycemia 
during the treatment period that poses a potential risk to the participant, as judged by the 
investigator. 
• The participant is unable to comply with the study protocol, at the investigator’s 
discretion. 
Whenever possible, all participants who discontinue study treatment or withdraw from the 
study prematurely will undergo all end-of-study and follow-up assessments. Participants who 
fail to return for final assessments will be contacted by the site in an attempt to have them 
comply with the protocol. 
Participants who withdraw from the study treatment should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented on the relevant page of the eCRF. 


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It is vital to obtain follow-up data on any participant who is withdrawn because of an AE or 
SAE. In every case, efforts must be made to undertake protocol-specified, safety, and 
follow-up procedures. 
4.4.4 Replacements 
Participants who discontinue the study will not be replaced. 


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 Study Treatments 
5.1 Study Drug 
• Formulation: Soliqua 100/33 will be supplied as a sterile, non-pyrogenic, clear, colorless 
solution in a SoloStar™ prefilled (disposable) pen for subcutaneous (SC) injection. The 
SoloStar pen is necessary for Soliqua 100/33 administration, and it is considered as an 
integral part of Soliqua 100/33 therapy. 
o The prefilled SoloStar disposable pen contains 3 mL of sterile solution containing 
100 units/mL insulin glargine and 33 μg/mL lixisenatide in a 3:1 ratio (ie, 3 units of 
insulin glargine to 1 μg lixisenatide). 
o The pen allows for administration of both ingredients simultaneously with doses 
ranging from 15 units/5 μg to 60 units/20 μg (insulin glargine U100/lixisenatide). 
o Soliqua pen instructions will be given to all participants at Visit 3.1. 
o A phone contact should be made to participants on weekly GLP-1 RA on the day 
before Soliqua 100/33 initiation, to remind them of the next morning’s injection and 
to provide instructions for SoloStar pen use. 
• Route of administration: SC injection using the SoloStar pen into the abdominal area, 
thigh, or upper arm. Injection sites should be rotated within the same region from 
one injection to the next to reduce the risk of lipodystrophy. 
5.2 Non-Investigational Medicinal Product 
The protocol-mandated background OADs (Section 5.2.1) are considered non-investigational 
medicinal product (NIMP). 
5.2.1 Background OADs Related to Glycemic Management 
The following oral classes of medication related to glycemic management are permitted 
during the screening and treatment periods of the study, initiated and at stable doses for a 
minimum of 3 months before the screening period: 
• SU (which will be down-titrated by 50% when starting Soliqua 100/33 on Day 0). 


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• Biguanides. 
• Thiazolidinediones. 
• α-glucosidase inhibitors. 
• Sodium-glucose co-transporter-2 (SGLT2) inhibitors. 
• Bile acid sequestrants. 
• Dopamine agonists. 
5.2.2 Appropriate Corrective Action/Rescue Therapy 
Titration will be exceedingly important throughout the first 12 weeks of this study and will 
require consistent reviews of fasting SMPG values, the daily insulin dose, and hypoglycemia 
events to identify participants whose Soliqua 100/33 dose is not being appropriately 
managed. 
If after Week 12 (ie, end of the titration period), the participant’s FPG level is >240 mg/dL 
with no reasonable explanation for severe hyperglycemia, such as intercurrent illnesses or 
nonadherence to instructed titration, the investigator should obtain an HbA1c measurement 
and decide whether rescue therapy is warranted. 
5.3 Storage and Dispensing 
Before first use, the Soliqua 100/33 pen should be stored in a refrigerator from 36°F to 46°F 
(2°C to 8°C) and protected from light and must not be frozen. Pens are to be discarded only 
after accountability and reconciliation is performed by PPD’s clinical research associate 
(CRA) and after the expiration date printed on the label. All pens in the same kit should have 
the same expiration date; therefore, pens from the same kit should be stored separately 
(eg, the pen currently being utilized should be stored at room temperature, whereas the other 
non-utilized pens should be stored in the refrigerator). The site should contact PPD for 
further instructions or notification if the expiration date of a pen/kit is near (eg, for possible 
re-labeling; do not automatically discard any pens/kits). Expired kits or pens should not be 
provided to participants. 


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The Soliqua 100/33 pen should not be stored in the freezer and should not be frozen. The 
Soliqua 100/33 pens should be separated (from the kit and any other pens) and stored (either 
at room temperature if the pen is in use, or in the refrigerator if not yet used) and should 
not be used if frozen or previously frozen. The site should not discard any Soliqua 100/33 
pens or the kit until reconciliation and accountability is performed by the CRA. 
After first use, the Soliqua 100/33 pen should be stored at room temperature below 77°F 
(25°C). The pen cap should be replaced after each use to protect it from light. The participant 
should keep any empty pens in the kit box to be returned to the site during the next site visit. 
Each pen should be replaced with a new pen 28 days after first use. 
The pen needle should be removed after each injection and discarded, and the Soliqua 100/33 
pen should be stored at room temperature without a needle attached. This type of storage 
should prevent infection and/or contamination or leakage of the Soliqua 100/33 pen and will 
ensure accurate dosing. A new needle should always be used for each injection to prevent 
infection and/or contamination. 
5.4 Method of Assigning Participants to Treatment Groups 
Not applicable. This is an open-label, single-arm study. 
5.5 Treatments Administered 
• Time of administration: 
o Soliqua 100/33 should be self-administered once-daily in the morning approximately 
60 minutes before breakfast. 
o The first dose of Soliqua 100/33 will be administered on the morning of Day 0 
(ie, Visit 3.2). This date should be 7 [± 2] days after the last weekly GLP-1 RA dose 
or the morning following the last dose of DPP-4i or daily GLP-1 RA (oral or 
injectable) administration. 
Starting dose 
• For all participants, the starting dose of Soliqua 100/33 will be 15 units of insulin 
glargine (corresponding to 5 μg of lixisenatide). 


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• The maximum daily dose of Soliqua 100/33 should not exceed 60 units of insulin 
glargine (corresponding to 20 μg of lixisenatide). 
5.5.1 Dose Modifications 
The dose of Soliqua 100/33 will be adjusted with the aim of attaining a target fasting SMPG 
value of 80 to 100 mg/dL (Table 5-1). The dose will be adjusted based on the lowest fasting 
SMPG values in conjunction with measurements from the previous 3 days throughout the 
study period. During the titration period (ie, Weeks 1 through 12), fasting SMPG should be 
assessed on each of the 3 to 4 days before each dose adjustment. During the titration period, 
the dose of Soliqua 100/33 should be adjusted upwards or downwards by 2 to 4 units every 
week (with additional titration also at the discretion of the investigator in accordance with the 
participant’s blood glucose monitoring result), with the objective of safely attaining a fasting 
SMPG level of 80 to 100 mg/dL, as well as other glycemic targets, while minimizing the risk 
of hypoglycemia and hyperglycemia), at the investigator’s discretion. The duration of the 
titration period and number of phone contacts to meet the study goals will also be at the 
discretion of the investigator. 
As stated above, dose titration will be at the investigator’s discretion and guided by the 
recommended dose adjustment algorithm with the objective of safely attaining a fasting 
SMPG value of 80 to 100 mg/dL (Table 5-1). Study participants should be trained and 
retrained on an ongoing basis to establish proper understanding of titration procedures 
because very close communication between the participant and the study site is necessary to 
ensure adequate titration while minimizing the associated risks. Investigators may adjust or 
stop titration or temporarily reduce the dose if they believe further titration would result in 
participants experiencing any AEs (eg, hypoglycemia, AESIs). After the target fasting SMPG 
value has been achieved, the dose of Soliqua 100/33 should be adjusted as necessary until the 
end of the study to maintain the target fasting SMPG value in accordance with the dose 
titration guidelines provided in Table 5-1. If the desired fasting SMPG target is not achieved 
in the first 8 weeks of treatment, the investigator has the option to continue weekly dose 
titration phone contacts for an additional 4 weeks (until Week 12) for the purpose of 
achieving glycemic targets. 
Doses will be adjusted at least weekly, but additional titration may be considered at the 
investigator’s discretion. Participants are, therefore, required to record their fasting SMPG 


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values before breakfast at least 3 to 4 times per week throughout the study period to inform 
each dose adjustment. 
Table 5-1 
Recommended Dose Adjustment Algorithm for Soliqua 100/33 
Median of Fasting SMPG Values (With 
Lowest Value Considered in Conjunction 
With Previous 3 Measurements) 
Soliqua 100/33 Dosage Adjustment 
(Units/Week) 
>140 mg/dL (>7.8 mmol/L) 
+4 units  
>100 to ≤140 mg/dL (>5.5 to ≤7.8 mmol/L)  
+2 units 
Glycemic target: 80 to 100 mg/dL 
(4.4-5.5 mmol/L), inclusive 
No change 
≥60 to <80 mg/dL (≥3.3 to <4.4 mmol/L)  
–2 units  
<60 mg/dL (<3.3 mmol/L) or occurrence of 
2 (or more) symptomatic hypoglycemia events 
or 1 severe hypoglycemia event (requiring 
assistance) documented in the preceding week 
–2 to –4 units or at the discretion of the 
investigator or any qualified designee 
Abbreviation: SMPG, self-measured plasma glucose. 
Notes: Dose changes should also be based on the median SMPG values (with the lowest value considered in 
conjunction with the previous 3 measurements). If the lowest value from the previous 3 measurements is 
from 80 to 100 mg/dL and the other 2 values are well above 100 mg/dL, further titration may be 
implemented at the investigator’s discretion. If the lowest value is <70 mg/dL and the other 2 values are 
near 100 mg/dL, the investigator may stop or temporarily reduce the dose if, in their judgment, further 
titration would be hazardous. 
5.6 Identity of Investigational Product 
Soliqua 100/33 (insulin glargine/lixisenatide) is a sterile, non-pyrogenic, clear, colorless 
solution in a SoloStar prefilled (disposable) pen for SC injection. 
Sanofi will provide adequate supplies of Soliqua 100/33 pen to the sites directly. 


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The following drug supplies will be used in the study: 
Product 
Supplied as: 
Soliqua 100/33 
SoloStar pens (containing a 3 mL of sterile 
solution of insulin glargine 100 units/mL 
and lixisenatide 33 μg/mL) 
5.7 Management of Clinical Supplies 
5.7.1 Study Drug Packaging and Storage 
Soliqua 100/33 is an injection supplied as a sterile, clear, colorless solution in a 3 mL, 
prefilled, disposable, single-patient-use pen injector and is shipped by Sanofi. Soliqua 100/33 
SoloStar pens will be supplied as open-label treatment kits. Packaging will be in accordance 
with the administration schedule. The content of the labeling will be in accordance with the 
local regulatory specifications and requirements. The appropriate number of kits (including 
pen needles as ancillary supplies) will be dispensed to provide participants with 
Soliqua 100/33 coverage up to the next site visit or phone contact with DTP Soliqua 100/33 
delivery (Section 13.1).Storage conditions and use-by-end date (ie, expiry date) are part of 
the Soliqua 100/33 label text. 
Investigators or other authorized persons (eg, pharmacists, IMP managers) are responsible for 
storing Soliqua 100/33 in a secure and safe place in accordance with local regulations, 
labeling specifications, policies, and procedures. Control of Soliqua 100/33 storage 
conditions, especially control of temperature (eg, refrigerated storage), and information on 
in-use stability and instructions for handling Soliqua 100/33 should be managed according to 
the rules provided by the sponsor. 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received, and any discrepancies must be reported 
and resolved before use of the study drug. 
5.7.2 Study Drug Accountability 
The investigator or other personnel designated by the investigator will maintain accurate 
records of receipt of study drug, including dates of receipt. In addition, accurate records will 
be kept regarding when and how much study drug is dispensed and used by each participant 


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in the study. The investigator or other personnel designated by the investigator will also be 
responsible for controlling the site stocks of Soliqua 100/33 and requesting any resupply, as 
needed. Reasons for departure from the expected dispensing regimen must also be recorded. 
At the completion of the study, to satisfy regulatory requirements regarding drug 
accountability, all study drug will be reconciled and retained or destroyed according to 
applicable regulations. 
All Soliqua 100/33 will be dispensed in accordance with the investigator’s oversight. It is 
also the investigator’s responsibility to ensure that an accurate recording of Soliqua 100/33 
kits issued and returned is maintained. 
Any quality issue noticed with the receipt or use of Soliqua 100/33 pen (deficiency in 
condition, appearance, documentation, labeling, expiration date, etc.) must be promptly 
reported to the sponsor. Some deficiencies may be recorded through a complaint procedure 
(Section 6.3.7). 
A potential defect in the quality of the Soliqua 100/33 pen may prompt 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 Soliqua 100/33 pens and 
eliminate potential hazards. 
Under no circumstances will the investigator supply Soliqua 100/33 pens to a third party, 
(except for DTP shipment, for which a courier company has been approved by the sponsor), 
allow the Soliqua 100/33 pen to be used other than as directed by this clinical study protocol, 
or dispose of the Soliqua 100/33 pen. 
5.7.3 Other Supplies 
5.7.3.1 Blood Glucose Meter Kit 
Each study participant will be provided with a blood glucose meter kit, in order to perform 
SMPG assessments. The blood glucose meter kit will include a blood glucose meter, lancing 
device, test strips, sterile lancets, storage box, control solution, and instructions for use. 


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5.7.3.2 CGM Device (FreeStyle Libre Pro Flash Glucose Monitoring 
System) 
The FreeStyle Libre Pro Flash Glucose Monitoring System (Abbott Laboratories) is a 
professional CGM device indicated for detecting trends and tracking patterns in people with 
diabetes (aged ≥18 years). The system automatically captures the glucose concentration in 
the interstitial fluid every minute. It also automatically records the glucose concentration 
every 15 minutes, storing that data in a rolling 8-hour log. The system has 3 main parts: a 
disposable sensor, a handheld reader, and FreeStyle Libre Pro software. Participants will not 
have access to the reader or software (these will remain with the investigator) and therefore 
will remain blinded to the data. 
The device will be applied to the back of the upper arm of each participant, and they will be 
required to wear it continuously for 14 days during CGM data collection at baseline (during 
the run-in period) and for 2 weeks at the end of the treatment period (ie, Weeks 14 to 16). 
The device does not require user calibration with blood glucose values. 
Clinical sites and participants will be provided with device adhesion guidance, including 
proper skin preparation and products to increase adhesion (TORBOT SKIN TAC™, a 
latex-free “tacky” skin barrier, and MASTISOL LIQUID ADHESIVE®, a clear, non-irritating 
liquid adhesive that secures dressings). Clinical sites will be thoroughly trained on the device 
adhesion guidance as well as the checks that must be performed to ensure that the devices are 
fully functioning before a participant leaves the site. 
5.8 Overdose Management 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by the 
investigator or spontaneously reported by the participant and is defined as any dose 
administration that, in the investigator’s opinion based on clinical judgment, is considered 
significantly greater than the prescribed dose of insulin or is at least twice the intended dose 
within the intended therapeutic interval. Any overdose, with or without associated AEs, must 
be promptly reported in eCRFs by the sites, which will then be notified to the sponsor’s 
representative (ie, PPD Pharmacovigilance). Overdoses without signs or symptoms should be 
recorded as a standard overdose; any AEs associated with the overdose should be reported on 
the relevant AE/SAE sections in the eCRF. 


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5.8.1 Treatment of Overdose 
Insulin Glargine 
Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of 
hypoglycemia can usually be treated with oral carbohydrates. Adjustments in study drug 
dose, meal patterns, or exercise may be needed. 
More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be 
treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After 
apparent clinical recovery from hypoglycemia, continued observation and additional 
carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia 
must be corrected appropriately. 
Lixisenatide 
During clinical studies, doses up to 30 µg of lixisenatide twice daily (3 times the daily 
recommended dose) were administered to patients with T2DM in a 13-week study. Increased 
incidence of GI disorders was observed (Soliqua 2019). 
In case of overdose, appropriate supportive treatment should be initiated according to the 
participant’s clinical signs and symptoms, and the Soliqua 100/33 dose should be reduced to 
the prescribed dose. 
5.9 Blinding 
Not applicable. This is an open-label, single-arm study. 
5.10 Treatment Accountability and Adherence 
Measures taken to ensure and document treatment adherence and IMP accountability include 
the following: 
• The treatment kit number should be properly recorded as required on the appropriate 
eCRF page, for accounting purposes. 
• All medication treatment kits (whether empty or unused) are to be returned by the 
participant at each visit when treatment dispensing is planned. 


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• Participants will record their daily dose details in an eDiary (Section 13.3). 
• The investigator or their delegate will track treatment accountability/adherence by 
comparing the treatment kit number captured in the electronic data collection (EDC) tool 
with the treatment/accountability log, eDiary information about daily doses, and number 
of treatment kits provided versus number of treatment kits returned (whether empty or 
unused). 
• The monitor in charge of the study will check the data entered on the Soliqua 100/33 
administration page of the eCRF and compare them with the Soliqua 100/33 study drug 
that has been returned and the participant’s treatment log form. 
5.11 Concomitant Therapy 
Use of all concomitant medications will be recorded in the participant’s eCRF. The minimum 
requirement is that drug name and the dates of administration are to be recorded. This 
includes all prescription drugs, herbal products, vitamins, minerals, and OTC medications. 
Any changes in concomitant medications will also be recorded in the participant’s eCRF. 
The participants should be reminded that vitamin C alone, supplements containing vitamin C 
with >1000 mg of ascorbic acid, aspirin alone, or aspirin-containing products with >650 mg 
of salicylic acid will interfere with CGM readings and should not be taken during the 14-day 
periods of CGM measure (ie, at baseline [from Visit 2 to Visit 3.1] and the end of the 
treatment period [from Visit 6 to Visit 7]). Additionally, medications known to affect 
glycemia, such as ≥5 mg/day of prednisone should be prohibited during this 16-week study 
period. Participants on meglitinides (eg, nateglinide, repaglinide) or weight loss drugs should 
also be prohibited from inclusion into the study. 
Any concomitant medication deemed necessary for the welfare of the participant during the 
study may be given at the discretion of the investigator. However, the investigator is 
responsible for ensuring that details regarding the medication are recorded in full in the 
eCRF. The Soliqua 100/33 label should be consulted for any additional information regarding 
concomitant medication administration. 


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 Study Assessments and Procedures 
Before performing any study procedures, all potential participants will sign an informed 
consent form (ICF). Participants will have the opportunity to have any questions answered 
before signing the ICF. The investigator must address all questions raised by the participant. 
The investigator will also sign the ICF. 
6.1 Study Visits 
The SoE is detailed in Section 13.1. 
• The screening period (Visit 1) will encompass up to 2 weeks and includes the following: 
o Obtaining informed consent. 
o Eligibility criteria. 
o Demographic assessment. 
o Review of medical/surgical history and current medications. 
o Physical examination (BMI calculation), dispensing of glucometer, HbA1c 
measurement, and setting up the eDiary. 
o Recording of vital signs, and clinical chemistry, calcitonin, hematology, urinalysis, 
and pregnancy tests. 
• The run-in period (Visit 2) will encompass 2 weeks, including the baseline period, and 
includes HbA1c measurement and application of blinded CGM device (FreeStyle Libre 
Pro). 
o Visit 3.1 will be a site visit and includes assessment of eligibility criteria, MMTT, 
CGM device removal and data download (after the MMTT), CGM compliance 
assessment, evaluation of PPG and biomarkers of β-cell function (insulin, C-peptide, 
plasma glucose) during the MMTT, instructions for certain therapies (eg, DPP-4i, oral 
daily or weekly GLP-1 RA, and down-titration of SU by 50% when starting 
Soliqua 100/33), dispensing of Soliqua 100/33 and providing instructions for SoloStar 
pen use HbA1c and FPG measurements, administration of the Diabetes Medication 
Satisfaction Tool (DM-SAT), recording of vital signs and body weight, and clinical 
chemistry, hematology, urinalysis, and pregnancy tests. 


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o Visit 3.2 (ie, Day 0) during the baseline period is the first day of Soliqua 100/33 
administration and includes a phone contact to ALL participants to ensure that all 
administration procedures were successfully executed and to answer any questions. 
(Note: The first day of Soliqua 100/33 administration [ie, Visit 3.2, Day 0] for 
participants on weekly GLP-1 RA will depend on their administration schedule and 
may not be the day immediately following Visit 3.1. Soliqua 100/33 administration 
for these participants should be 7 [± 2] days after their last weekly GLP-1 RA dose.) 
 A phone contact should also be made ONLY to participants on weekly GLP-1 
RA on the day before Soliqua 100/33 initiation, to remind them of the next 
morning’s injection and to provide instructions for SoloStar pen use. The 
participants will provide their concomitant medication details to the site personnel 
over the phone. 
• The treatment period will encompass up to 16 weeks (Visits 3.2 through 7) and includes 
the following: 
o Visit 3.2 (ie, Day 0) is the first day of Soliqua 100/33 administration and begins the 
open-label treatment period (with different initiation requirements based on weekly or 
daily GLP-1 RA use, as explained above). 
o Titration period (Visits 4.0 to 4.6, 5, and 5.1 to 5.4). 
 For Visits 4.0 to 4.6, titration of the Soliqua 100/33 dose will occur via phone 
contacts, but it can occur at the study site or at home for Visit 5. For Visits 5.1 
through 5.4, titration of Soliqua 100/33 dose will again occur via phone contacts. 
 During the titration period, participants will continue to make entries into their 
eDiary, administer Soliqua 100/33, adjust the Soliqua 100/33 dose, and capture 
any product complaints. 
 Other than an unscheduled visit, dispensing of Soliqua 100/33 will occur at 
Visit 5, if required. A pregnancy test will be conducted at Visit 5. 
o Visit 6: 
 Application of blinded CGM device and assessment of Soliqua 100/33 adherence. 
 Capturing of any product complaints.  


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o
Visit 7 (ie, end of the treatment period):

Physical examination (including body weight), MMTT (only to derive PPG
measures), removal of CGM device and download of data, and assessment of
Soliqua 100/33 adherence.

HbA1c and FPG measurements and recording of the DM-SAT.

Vital signs and clinical chemistry, hematology, urinalysis, and pregnancy tests.
o
At the end of the study (ie, Visit 7), participants should discuss with the investigator,
in collaboration with their HCP, whether to continue on the Soliqua 100/33 treatment
regimen or transition to an alternate antihyperglycemic therapy.
•
An unscheduled visit can be performed at any time during the treatment period and may
include the following:
o
Dispensing and adjustment of Soliqua 100/33 dose.
o
Review of concomitant medications.
o
Recording of hypoglycemia events and AEs/SAEs (including AESIs).
•
The follow-up safety period (Visit 8) will occur 2 weeks after the end of the treatment
period.
•
Fasting SMPG values and those measures required to manage hypoglycemia events will
occur from the run-in period (Visit 2) through the end of the treatment period (Visit 7).
•
Soliqua 100/33 dosing will occur from the end of the baseline period (Visit 3.2) through
the end of the treatment period (Visit 7).
•
eDiary completion, recording of hypoglycemia events, and AEs/SAEs (including AESIs)
will occur from the screening period (Visit 1) through the follow-up period (Visit 8),
whereas review of concomitant medications will occur from the baseline period
(Visit 3.1) through the follow-up period (Visit 8).


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6.2 Efficacy Assessments 
6.2.1 CGM Measures 
Blinded CGM will be performed for 14 continuous days during baseline (ie, from Visit 2 to 
Visit 3.1) and again for 14 days at the end of the treatment period (ie, from Visit 6 to Visit 7; 
Section 13.1). The baseline CGM measure will be captured before discontinuing the daily 
(oral or injectable) or weekly GLP-1 RA, DPP-4i, or down-titration of SU by 50%, and 
before initiation of Soliqua 100/33 treatment. The blinded CGM device (FreeStyle Libre Pro) 
will be applied to the back of the upper arm of the participant and activated at Visit 2 (ie, the 
run-in period). Participants will be required to wear the device continuously for 14 days for 
baseline CGM data collection, with device removal and data download on Day –1 at their 
next site visit during the baseline period (ie, Visit 3.1), after collection of C-peptide, insulin, 
and plasma glucose data from the MMTT. Downloaded CGM data will be reviewed by the 
investigator to determine the participants’ study eligibility. (Note: During the run-in period, 
CGM device reinsertion will be allowed for participants who do not meet the equivalent of at 
least 8 days of evaluable CGM data [not necessarily consecutive] over a 14-day period as a 
result of premature sensor failure [eg, days of CGM device wear × % time CGM device 
active < 8].) Similarly, participants will be required to continuously wear the device for 
14 days at the end of the treatment period from Weeks 14 to 16 (ie, Visit 6 to Visit 7) to 
collect CGM data, with device removal and data download on the fifteenth day after CGM 
placement (ie, Visit 7), after collection of only plasma glucose data from the MMTT. 
Downloaded CGM data will be verified by the investigator at the site to determine 
participants’ study completion. During the end of the treatment period, CGM device 
reinsertion will also be allowed for participants who do not meet the equivalent of at least 
8 days of evaluable CGM data (not necessarily consecutive) over a 14-day period as a result 
of premature sensor failure (eg, days of CGM device wear × % time CGM device active < 8), 
if data can be captured during the 14-day end of treatment window. (Note: The minimum 
requirement for evaluable CGM data is if at least 10 out of 14 days [not necessarily 
consecutive] have at least ≥80% of evaluable CGM data per 24-hour period during the run-in 
period as well as the end of the treatment period [ie, from Weeks 14 to 16]; Battelino et al 
2020.) Criteria for CGM device reinsertion are provided in Table 6-1 and Figure 6–1. Any 
combination of number of days of CGM device worn and % time CGM device is active 
(Table 6-1) that results in fewer than 8 equivalent days (defined as ineligibility) of evaluable 


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CGM data will require device reinsertion. Eligibility and analysis criteria for CGM measures 
are provided in Section 13.9. 
Table 6-1 
Criteria for CGM Device Reinsertion 
No. of Days CGM Device 
Worna  
Time CGM Device 
Active (%)a  
Equivalent Days 
8 
100 
8.00 
9 
89 
8.01 
10 
80 
8.00 
11 
73 
8.01 
12 
67 
8.04 
13 
62 
8.01 
14 
57 
7.98 
Abbreviations: AGP, Ambulatory Glucose Profile; CGM, continuous glucose monitoring. 
a AGP report. 
Figure 6–1 
Criteria for CGM Device Reinsertion 
 
Abbreviation: CGM, continuous glucose monitoring. 
Participants with less than equivalent of 8 days of evaluable CGM data (not necessarily 
consecutive) of a 14-day period (eg, days of CGM device wear × % time CGM device 
active < 8) during the run-in period will be considered as screen failures. For participants 


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who discontinue study treatment prematurely, the visit window can be extended by 14 days 
to collect the CGM data before they permanently discontinue the treatment. 
6.2.2 MMTT-Derived β-Cell Function and PPG Measures 
Participants will undergo the MMTT (while wearing the CGM device) to assess maximum 
PPG exposure in the 4-hour period after the breakfast meal (tested at a central laboratory) 
with biomarkers of β-cell function (plasma glucose, insulin, and C-peptide) measured at 
Visit 3.1 (ie, site visit during the baseline period). The baseline MMTT will be conducted 
before discontinuing the daily (oral or injectable) or weekly GLP-1 RA, DPP-4i, or 
down-titration of SU by 50%. At Visit 3.1, participants on OADs or an oral or injectable 
GLP-1 RA will be required to take their dose after the blood sample for FPG and HbA1c is 
collected and 30 minutes before administration of the meal during the MMTT. Participants 
on weekly GLP-1 RA should have their baseline MMTT conducted within 7 (± 3) days after 
their last dose. During baseline (Visit 3.1), blood samples will be collected at the following 
time points: premeal (30 min) and just before administration of OADs or GLP-1 RA (oral or 
injectable) (baseline); time 0 (just before meal administration), 10 min, 20 min; and 0.5, 1.0, 
1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal for plasma glucose, C-peptide, and insulin levels.  
At the end of the treatment period (Visit 7), participants will again undergo the MMTT 
(while wearing the CGM device; only to derive PPG measures). Soliqua 100/33 should be 
administered 30 minutes before administration of the meal during the MMTT at Visit 7. At 
the end of the treatment period (Visit 7), blood samples will be collected for plasma glucose 
levels, as follows: premeal (30 min) and just before administration of Soliqua 100/33; and 
time 0 (just before meal administration), 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal. 
These values will be used for PPG analyses with the goal of deriving reduction in the 
maximum glucose exposure in the 4-hour period after the breakfast meal following Soliqua 
100/33 administration at Week 16 compared with baseline. During both baseline and 
end-of-treatment assessments, removal of the CGM device and download of data will be 
done after completion of the MMTT (Section 13.1). 
The MMTT includes a standardized meal (ie, Boost Very High Calorie) that contains 
approximately 530 kcal and is composed of 19% carbohydrates, 44% protein, and 33% fat. 
The composition and the quantity of the standardized meal must be identical throughout the 
study period. 


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During the baseline period (ie, Visit 3.1), on the day of the MMTT, the participants must not 
eat any food or drink, except water, for at least 8 hours before the scheduled meal test (to be 
completed in the morning). At the end of the treatment period (ie, Visit 7), the MMTT will 
also be performed in a fasted state (eg, no consumption of any food or drink for at least 
8 hours, except water, before the scheduled meal test), and participants will receive their 
Soliqua 100/33 dose at the study site 30 minutes before the start of the test (ie, consumption 
of the meal and just after the first blood draw). 
For participants who discontinue study treatment prematurely, the visit window can be 
extended by 14 days to collect the CGM data, followed by the MMTT data, before they 
permanently discontinue the treatment. 
6.2.3 Fasting SMPG 
Participants will be supplied with a glucometer kit and an eDiary at the screening visit. 
Appropriate training will be provided to the participants related to proper use of the 
glucometer and eDiary completion. Fasting SMPG values (lowest values in conjunction with 
measurements from the previous 3 days) will be used to titrate and adjust Soliqua 100/33 
doses and monitor glycemic control. Sound clinical judgment should be exercised during 
titration to further up-titrate if the lowest value from the last 3 measurements is between 
80 to 100 mg/dL but the 2 other values are above 100 mg/dL and further titration is required 
to manage hyperglycemia. The participants are required to measure fasting SMPG values 
before breakfast at least 3 to 4 times per week throughout the study period (to inform each 
dose adjustment) and record the results in the eDiary. During the titration period, fasting 
SMPG should be performed on each of the 3 to 4 days before each dose adjustment. 
(Note: Additional titration is at the discretion of the investigator with the goal of achieving 
glycemic targets while minimizing the risk of hypoglycemia and hyperglycemia.) 
6.2.3.1 SMPG During Symptomatic Hypoglycemia 
Whenever participants experience hypoglycemia symptoms, they (or others, if applicable) 
should measure plasma glucose, if possible. Participants should be instructed to measure 
plasma glucose levels before carbohydrate intake/administration of glucose whenever 
symptomatic hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue before confirmation with the SMPG values. Participants must 
contact the investigator as soon as possible following hypoglycemia events for review and so 


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that a decision regarding any necessary actions can be made. Participants should be 
instructed to measure plasma glucose levels again after the event resolves. 
6.2.4 FPG Measurements 
Blood samples will be collected to determine FPG at the time points specified in the SoE 
(Section 13.1) and will be measured at a central laboratory. For the scheduled site visits, 
participants are required to arrive fasting without administering the Soliqua 100/33 injection. 
Fasting is defined as no food intake in the 8 hours before blood sampling, except water. 
6.2.5 HbA1c Measurements 
Blood samples will be collected to measure HbA1c during the screening and run-in periods 
and at Visit 3.1 (before administration of the meal) at the central laboratory, to determine 
study eligibility and at the end of the 16-week treatment period (Visit 7), to determine change 
in glycemic control. 
6.2.6 Assessment of Patient-Reported Outcome 
Diabetes Medication Satisfaction Tool 
The assessment of treatment-related impact on participants’ health-related quality of life 
(HRQoL) and their satisfaction with diabetes therapy will be assessed using the DM-SAT 
questionnaire (Anderson et al 2009) at the baseline visit before stopping or down-titration of 
baseline therapies and at the end of the treatment period (Section 13.1). The DM-SAT 
questionnaire (Section 13.2) is a 16-item measure with 4 subscales assessing wellbeing 
(3 items), medical control (3 items), lifestyle (5 items), and convenience (5 items). 
Participants will be requested to complete the DM-SAT questionnaire by themselves, 
independently from the investigator or site staff, and without any help from friends or 
relatives. For validity purposes, the questionnaire should be completed by participants in a 
quiet place, at the start of the visit before any other study tests or procedures are performed or 
Soliqua 100/33 is administered. 


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6.3 Safety Assessments 
6.3.1 Physical Examination 
A complete physical examination (including body weight) will be performed, per standard of 
care, in order to assess the health status of the participants at time points described in the SoE 
(Section 13.1). Height measurements in conjunction with body weight will be utilized to 
calculate BMI during the screening period. 
Body weight will be measured to allow the estimation of change from baseline to Week 16. 
While measuring body weight the participant should be wearing only undergarments or very 
light clothing and no shoes and have an empty bladder. 
The same weight scale should be used throughout the study and calibrated on a regular basis 
as recommended by the manufacturer. Calibration should be documented in source 
documents by the site. 
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 the measurement. The weights are 
moved until the beam balances (the arrows are aligned). The weight should be read and 
recorded in the eCRF and source documents. 
Self-reported weights are not acceptable on physical examination; participants must not read 
the scales themselves. 
6.3.2 Hypoglycemia Events 
During the study, participants must be instructed to document any hypoglycemia events in 
their eDiary. Hypoglycemia will be reported in the specific hypoglycemia event information 
form in the eCRF with onset date and time; symptoms and/or signs; the SMPG value, if 
available; and the treatment. A hypoglycemia event that fulfills the seriousness criteria will 
also be documented on the SAE form in the eCRF. 


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Hypoglycemia will be evaluated in accordance with the consensus report of a steering 
committee on levels of hypoglycemia (Agiostratidou et al 2017). These levels are consistent 
with ADA standard of care 2021 recommendations (ADA 2021a). 


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The following are the categories of interest: 
• Overall hypoglycemia. 
• Confirmed hypoglycemia. 
o ADA Level 1: A measurable glucose concentration of <70 mg/dL (3.9 mmol/L) but 
≥54 mg/dL (3.0 mmol/L) that can alert a person to take action. Blood glucose 
concentration of 70 mg/dL (3.9 mmol/L) has been recognized as a marker of 
physiological hypoglycemia in humans. Recurrent episodes of hypoglycemia lead to 
increased hypoglycemia unawareness, Therefore, glucose levels <70 mg/dL 
(3.9 mmol/L) are clinically important, independent of the severity of acute symptoms. 
o ADA Level 2: A measurable glucose concentration of <54 mg/dL (3.0 mmol/L) that 
needs immediate action. At approximately 54 mg/dL (3.0 mmol/L), neurogenic and 
neuroglycopenic hypoglycemia symptoms begin to occur, ultimately leading to brain 
dysfunction at levels <50 mg/dL (2.8 mmol/L). Neuroglycopenic symptoms, 
including behavioral changes, visual changes, seizure, and loss of consciousness, are 
the result of central nervous system neuronal glucose deprivation. 
o ADA Level 3: A severe event characterized by altered mental and/or physical 
functioning that requires assistance* from another person for recovery. Severe 
hypoglycemia captures events during which the symptoms associated with 
hypoglycemia affect a patient such that the patient requires assistance from others. 
*Note that “requires assistance” means that the person could not help themselves. Assisting a 
person out of kindness, when assistance is not required, should not be considered a “requires 
assistance” incident. 
Clinical symptoms that are related to a hypoglycemia episode can include (but are not 
necessarily limited to) increased sweating, nervousness, asthenia, tremor, dizziness, increased 
appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and 
coma (Agiostratidou et al 2017). 
6.3.3 Clinical Safety Laboratory Assessments 
All clinical safety laboratory assessments will be performed by a central laboratory. The list 
of clinical laboratory tests to be performed is provided in Section 13.4. The timing and 


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frequency of sample collections are provided in the SoE (Section 13.1). Additional tests may 
be performed at a local or central laboratory at any time during the study as determined 
necessary by the investigator or required by local regulations. If they are used to evaluate an 
AE (diagnostic, follow-up, outcome), the results must be entered into the eCRF 
(Section 13.4). 
• The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. 
• The laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings associated with the underlying disease or vital signs will 
not be considered clinically significant or be reported as AEs unless one of the following 
criteria is met: 
o Participant is symptomatic (and/or laboratory values are or vital signs are clinically 
significant per the investigator’s discretion). 
o Participant requires either corrective treatment or consultation. 
o Participant requires Soliqua 100/33 treatment to be discontinued or modification of 
dosing. 
o Event fulfills a seriousness criterion. 
o Event meets the definition of an AESI (Section 6.3.5.2). 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal/baseline or 
are no longer considered clinically significant by the investigator. 
o 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 assessments, as defined in Section 13.4, must be 
conducted in accordance with the laboratory manual and the SoE (Section 13.1). 
• The recommended decision tree for the management of ALT increase is provided in 
Appendix 13.6. 


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6.3.4 Vital Signs 
Vital signs (heart rate, systolic blood pressure [BP], and diastolic BP) will be recorded at the 
time points specified in the SoE (Section 13.1). 
• Blood pressure will be assessed in a seated position using the same device (automated BP 
monitor or a manual sphygmomanometer) for each participant. 
• Seated BP should be measured in both arms after at least a 5-minute rest, and then again 
after 1 minute in both arms while the participant is in a seated position. The arm with the 
highest systolic BP will be determined at this visit, and the BP should be measured using 
this arm throughout the study. This highest value will be recorded in the eCRF. 
• At subsequent visits, BP should be measured using the participant’s designated arm, to be 
preceded by at least 5 minutes of rest in a quiet setting without distractions 
(eg, television, cell phones). 
• Heart rate will be measured concurrently with the measurement of seated BP. 
• Vital sign abnormalities are to be recorded as AEs only if at least one of the following 
criteria is met: 
o Participant is symptomatic (and/or vital signs are clinically significant per the 
investigator’s discretion). 
o Participant requires either corrective treatment or consultation. 
o Participant requires Soliqua 100/33 treatment to be discontinued or the dose to be 
modified.  
o Event fulfills a seriousness criterion. 
o Event meets the definition of an AESI (Section 6.3.5.2). 
6.3.5 Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study drug or their clinical significance. The 
investigator remains responsible for following up on all AEs that are serious, considered 


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related to the study treatment or study procedures, or caused the participant to discontinue 
Soliqua 100/33 treatment and/or the study. 
All AEs (serious or nonserious) will be collected from the signing of the ICF until the 
follow-up visit (Section 13.1). 
The definitions of AEs and SAEs are provided in Section 13.5. The definition of an AESI is 
provided in Section 6.3.5.2. 
All SAEs and AESIs will be recorded and reported to the sponsor or designee immediately 
and under no circumstances should this be longer than 24 hours of awareness, as indicated in 
Section 6.3.5.5. The investigator will submit any updated SAE data to the sponsor or 
designee within 24 hours of receipt of the information. 
After the initial AEs/AESIs/SAEs report, the investigator is required to proactively follow-up 
with each participant at subsequent visits/contacts. At the prespecified study end date, all 
SAEs and AESIs (as defined in Section 6.3.5.2), will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 4.4.2). Further information on follow-up procedures is provided in 
Section 13.5.3. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of 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 they consider 
the event to be reasonably related to study treatment or study participation, the investigator 
must promptly notify the sponsor. 
6.3.5.1 Suspected Unexpected Adverse Events 
A suspected unexpected serious adverse reaction (SUSAR) is defined as an adverse reaction, 
the nature or severity of which is not consistent with the applicable product 
information/labeling (eg, investigator’s brochure for an unapproved IMP). 
A “Dear Investigator” letter must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 


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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 package insert and will notify the institutional review 
board (IRB), 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 thus is expedited to 
regulatory authorities. 
6.3.5.2 Adverse Events 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. Adverse events of special interest may be added, 
modified, or removed during a study by protocol amendment. 
The following AEs will be considered as AESIs in this study: 
• Pregnancy of a female participant enrolled in the study as well as pregnancy occurring in 
a female partner of a male participant enrolled in the study with IMP/NIMP. 
o Pregnancy will qualify as an SAE only if it fulfills one of the seriousness criteria 
(Section 13.5.2). 
o If it is a pregnancy in a female participant, IMP should be discontinued. 
o Follow-up of the pregnancy of a female participant or a female partner of a male 
participant is mandatory until the outcome has been determined. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP. 
o An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the investigator or spontaneously reported by the participant and is defined as any 
dose administration that, in the investigator’s opinion based on clinical judgment, is 
considered significantly greater than the prescribed dose of insulin or is at least twice 
the intended dose within the intended therapeutic interval (for example, for a 
participant prescribed 60 units/20 μg of Soliqua 100/33 once a day, administration of 
≥120 units of insulin glargine and ≥40 μg of lixisenatide once a day would be 
considered an overdose), adjusted according to the tested drug. 


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o Asymptomatic overdose has to be reported as a standard overdose. The circumstances 
(ie, accidental or intentional) should be clearly specified in the verbatim, and 
symptoms, if any, must be entered on separate AE/SAE forms. 
• Increase in ALT (>3 × ULN; Section 13.6). 
6.3.5.3 Pregnancy 
A urine pregnancy test will be performed at time points specified in the SoE (Section 13.1). 
To ensure participant safety, each pregnancy must be reported to Sanofi within 24 hours of 
learning of its occurrence. The pregnancy must be followed up to determine the outcome 
(including spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) and the status of mother and child, even if the participant was discontinued 
from the study. Pregnancy complications and elective terminations for medical reasons must 
be reported as an AE or SAE. Spontaneous miscarriages must be reported as an SAE. 
Any SAE occurring in association with a pregnancy that is brought to the investigator’s 
attention after the participant has completed the study and is considered by the investigator as 
possibly related to the study treatment must be promptly reported to Sanofi. 
Any female participant who becomes pregnant while participating in the study will be 
discontinued from study drug treatment. 
6.3.5.4 Eliciting and Documenting AEs 
Adverse events will be assessed from the time the participant signs the ICF until exit from 
the study. 
Serious AEs that occur more than 30 days after the last dose of study drug need not be 
reported unless the investigator considers them related to study drug. 
At every study visit, participants will be asked a standard nonleading question to elicit any 
medically related changes in their wellbeing. They will also be asked if they have been 
hospitalized, had any accidents, used any new medications, or changed concomitant 
medication regimens (both prescription and OTC medications). 
In addition to participant’s observations, AEs identified from any study data (eg, laboratory 
values, physical examination findings) or identified from review of other documents 


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(eg, participant’s eDiary) that are relevant to participant’s safety will be documented on the 
AE page in the eCRF. 
6.3.5.5 Reporting AEs 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes drug treatment, dose, event term, time of onset, 
investigator-specified assessment of severity and relationship to study drug, time of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs. 
Any medical condition that is present at the time that the participant is screened but does not 
deteriorate should not be reported as an AE. However, if it deteriorates at any time during the 
study, it should be recorded as an AE. 
Any AE that meets criteria of an SAE (Section 13.5.2) or an AESI (Section 6.3.5.2) must be 
reported to PPD Pharmacovigilance immediately (ie, within 24 hours) after site personnel 
first learn about the event (Section 13.5.4). 
6.3.5.6 Assessment of Severity 
The severity or intensity of an AE refers to the extent to which an AE affects the participant’s 
daily activities. The intensity of the AEs will be rated as mild, moderate, or severe as 
described in Section 13.5.3. 
Changes in the severity of an AE should be documented to allow an assessment of the 
duration of the event at each level of intensity to be performed. Adverse events characterized 
as intermittent do not require documentation of the onset and duration of each episode. 
6.3.5.7 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study drug is part of the 
documentation process (Section 13.5.3), but it is not a factor in determining what is or is not 


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reported in the study. If there is any doubt as to whether a clinical observation is an AE, the 
event should be reported. 
The relationship or association of the study drug in causing or contributing to the AE will be 
characterized using the following classification and criteria: 
Related: 
If the cause of the AE is related to IMP/NIMP and cannot be reasonably 
explained by other factors, such as the participant’s clinical state, 
concomitant therapy, and/or other interventions OR if the cause of the AE 
is unknown after a thorough review of the other factors. 
Not Related: 
When there is a clear alternative cause for the event other than the 
IMP/NIMP. 
6.3.5.8 Follow-up of Participants Reporting AEs 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant or until the participant is considered to be stable (Section 13.5.3). 
6.3.6 Safety Monitoring Committee 
An independent safety monitoring committee will not be formed for this study. The medical 
monitor and sponsor will hold monthly reviews of all AEs. 
6.3.7 Guidelines for Reporting Product Complaints 
Any defect in the IMP device must be reported as soon as possible by the investigator to the 
monitoring team, who will complete a product complaint form within the required timelines. 
Appropriate information (eg, samples, labels, or documents like pictures or photocopies) 
related to product identification and to the potential deficiencies may need to be gathered. 
The investigator will assess whether the quality issue has to be reported with an AE or SAE. 


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6.4 Outcomes Research Assessments 
The assessment of treatment-related impact on participants’ HRQoL and their satisfaction 
with diabetes therapy will be assessed using the DM-SAT questionnaire, as described in 
Section 6.2.6. 
6.5 Sample Collections 
Site personnel will collect blood samples at the visits specified in the SoE (Section 13.1). 
These samples will be processed at the site and shipped the same day to a central laboratory, 
as specified in the laboratory manual. The central laboratory will analyze blood samples for 
PPG measures, HbA1c, and FPG, clinical chemistry, hematology, and biomarkers of β-cell 
function (during the MMTT). Results will be returned to the site within 48-72 hours. 
6.6 Use of Biological Samples And Data For Future Research 
Future research may help further the understanding of disease subtypes, disease biology, 
related conditions, drug response, and toxicity and can help identify new drug targets or 
biomarkers that predict participant response to treatment. Therefore, data and biological 
samples will be stored and used for future research when consented to by participants 
(Section 9.3) unless prohibited by local laws or IRBs (in such case, consent for future use of 
sample will not be included in the local ICF). 
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research 
related to the drug, the mechanism of action, the disease, or its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins, 
or metabolites. If future research on genetic material is performed, this will also be limited to 
the purpose of addressing research questions related to the drug, the mechanism of action, the 
disease, or its associated conditions. 
In the event future research is conducted for other purposes, study participants will be 
informed of those purposes and will be given the means to object to those research projects. 
Data and samples will be used in compliance with the information provided to participants in 
the ICF Part 2 (future research). 


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All study participant data and samples will be coded such that no participant’s directed 
identifiers will be linked to them. Coded data and samples may be transferred to a sponsor 
site (or a subcontractor site) that may be located outside of the country where the study is 
conducted. The sponsor adopts safeguards for protecting participant confidentiality and 
personal data (Section 10.2). 
The samples will be stored for a maximum of 15 years after the end of the study. Any 
samples remaining at the end of the retention period will be destroyed. If a participant 
requests destruction of their samples before the end of the retention period, the investigator 
must notify the sponsor in writing. In such cases, samples will be destroyed, and related 
coded data will be anonymized unless otherwise required by applicable laws. 
Study participants’ coded data will be stored for future research for up to 25 years after the 
end of the study. If the data are still considered of important scientific value after this period, 
coded data already available will be anonymized unless otherwise required by applicable 
laws (the same will apply to the data of a study participant who has requested the destruction 
of their samples). 
Participants’ 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). 
6.6.1 Assessment of β-Cell Function Indices 
β-cell function biomarkers (plasma glucose, C-peptide, and insulin) will be collected from all 
eligible participants at baseline during the MMTT for assessment of β-cell responsivity, 
insulin and glucose sensitivity, and any relationships to glycemic control. After database 
lock, data will be transferred to an academic partner who will utilize modelling techniques to 
derive these measures. These results will be reported separately. 


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 Study-Specific Committees 
No scientific steering committee, data safety monitoring committee, or clinical endpoint 
committee will be used in this study. 


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 Statistical Considerations 
8.1 Estimands and Intercurrent Events 
The estimand framework is provided in Table 8-1. 
Table 8-1 
Estimand Framework 
Estimand Definition 
Variable (or Endpoint) 
Strategy for Addressing 
Intercurrent Event  
Population-Level 
Summary 
Estimand [Primary] 
 
 
 
The primary estimand is 
the mean change in the 
percentage of TIR 
(70‑180 mg/dL) from 
baseline to Week 16. 
The primary estimand 
will be estimated based 
on the efficacy analysis 
set using obtained 
measurements, 
regardless of 
intercurrent events. 
Mean change in percentage 
of TIR at Week 16 from 
baseline 
Treatment policy strategy 
Mean and 95% CI of 
change in percentage 
of TIR at Week 16 
from baseline 
Estimand [Key 
Secondary] 
 
  
 
Mean percent changes 
of CV at Week 16 from 
baseline among the 
efficacy analysis set, 
regardless of 
intercurrent events 
Mean percent changes of 
CV at Week 16 from 
baseline 
Treatment policy approach 
Mean and 95% CI 
Mean mg/dL change of 
mean daily blood 
glucose at Week 16 
from baseline among the 
efficacy analysis set, 
regardless of 
intercurrent events  
Mean mg/dL change of 
mean daily blood glucose 
at Week 16 from baseline 
Treatment policy approach 
Mean and 95% CI 
Mean mg/dL change in 
the maximum PPG 
exposure in the 4-hour 
period after the 
breakfast meal at 
Week 16 from baseline 
among the efficacy 
analysis set, regardless 
of intercurrent events  
Mean mg/dL change in 
maximum PPG exposure in 
the 4-hour period after the 
breakfast meal at Week 16 
from baseline 
Treatment policy approach 
Mean and 95% CI 


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Estimand Definition 
Variable (or Endpoint) 
Strategy for Addressing 
Intercurrent Event  
Population-Level 
Summary 
Mean percent change in 
TAR >180 mg/dL at 
Week 16 from baseline 
among the efficacy 
analysis set, regardless 
of intercurrent events  
Mean percent change in 
TAR >180 mg/dL at 
Week 16 from baseline 
Treatment policy approach 
Mean and 95% CI 
Abbreviations: CI, confidence interval; CV, coefficient of variation; PPG, postprandial glucose; TAR, time 
above range; TIR, time in range. 
The following intercurrent events for the primary estimand will be handled by the treatment 
policy strategy: initiation of rescue medication other than the study IMP, discontinuation of 
IMP, withdrawal from the study, and recording of <80% of evaluable CGM data per 24-hour 
period over 10 days of a 14-day period, during the run-in period as well as the end of the 
treatment period (ie, from Weeks 14 to 16; Section 13.9). This estimand aims to reflect the 
estimated treatment effect under the intention-to-treat (ITT). 
8.2 Statistical Hypothesis 
The null hypothesis (H0) for the primary endpoint is that the efficacy analysis set will have 
no improvement in TIR at Week 16 compared with baseline. The alternative statistical 
hypothesis is that the efficacy analysis set will have an increased TIR at Week 16 compared 
with baseline at the significance level of 0.05. 
8.3 Sample Size Determination 
A total of 100 participants will be enrolled in the study. Sufficient participants will be 
screened from approximately 15 sites to include 100 patients, such that approximately 
82 evaluable participants complete the study (anticipating that approximately 15% of 
participants discontinue the study before Week 16). 
The sample size is based on the primary objective to demonstrate the significant mean 
change (ie, increase) in the percentage of TIR (70‑180 mg/dL) from baseline to Week 16 with 
sufficient power. A sample size of 82 participants will have 95% power to detect an absolute 
increase in TIR means of 10%, assuming a standard deviation (SD) of 25 for the change in 
TIR, with a two-sided type I error of 0.05. Anticipating a 15% loss to follow-up rate, 
100 participants would need to be enrolled. 


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Assumptions for Sample Size Determinations 
• Patients with an HbA1c ≥9% are in range 40% of the time or less (Batellino et al 2019). 
• Per Vigersky and McMahon, every 10% increase in TIR corresponds to 0.8% HbA1c 
reduction (Vigersky and McMahon 2019). 
• Post hoc analyses from the LixiLan-O study in patients with an HbA1c of ≥9% produced 
an HbA1c reduction of 2.9% at 30 weeks (Davies et al 2019). Therefore, 0.8% HbA1c 
reduction (considered equal to 16% improvement in TIR) at Week 16 seems reasonable. 
• Assumption for SD is 25. In the AWARD-4 study in patients with T2DM, the increase in 
TIR at Week 26 was 20% to 30%, and the SE was approximately 3.0 (corresponding to 
an SD of approximately 20) (Jendle et al 2016). 
8.4 Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
• Enrolled set: All eligible participants who are dispensed Soliqua 100/33 and sign the ICF. 
• Efficacy analysis set: All enrolled participants who receive ≥1 dose of Soliqua 100/33 and 
have evaluable CGM data at baseline.  
• Safety set: All enrolled participants who receive ≥1 dose of Soliqua 100/33.  
8.5 Description of Subgroups to Be Analyzed 
The following subgroups are planned for the primary analyses, if the number of participants 
in each subgroup is sufficient: participants with OAD only or OAD plus GLP-1 RA at 
baseline. The number of patients deemed sufficient for a subgroup analysis will be 
determined in the statistical analysis plan (SAP). 
8.6 Accountability, Demographics, and Baseline Characteristics 
Treatment adherence, demographics, and baseline characteristics will be summarized in 
descriptive tables. Continuous data will be summarized using number of observations 


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available, mean, SD, quartile ranges, minimum, median, and maximum. Categorical data will 
be summarized using count and percentage. 
8.6.1 Adherence 
Overall treatment adherence is defined as the actual number of days with IMP injection 
compared with the planned number of days with IMP injection during the treatment period, 
up to treatment discontinuation. It is calculated according to the following formula: 
 
A given administration will be considered noncompliant if the participant did not take the 
planned dose of treatment as required by the protocol. No imputation will be made for 
participants with missing or incomplete data. 
Treatment adherence will be summarized using mean, SD, median, and range for the safety 
set. In addition, the percentage of participants who have <60%, ≥60% to <80%, ≥80% to 
≤100%, and >100% adherence will be summarized. 
The duration of IMP exposure will be calculated as date of the last IMP injection – date of 
the first IMP injection + 1. 
8.7 Statistical Analysis Methodology 
Statistical analysis will be performed using SAS Enterprise software Version 7.1 or higher. In 
general, descriptive statistics of quantitative efficacy and safety parameters (result and 
change from baseline) by scheduled visits will be provided on observed cases (OC; 
ie, inclusion of only participants having non-missing assessments at a specific visit). The 
baseline value is defined as the last available value before the first injection of Soliqua 
100/33. All efficacy analyses (primary, key secondary, secondary, and other efficacy 
endpoints) will be performed on the efficacy analysis set. Analysis of demographics, baseline 
characteristics, and prior and concomitant medications will be provided in detail in the SAP. 
The extent of study treatment exposure and adherence will be assessed and summarized with 
dose frequency and duration of treatment. 


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Continuous data will be summarized using number of observations available, mean, SD, 
minimum, median, and maximum. Categorical data will be summarized using count and 
percentage. 
Details of the statistical analyses, methods, and data conventions are described in the SAP. 
All statistical tests will be 2-sided and performed using a 0.05 significance level, leading to 
95% (2-sided) confidence intervals (CIs). 
Laboratory values below the lower limit of quantification (LLOQ) will be set to ½LLOQ. 
 


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8.7.1 Overview of Statistical Methods: Estimation of Estimands and Sensitivity Analyses 
A summary of statistical methods, including sensitivity analyses, is provided in Table 8-2. 
Table 8-2 
Summary of Statistical Methods, Including Sensitivity Analyses 
 
 
 
Main Estimation 
 
 
Estimand 
Label 
Estimand Description 
Analysis Set 
Imputation/Data/ 
Censoring Rules 
Analysis Model/Method 
Sensitivity Analysis 
Estimand 1a 
(Primary) 
Mean change in the 
percentage of TIR 
(70‑180 mg/dL) from baseline 
to Week 16 among the entire 
study population. The primary 
estimand will be estimated 
based on the efficacy analysis 
set using obtained 
measurements. The value for 
the mean change in the 
percentage of TIR will be 
used regardless of intercurrent 
events at Week 16. 
Efficacy 
analysis set 
Missing endpoint at 
Week 16 due to 
technical issues with the 
CGM device will be 
excluded from the 
analysis. Missing 
endpoint at Week 16 due 
to other reasons than 
technical issues will be 
imputed by the baseline 
value. 
Mean and its associated 
95% CI will be calculated 
on an overall efficacy 
analysis set. A one-sample 
t-test will be applied to 
test the significance of 
changes at Week 16 over 
baseline. 
The sensitivity analysis for the 
primary outcome will be conducted 
with all missing data imputed using 
BOCF approach. In case there is 
substantial missing CGM data, a 
second sensitivity analysis may be 
conducted on participants with 
evaluable data to estimate the 
primary endpoint at Week 16. 
Mean and its associated 95% CI 
will be reported.  
Abbreviations: BOCF, baseline observation carry forward; CI, confidence interval; CGM, continuous glucose monitoring; TIR, time in range. 
 


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8.7.2 Analysis of Primary Endpoint 
8.7.2.1 Main Estimation of Primary Estimand 
The primary endpoint is to demonstrate the improvement from baseline in the percentage 
of TIR of 70 to 180 mg/dL during the last 2 weeks of treatment (Weeks 15 and 16) for the 
entire study population. The percentage of time spent in the glycemic target range will be 
calculated as 100 times the number of recorded measurements in the glycemic target range, 
(70-180 mg/dL) inclusive, divided by the total number of recorded measurements. 
As described in Table 8-2, the mean and its associated 95% CI will be used to describe the 
changes in TIR (70-180 mg/dL) at Week 16 from baseline. A one-sample t-test will be 
applied to test the significance of changes. A p-value <0.05 will be considered significant. 
As part of the definition for the efficacy analysis set, evaluable data (ie, not missing) is 
defined as the availability of at least 10 out of 14 days (not necessarily consecutive) with at 
least ≥80% of evaluable CGM data per 24-hour period during the run-in period as well as 
the end of the treatment period (ie, from Weeks 14 to 16; Section 13.9), otherwise it will be 
considered as missing. 
The primary estimand will be estimated based on the efficacy analysis set using obtained 
measurements, regardless of intercurrent events. Table 8-2 provides more details regarding 
the missing data definition. 
The missing data related to the primary estimand due to lost-to-follow-up or treatment 
discontinuation will be imputed with their baseline observation carry forward (BOCF). 
Missing data due to technical issues of CGM devices will not be imputed. Details of 
handling missing data are provided in Section 8.7.3.3. 
8.7.2.2 Sensitivity Analysis of Primary Endpoint 
Sensitivity analysis for the primary outcome will be conducted by imputing all missing 
data (regardless of reasons) with BOCF.  
If there is substantial missing CGM data from for the primary outcome, an additional 
sensitivity analysis will be conducted on participants with evaluable data to estimate the 


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primary endpoint at Week 16 (data from participants who discontinue their treatment 
before Week 16 will also be included as long as they have evaluable CGM data). Mean and 
its associated 95% CI will be reported.  
8.7.2.3 Supplementary Analysis of Primary Endpoint 
Analysis of the primary endpoint will be summarized by baseline subgroups (ie, OAD only 
or OAD plus GLP-1 RA). 
8.7.3 Analysis of Key Secondary Efficacy Endpoints 
8.7.3.1 Main Estimation of Key Secondary Estimand 
Change in Glycemic Control and Variability 
Mean changes for continuous outcomes (eg, CV, mean daily blood glucose, maximum PPG 
exposure in the 4 hours after the breakfast meal, TAR >180 mg/dL) will be presented at 
baseline and at the end of the treatment period (Week 16). Mean (SD) and associated 95% 
CI, as well as minimum, median, and maximum will be provided. 
The key secondary estimand will be estimated based on the efficacy analysis set using 
measurements obtained during the study, regardless of intercurrent events. Missing data 
related to the key secondary estimand will be imputed with their BOCF. Similarly to 
analysis of primary estimand, missing data due to technical issues of CGM devices will not 
be imputed. 
8.7.3.2 Sensitivity Analysis of Key Secondary Endpoints 
No sensitivity analysis is planned for key secondary endpoints. 
8.7.3.3 Handling of Missing Data 
Missing data will be handled differently in accordance with the reasons for the missing 
data for both primary and key secondary endpoints. If the missing data are due to technical 
issues with the CGM device (ie, CGM data are not evaluable if at least 10 out of 14 days 
[not necessarily consecutive] have <80% of evaluable CGM data per 24-hour period 
during the run-in period as well as the end of the treatment period [ie, from Weeks 14 


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to 16]), the participant will be excluded from the analysis (missing completely at random 
[MCAR] approach). For other reasons for missing measurements (eg, lost to follow-up, 
discontinued treatment), the Week 16 assessment will be imputed with the baseline value 
carried forward (missing not at random [MNAR], conservative approach). The assumption 
that data are MCAR will be evaluated using an association test (eg, Chi-square test for 
categorical covariates and Pearson correlation coefficient or two-sample t-test for 
continuous covariates) between baseline covariates and missing data status 
(ie., participants who have missing data for primary endpoint versus those who have 
complete data). The reasons for missing the primary endpoint at Week 16 (eg, lost to 
follow-up, discontinued treatment) will also be presented. 
Multiple Comparisons and Multiplicity 
A hierarchical testing procedure will be performed. Key secondary endpoints will be 
evaluated with a one-sample t-test to determine whether there is any change at Week 16 
over baseline in succession in accordance with the hierarchy and as long as the endpoints 
continue to show statistical significance. If one test is nonsignificant (p >0.05), then the 
testing will be stopped (or consider all further tests to be only secondary, and no formal 
conclusions can be drawn). 
8.7.4 Analyses of Secondary Endpoints 
Mean changes for continuous outcomes (eg, other measures of glycemic control and 
variability: TIR [70-180 mg/dL] for four 6-hour time segments, Glucose Management 
Indicator [GMI] <7% and <9%, 4-hour PPG area under the concentration versus time 
curve from 0 to 4 hours (AUC0-4h) after start of the breakfast meal, and time to maximal 
PPG concentration) will be presented at baseline and at the end of the treatment period 
(Week 16). Mean (SD) and associated 95% CI, as well as minimum, median, and 
maximum will be provided. 
Binary outcomes (eg, change in the proportion of patients achieving CV <36% at Week 16, 
the proportion of patients at Week 16 who spend <15 minutes/day at a glucose level 
<54 mg/dL) will be summarized with proportions and 95% CI using the Clopper Pearson 
exact method. 


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8.7.5 Analyses of Other Efficacy Endpoints 
Mean changes for continuous outcomes (eg, additional measures of glycemic control and 
variability: mean of daily difference [MODD] of glucose levels, TAR >250 mg/dL, TBR 
<70 mg/dL, and HbA1c %) will be presented at baseline and at the end of the treatment 
period (Week 16). Mean (SD) and associated 95% CI, as well as minimum, median, and 
maximum will be provided. 
The correlation of TIR to patient-reported outcome (PRO), HbA1c, and relationship of 
patients requiring 60 units/day of insulin glargine (related to TIR >70%) at Week 16 will 
be assessed using Pearson correlation coefficient. 
8.7.6 Assessment of β-Cell Function Indices 
β-cell function biomarkers (plasma glucose, C-peptide, and insulin) collected at baseline 
will be analyzed utilizing minimal modelling by an external academic partner for all 
eligible participants to determine β-cell responsivity, insulin and glucose sensitivity, and 
any relationships to glycemic control. The β-cell function indices will be included as a post 
hoc analyses and reported separately. 
8.7.7 Analysis of PRO Endpoint 
Change in diabetes medication treatment-related impact and satisfaction, as measured by 
the DM-SAT, from baseline to Week 16 will be analyzed using the efficacy analysis set and 
described as mean (SD) and associated 95% CI, as well as minimum, median, and 
maximum for overall score and by subscales. 
8.7.8 Safety Analyses 
All safety and tolerability endpoints will be described by number, proportion, and the 
associated 95% CI for proportions. Adverse event incidence tables will be presented by 
system organ class (SOC; sorted by internationally agreed order), high-level group term 
(HLGT), high-level term (HLT), and preferred term (PT) sorted in alphabetical order with 
the number (n) and percentage of participants experiencing an AE. Participants with more 
than 1 AE will be counted only once. The denominator for computation of percentages will 
be the safety set. 


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8.7.8.1 Adverse Events 
A treatment-emergent AE is an event that has onset date (or increase in severity) during the 
on-treatment observation period.  
The most frequent AEs will be defined as PTs that are experienced by at least 5% of the 
participants in any of the treatment arms. 
All AEs will be coded using the most recent version of the MedDRA in-use by the sponsor 
at the time of database lock. 
8.7.8.2 Hypoglycemia Events 
Hypoglycemia events will be summarized similarly to the treatment-emergent AEs for 
on-treatment observation periods based on the safety set. In addition, hypoglycemia events 
will be counted with multiple episodes per participant, if available, and the event rate per 
person-years will be reported overall and by level. 
8.8 Data Quality Assurance 
• All participant data relating to the study will be recorded on printed case report forms 
(CRFs) or eCRFs 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 a set of CRF Completion 
Guidelines. 
• The investigator must permit study-related monitoring, audits, IRB 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. 


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• 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 signing 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. 
8.8.1 Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees 
to maintain adequate case histories for the participants treated as part of the research under 
this protocol. The investigator agrees to maintain accurate eCRFs and source 
documentation as part of the case histories. These source documents may include a 
participant’s eDiary, laboratory reports (Section 13.8). 
PPD will supply access to the eCRF, which will be limited to personnel directly 
participating in the study, and all eCRFs should be completed in English. 
All eCRF information must be completed. If an item is not available or is not applicable, 
this fact should be indicated per the guidelines for completion. Blank spaces should not be 
present unless otherwise directed. 
Investigative site personnel will enter participant data into Medidata Rave. The analysis 
data sets will be a combination of these data and data from other sources (eg, laboratory 
data, CGM device, PRO). 
Clinical data management will be performed in accordance with applicable PPD standards 
and data cleaning procedures to ensure the integrity of the data (eg, removing errors and 
inconsistencies in the data). Adverse events and concomitant medication terms will be 
coded using MedDRA and WHODrug, respectively. After database lock, each study site 
will receive their site-specific eCRF data as entered into Medidata Rave for the study, 


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including full discrepancy and audit history. Additionally, a copy of all data from the study 
will be created and sent to the sponsor for storage. In all cases, participant initials will not 
be collected or transmitted to the sponsor. 


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 Ethics 
9.1 Institutional Review Board 
Federal regulations and International Council for Harmonisation (ICH) guidelines require 
IRB approval before the involvement of human participants in research studies. Before 
study onset, any information related to this study or provided to the participant (eg, the 
protocol, informed consent, advertisements for recruitment of study participants, and any 
other written information) must be approved by the IRB. Documentation of all IRB 
approvals and IRB compliance with ICH harmonised tripartite guideline E6(R1): Good 
Clinical Practice (GCP) will be maintained by the site and will be available for review by 
the sponsor or its designee. 
All IRB approvals should be signed by the IRB chairman or designee and must identify the 
IRB name and address and the clinical protocol by title or protocol number or both, with 
the approval date, if a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status 
of the study at intervals not exceeding 1 year or otherwise specified by the IRB. The 
investigator must promptly supply the sponsor or its designee, the IRB, and the institution, 
where applicable, with written reports on any changes significantly affecting the conduct 
of the study or increasing the risk to participants. 
9.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki, ICH GCP, and all applicable regulations. 
9.3 Participant Information and Consent 
A written informed consent in compliance with US Title 21 Code of Federal Regulations 
(CFR) Part 50 shall be obtained from each participant before entering the study or 
performing any unusual or nonroutine procedure that involves risk to the participant. An 
informed consent template may be provided by the sponsor to investigative sites. If any 
institution-specific modifications to study-related procedures are proposed or made by the 
site, the consent should be reviewed by the sponsor or its designee or both before IRB 


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submission. Once reviewed, the consent will be submitted by the investigator to their IRB 
for review and approval before the start of the study. If the ICF is revised during the course 
of the study, all active participants must sign the revised form. 
Before recruitment and enrollment, each prospective participant will be given a full 
explanation of the study and be allowed to read the approved ICF. Once the investigator is 
assured that the participant understands the implications of enrolling in the study, the 
participant will be asked to give consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed 
original form to the participant. 


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 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of 
the study but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be reported 
to the IRB but will not result in protocol amendments. 
10.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in 
a manner designed to maintain participant confidentiality. All records will be kept in a 
secure storage area with limited access. Clinical information will not be released without 
the written permission of the participant, except as necessary for monitoring and auditing 
by the sponsor, its designee, the FDA, or the IRB. 
The investigator and all employees and coworkers involved with this study may not 
disclose or use for any purpose other than performance of the study any data, record, or 
other unpublished confidential information disclosed to those individuals for the purpose 
of the study. Written agreement from the sponsor or its designee must be obtained before 
the disclosure of any said confidential information to other parties. 
10.2 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 
these data by any unauthorized third party. 


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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. 
This CGM study will attempt to represent a diverse set of US people with T2DM as 
advised by the FDA. These people represent a growing proportion of the US population, 
are historically under-represented in clinical studies, and are disproportionately affected by 
T2DM. For example, non-Hispanic Black, Hispanic, and American Indian/Alaska native 
adults are twice as likely to have diagnosed diabetes as non-Hispanic White adults. 
• 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 that would make 
the participant identifiable will not be transferred to the sponsor. 
• The participant must be informed that their 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. 
• The participant must be informed that their medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the 
following steps necessary for the development of the investigational product, including 
to support negotiations with payers and the publication of results. 
Protection of Data Related to Professionals Involved in the Study 
• Personal data (eg, contact details, affiliation 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 member of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 


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• Personal data can be processed for other studies and projects. Objection to processing 
can be made at any time by contacting the Sanofi Data Protection Officer (link 
available at Sanofi.com). 
• In cases of refusal to process personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any future 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 if the professionals are 
listed on a regulatory agency disqualification list. 
• Personal data can be communicated to the following recipients: 
o Personnel within Sanofi or partners or service providers involved in the study. 
o 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 to 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 the following: 
o The standard contractual clauses of the European Commission for transfers to our 
partners and service providers. 
o Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals are able to lodge a complaint with Sanofi leading Supervisory Authority, 
the “Commission Nationale de l’Informatique et des Libertés” (CNIL), or any 
competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to 30 years, unless 
further retention is required by applicable regulations. 


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• 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 pharmaceutical company 
members of the Transcelerate project. This sharing allows investigators to keep their 
data up-to-date once, for access by all 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 access to and 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). 
10.3 Financial Disclosure and Obligations 
Investigators and sub-investigators are required to provide financial disclosure information 
to allow the sponsor to submit the complete and accurate certification or disclosure 
statements required under 21 CFR 54. In addition, the investigator must provide to the 
sponsor a commitment to promptly update this information if any relevant changes occur 
during the course of the investigation and for 1 year following completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of 
any medical condition that may be detected during the screening process. In addition, in 
the absence of specific arrangements, neither the sponsor nor PPD is financially 
responsible for further treatment of the participant’s disease. 
10.4 Investigator Documentation 
Before beginning the study, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR by providing all essential documents, including but not 
limited to the following: 


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• IRB approval. 
• Original investigator-signed agreement page of the protocol. 
• Curriculum vitae for the investigator and each sub-investigator. 
• Financial disclosure information to allow the sponsor to submit complete and accurate 
certification or disclosure statements required under 21 CFR 54. In addition, 
investigators must provide to the sponsor a commitment to promptly update this 
information if any relevant changes occur during the course of the investigation and for 
1 year after the completion of the study. 
• IRB-approved informed consent, samples of site advertisements for recruitment for this 
study, and any other written information regarding this study that is to be provided to 
the participant. 
• Signed Clinical Study Agreement. 
10.5 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of ICH 
E6(R2) and all applicable guidelines and regulations. The investigator will conduct all 
aspects of this study in accordance with all national, state, and local laws or regulations. 
Study information from this protocol will be posted on publicly available clinical study 
registers before enrollment of participants begins. 
10.6 Adverse Events and Study Report Requirements 
The investigator agrees to submit reports of SAEs to the sponsor and/or the IRB according 
to the timeline and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the study site IRB as appropriate. 
10.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB with a summary of the 
study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 


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 Study Management 
11.1 Monitoring 
11.1.1 External Data Monitoring Committee 
No data monitoring committee is planned for this study. 
11.1.2 Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the 
study closely. In doing so, the monitor will visit the investigator and study site at periodic 
intervals, in addition to maintaining necessary phone and letter contact. The monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and personnel. 
The medical monitor and sponsor will hold monthly meetings to review AEs noted during 
the month, unless an SAE is noted and reported as described in Section 6.3.5.5. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
11.1.3 Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB review, and regulatory inspections by providing direct access to all study 
records. In the event of an audit, the investigator agrees to allow the sponsor, 
representatives of the sponsor, or a regulatory agency access to all study records. 
The investigator should promptly notify the sponsor and PPD of any audits scheduled by 
any regulatory authorities and promptly forward copies of any audit reports received to the 
sponsor. 


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11.2 Management of Protocol Amendments and Deviations 
11.2.1 Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent 
immediate hazard to the participants, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB for approval before participants can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the participant’s source 
documentation any deviation from the approved protocol. The investigator may implement 
a deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
participants without prior IRB approval. As soon as possible after such an occurrence, the 
implemented deviation or change, the reasons for it, and any proposed protocol 
amendments should be submitted to the IRB for review and approval, to the sponsor for 
agreement, and to the regulatory authorities, if required. 
A deviation from the protocol is an unintended or unanticipated departure from the 
procedures or processes approved by the sponsor and the IRB and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by 
the participant or investigator that results in a significant additional risk to the participant. 
Significant deviations can include nonadherence to inclusion or exclusion criteria, 
enrollment of the participant without prior sponsor approval, or nonadherence to FDA 
regulations or ICH GCP guidelines and will lead to the participant being withdrawn from 
the study (Section 4.4). 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB should be notified of all protocol deviations in a timely manner. 
11.3 Study Termination 
Although Sanofi has every intention of completing the study, Sanofi reserves the right to 
discontinue the study at any time for clinical or administrative reasons. 


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The end of the study is defined as the date of the last visit of the last participant in the 
study. 
11.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study report (CSR) is prepared and provided to the regulatory agencies as required 
by the applicable regulatory requirements. The sponsor will also ensure that the CSRs in 
marketing applications meet the standards of the ICH harmonised tripartite guideline 
E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for approval of the CSR. The investigator will be provided reasonable access to 
statistical tables, figures, and relevant reports and will have the opportunity to review the 
complete study results. 
Upon completion of the CSR, the sponsor will provide the investigator with the full 
summary of the study results. The investigator is encouraged to share the summary results 
with the study participants, as appropriate. The study results will be posted on publicly 
available clinical study registers. 
11.5 Records Retention 
Essential documents should be retained for 25 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 25 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period; however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. The sponsor is responsible for 
informing the investigator/institution as to when these documents no longer need to be 
retained. 


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11.6 Publication Policy, Disclosure, and Clinical Study Registration 
11.6.1 Publication Policy and Disclosure 
• 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 between the sponsor and the 
investigator and in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6.2 Clinical Study Registration 
In order to ensure that information regarding clinical studies reaches the public in a timely 
manner and to comply with applicable laws, regulations, and guidance, the sponsor (or its 
representative) will register interventional clinical studies it sponsors globally on 
ClinicalTrials.gov or other publicly accessible registers before the start of the study. 
11.6.3 Clinical Study Results Disclosure 
Study Participants 
Sanofi shares information about clinical studies and results on publicly accessible 
websites, based on company commitments, international and local legal and regulatory 
requirements, and other clinical study disclosure commitments established by 
pharmaceutical industry associations. These websites include clinicaltrials.gov, European 
Union (EU) clinicaltrialregister (eu.ctr), and sanofi.com, as well as some national 
registries. 


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In addition, results from clinical studies in patients are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance, and 
intellectual property. For those journals that request sharing of the analyzable data sets that 
are reported in the publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available by request at 
clinicalstudydatarequest.com. While making information available we continue to protect 
the privacy of participants in our clinical studies. Details on data sharing criteria and the 
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 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.” 


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adherence: systematic review and meta-analysis. Curr Med Res Opin. 2015;31(1):145-60. 
Critchley JA, Carey IM, Harris T, et al. Variability in glycated hemoglobin and risk of poor 
outcomes among people with type 2 diabetes in a large primary care cohort study. Diabetes 
Care. 2019;42(12):2237-46. 
Danne T, Nimri R, Battelino T, et al. International consensus on use of continuous glucose 
monitoring. Diabetes Care. 2017; 40(12):1631-40. 
Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 
diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the 
European Association for the Study of Diabetes (EASD). Diabetes Care. 
2018;41(12):2669-2701. 


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Davies MJ, Russell-Jones D, Barber TM, et al. Glycaemic benefit of iGlarLixi in 
insulin-naïve type 2 diabetes patients with high HbA1c or those with inadequate glycaemic 
control on two oral antihyperglycaemic drugs in the LixiLan-O randomized trial. Diabetes 
Obes Metab. 2019;21(8):1967-72. 
HEDIS Comprehensive Diabetes Care; 2021 [cited 2021 May 03] [11 screens]. Available 
from: https://www.ncqa.org/hedis/measures/comprehensive-diabetes-care/. 
Jendle J, Testa MA, Martin M, et al. Continuous glucose monitoring in patients with type 2 
diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination 
with prandial insulin lispro: an AWARD-4 substudy. Diabetes Obes Metab. 
2016;18(10):999-1005. 
Johnson EL, Kayne DM. Implementation of diabetes technologies in primary care: 
challenges and rewards. Clin Diabetes. 2020;38(5):495-500. 
Rosenstock J, Aronson R, Grunberger G, 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 controlled on oral agents: the LixiLan-O 
randomized trial. Diabetes Care. 2016; 39(11):2026-35. 
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. 
SOLIQUA™ 100/33 (insulin glargine and lixisenatide injection) [package insert]. 
Sanofi-aventis U.S. LLC. A SANOFI COMPANY. Bridgewater (NJ); 2019 [cited 
2021 Feb 12] [41 screens]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208673s007lbl.pdf. 
Stone MA, Charpentier G, Doggen K, et al. Quality of care of people with type 2 diabetes 
in eight European countries: findings from the Guideline Adherence to Enhance Care 
(GUIDANCE) study. Diabetes Care. 2013;36(9):2628-38. 
Vigersky RA, McMahon C. The relationship of hemoglobin A1c to time-in-range in 
patients with diabetes. Diabetes Technol Ther. 2019;21(2):81-85. 










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while minimizing the risk of hypoglycemia and hyperglycemia. The duration of the titration period and number of phone contacts to safely meet the study goals 
will also be at the discretion of the investigator. 
c Participants will have the choice to have Visits 2, 5, and 6 performed at the study site or at home. This choice is to be determined at the screening visit. Participants 
who opt for site visits should be encouraged not to change to home visits during the study period. However, if this is unavoidable, the home health provider and 
the sponsor-approved courier company for IMP shipment will need at least 72 hours’ notice from the investigator to arrange a home visit and DTP IMP supply, if 
required. 
d Participants on weekly GLP-1 RA should administer their last dose 7 (± 2) days before the first dose of Soliqua 100/33, whereas the last dose of daily DPP-4i and 
daily GLP-1 RA (oral or injectable) should be administered on the morning of Day –1, the day before the first dose of Soliqua 100/33. 
e It is the first day of Soliqua 100/33 administration and includes a phone contact to ALL participants to ensure that all administration procedures were successfully 
executed and to answer any questions. The first day of Soliqua 100/33 administration (ie, Visit 3.2, Day 0) for participants on weekly GLP-1 RA will depend on 
their administration schedule and may not be the day immediately following Visit 3.1. Soliqua 100/33 administration for these participants should be 7 (± 2) days 
after their last weekly GLP-1 RA dose. A phone contact should be made to participants on weekly GLP-1 RA on the day before Soliqua 100/33 initiation, to 
remind them of the next morning’s injection and to provide instructions for SoloStar pen use. The participants will provide their concomitant medication details to 
the site personnel over the phone. 
f Doses of SU should be down-titrated by 50% when Soliqua 100/33 is started on Day 0. 
g Weekly phone contacts for dose adjustments will be continued at the investigator’s discretion until the desired fasting SMPG value is achieved. 
h If the desired fasting SMPG value is not achieved in the first 8 weeks of treatment; the investigator has the option to continue weekly dose titration phone contacts for 
an additional 4 weeks (until Week 12) for the purpose of achieving glycemic targets. 
i At the end of the study, participants should discuss with the investigator, in collaboration with their HCP, whether to continue on the Soliqua 100/33 treatment 
regimen or transition to an alternate antihyperglycemic therapy. 
j An unscheduled visit can be planned anytime during the treatment period if IMP resupply is required. This can be a site visit or via phone contact with DTP IMP 
delivery. If DTP Soliqua 100/33 supply is required, the sponsor-approved courier company will need at least 72 hours’ notice to collect Soliqua 100/33 treatment 
kits from a study site. 
k Visit 2 will be performed at Day –15 for ALL participants, including those on weekly GLP-1 RA, who will administer their last dose 7 (± 2) days before the first dose 
of Soliqua 100/33; those taking daily SU (dose will be down-titrated by 50% on the morning of Soliqua 100/33 initiation); and those taking daily DPP-4i, and 
daily GLP-1 RA (oral or injectable; their last dose will be administered on the morning of Day –1, the day before the first dose of Soliqua 100/33). 
l Body weight and height will be recorded during the screening period for the calculation of BMI (metric: BMI = weight (kg)/height [m2]) and only body weight will be 
recorded during the baseline and at the end of the treatment period. 
m Participants are required to measure fasting SMPG values before breakfast at least 3 to 4 times per week throughout the study period (to inform each dose 
adjustment) and record the results in the eDiary. During the titration period, fasting SMPG should be performed on each of the 3 to 4 days before each dose 
adjustment. 
n HbA1c will be measured during the screening and run-in periods, and at Visit 3.1 (before administration of the meal) at the central laboratory, to determine study 
eligibility, and at the end of the 16-week treatment period (Visit 7), to determine change in glycemic control. 
o Blinded CGM will be performed for 14 continuous days. The baseline CGM measure will be captured before discontinuing the daily (oral or injectable) or weekly 
GLP-1 RA, DPP-4i, or down-titration of SU by 50%, and before initiation of Soliqua 100/33 treatment. During the run-in period, CGM device reinsertion will be 
allowed for participants who do not meet the equivalent of at least 8 days of evaluable CGM data (not necessarily consecutive) over a 14-day period as a result of 
premature sensor failure (eg, days of CGM device wear × % time CGM device active < 8; Section 6.2.1). During the end of the treatment period, CGM device 
reinsertion will also be allowed for participants who do not meet the equivalent of at least 8 days of evaluable CGM data (not necessarily consecutive) over a 
14-day period as a result of premature sensor failure (eg, days of CGM device wear × % time CGM device active < 8), if data can be captured during the 14-day 
end-of-treatment window (Section 6.2.1). 


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p The MMTT includes a standardized meal (ie, Boost Very High Calorie) that contains approximately 530 kcal and is composed of 19% carbohydrates, 44% protein, 
and 33% fat. The composition and the quantity of the standardized meal must be identical throughout the study period. Baseline MMTT is to be performed before 
discontinuation of daily (oral or injectable) or weekly GLP-1 RA, DPP-4i, or down-titration of SU medications. Participants on weekly GLP-1 RA should have 
their baseline MMTT conducted within 7 (± 3) days after their last dose. During the baseline (Visit 3.1), blood samples will be collected at the following time 
points: premeal (30 min) and just before administration of OADs or GLP-1 RA (oral or injectable) (baseline); time 0 (just before meal administration); 10 min; 
20 min; and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal for plasma glucose, C-peptide, and insulin levels. At Visit 3.1, participants on OADs or an oral or 
injectable GLP-1 RA will be required to take their dose after blood sample for FPG and HbA1c is collected and 30 minutes before administration of the meal 
during the MMTT (during which measures for both β-cell function and PPG analyses will be captured). Soliqua 100/33 should be administered 30 minutes before 
administration of the meal during the MMTT at Visit 7 (during which only measures for PPG analyses will be captured). At the end of the treatment period (Visit 
7), blood samples will be collected for plasma glucose levels, as follows: premeal (30 min) and just before administration of Soliqua 100/33; and time 0 (just 
before meal administration); 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal. These values will be used for PPG analyses with the goal of deriving reduction in 
maximum glucose exposure in the 4-hour period after the breakfast meal after Soliqua 100/33 administration at Week 16 compared with baseline.  
q At baseline, the CGM device will be removed and the data will be downloaded on Day –1 at their next site visit (ie, Visit 3.1), after collection of C-peptide, insulin, 
and plasma glucose data from the MMTT. Downloaded CGM data will be reviewed by the investigator to determine participants’ study eligibility. At the end of 
the treatment period, the CGM device will be removed and the data will be downloaded on the fifteenth day after CGM placement (ie, Visit 7; after collection of 
only plasma glucose data from the MMTT). Downloaded CGM data will be verified by the investigator at the site to determine participants’ study completion. 
r Participants with less than equivalent of 8 days of evaluable CGM data (not necessarily consecutive) of a 14-day period (eg, days of CGM device wear × % time 
CGM device active < 8) during the run-in period will be considered as screen failures. 
s Participants will undergo the MMTT to assess maximum PPG exposure in the 4-hour period after the breakfast meal with biomarkers of β-cell function (plasma 
glucose, insulin, and C-peptide) measured at Visit 3.1 (ie, site visit during the baseline period), whereas only plasma glucose will be assessed at Visit 7 (ie, end of 
the treatment period). 
t Participants should discontinue GLP-1 RA, DPP-4i, or down-titrate SU medications after all baseline assessments have been completed. SU doses should be 
down-titrated by 50% when starting Soliqua 100/33, whereas the last dose of daily DPP-4i and daily GLP-1 RA (oral or injectable) should be administered on the 
morning of Day –1, the day before the first dose of Soliqua 100/33. Participants on weekly GLP-1 RA should administer their last dose 7 (± 2) days before the 
first dose of Soliqua 100/33. 
u Soliqua pen instructions will be given to all participants at Visit 3.1. A phone contact should be made to participants on weekly GLP-1 RA on the day before 
Soliqua 100/33 initiation, to remind them of the next morning’s injection and to provide instructions for SoloStar pen use. 
v For the scheduled site visits, participants are required to arrive fasting without administering the Soliqua 100/33 injection. Fasting is defined as no food intake in the 
8 hours before blood sampling, except water. 
w Baseline DM-SAT should be completed before discontinuation or down-titration of baseline therapies. The questionnaire should be completed at the start of the visit 
before any other study tests or procedures are performed or Soliqua 100/33 is administered. 
x The following hypoglycemia categories of interest will be presented: overall hypoglycemia and confirmed hypoglycemia (ADA Levels 1, 2, and 3; Section 6.3.2). 
y Urinalysis: pH, glucose, ketones, leukocytes, blood/Hb, protein. 
z Only for women of childbearing potential; urine pregnancy test. 


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13.2 Appendix: Diabetes Medication Satisfaction Tool 
(For information only) 


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13.3 Appendix: Participant eDiary Information 
Participants will be provided with an eDiary to use during the study. Participants will be 
instructed on how to complete the eDiary. 
eDiary completion will occur from the screening period (Visit 1) through the follow-up 
period (Visit 8). The participant is expected to return for site visits with the eDiary 
completed. The eDiary will be reviewed by the study site staff by viewing the data 
transmitted from eDiaries into the database. 
The following information is to be recorded in the eDiary: 
• Each dose taken (date/time and actual dose). The participant will document any 
temporary treatment discontinuations. 
• Fasting SMPG values before breakfast at least 3 to 4 times per week throughout the study 
period (to inform each dose adjustment). 
• Symptoms of hypoglycemia: Participants will be trained on the hypoglycemia eDiary 
completion requirements and the need to contact the investigator as soon as possible in 
case of a significant hypoglycemia occurrence, so that appropriate actions can be taken 
(eg, intolerance to the study drug injection). 
• If assistance to resolve the hypoglycemia event was required out of necessity or 
convenience. 


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13.4 Appendix: Clinical Laboratory Tests 
• The tests detailed in Table 13-2 will be performed by the central laboratory, except urine 
pregnancy tests, which will be performed at sites, using urine pregnancy test kits that are 
provided by the sponsor. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 4 of the protocol. 
• Additional tests may be performed at a local or central laboratory at any time during the 
study as determined necessary by the investigator or required by local regulations. If they 
are used to evaluate an AE (diagnostic, follow-up, outcome), the results must be entered 
into the eCRF. 


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Table 13-2 
Protocol-Required Safety Laboratory Assessments 
Laboratory Assessmentsa 
Parameter 
Hematology 
Erythrocytes 
Platelet count 
Leukocytes 
Hb 
Hematocrit 
Clinical chemistry 
AST 
ALT 
Alkaline phosphatase, total bilirubin (if >ULN, 
then the direct and indirect subfractions must be 
measured) 
Amylase 
Lipase 
Creatinine 
Uric acid 
Sodium 
Potassium 
Urinalysis 
pH 
Glucose 
Ketones 
Leukocytes 
Blood/Hb 
Protein 
Calcitonin 
Calcitonin 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; eCRF, electronic case report 
form; Hb, hemoglobin; ULN, upper limit of normal. 
a All study-required laboratory assessments will be performed by a central laboratory except urine pregnancy 
tests, which will be performed locally; the results of each test must be entered into the eCRF. 


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13.5 Appendix: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
13.5.1 Definition of AEs 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
whether or not considered related to the study drug. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated). 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (eg, hematology, clinical chemistry, urinalysis) or 
other safety assessments (eg, electrocardiogram [ECG], radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (ie, not related to 
progression of underlying disease), eg, that meet the following criteria: 
o Are symptomatic.  
o Require either corrective treatment or consultation. 
o Lead to IMP discontinuation or modification of dosing. 
o Fulfill a seriousness criterion. 
o Meet the definition of 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 drug 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 drug or 
a concomitant medication. 


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• “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 AEs or SAEs 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 that 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. 
13.5.2 Definition of SAEs 
An SAE is defined as any AE that, at any dose, meets one of the following criteria: 
• Results in death 
• Is life-threatening 
o 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 that hypothetically might have caused death if it were more severe. 


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• Requires inpatient hospitalization or prolongation of existing hospitalization 
o In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered serious. 
o Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
• Results in persistent or significant disability/incapacity 
o The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
o 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), that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
• Is a congenital anomaly/birth defect 
• Other situations: 
o 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. 


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13.5.3 Recording and Follow-up of AEs and/or SAEs 
AE and SAE Recording 
• When an AE/SAE occurs, the investigator is responsible for reviewing 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 proactively send photocopies of the 
participant’s medical records, except an autopsy report in the event of death, 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 one of the following categories: 
• Mild: An event that is easily tolerated by the participant, causes minimal discomfort, and 
does not interfere with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; both AEs and SAEs can be assessed as severe. 


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An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
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 drug and each 
occurrence of an AE/SAE/AESI. 
• 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 drug administration will 
be considered and investigated. 
• The investigator will also consult the prescribing information, for marketed products, in 
their assessment. 
• For each AE/SAE/AESI, the investigator must document in the medical notes that they 
have reviewed the AEs/SAEs/AESIs and have provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important 
that the investigator makes an assessment of causality for every event before initial 
transmission of the SAE data to the sponsor. 
• The investigator may change their 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. 


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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 AEs/SAEs/AESIs as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide the sponsor 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 or designee within 
24 hours of receipt of the information. 
13.5.4 Reporting of SAEs 
SAE Reporting to the Sponsor via an EDC Tool 
• The primary mechanism for reporting an SAE to the sponsor’s representative (ie, PPD 
Pharmacovigilance) will be the EDC tool.  
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see the following 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 EDC 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 EDC tool has been taken off-line, then the site can 


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report this information on a paper SAE form (see the following section) or to the 
sponsor’s representative by phone. 
• Contacts for SAE reporting can be found in the Investigator’s Study 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 the unlikely event of EDC downtime, the paper forms must be used for reporting of 
events that require expedited reporting (SAEs/AESIs). Paper forms should be faxed to 
PPD Pharmacovigilance at 1-888-488-9697. 
• Initial notification via fax 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’s Study File.


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13.6 Appendix: Liver Safety 
 
Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; CMV, cytomegalovirus; 
CPK, creatine phosphokinase; CRF, case report form; DNA, deoxyribonucleic acid; EBV, Epstein-Barr 
virus; HAV, hepatitis A virus; HBc, hepatitis B core; HBV, hepatitis B virus; HCV, hepatitis C virus; 


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HEV, hepatitis E virus; IgM, immunoglobulin M; IMP, investigational medicinal product; 
INR, international normalized ratio; LFT, liver function test; LKM, liver-kidney microsome; 
PT, prothrombin time; RNA, ribonucleic acid; ULN, upper limit of normal. 
*If unable to retest in 72 hours, use original laboratory results to decide on further 
reporting/monitoring/discontinuation. 
Notes: 
“Baseline” refers to ALT value at the baseline visit or, if the baseline value is unavailable, to the last ALT value 
before the baseline visit. The algorithm does not apply to instances of an increase in ALT during screening. 
Section 13.5 provides guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if the baseline value is >ULN.


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13.7 Appendix: Contraceptive and Barrier Guidance 
DEFINITIONS 
Woman of Childbearing Potential 
• A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (as follows) unless permanently sterile (as follows). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
o 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). 
o 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. 
Permanent sterilization methods include the following: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to a medical cause other than these 
procedures (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied in determining study eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first administration of study drug, additional evaluation should be 
considered. 


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Woman of Non-childbearing Potential 
Women in the following categories are considered WONCBP: 
1. Any female with permanent infertility due to one of the following: 
o Documented hysterectomy. 
o Documented bilateral salpingectomy. 
o Documented bilateral oophorectomy. 
o For individuals with permanent infertility due to a medical cause other than these 
procedures (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied in determining study eligibility. 
2. Postmenopausal female. 
A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high FSH level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or HRT. 
• Females on HRT and whose menopausal status is in doubt must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE THE 
FOLLOWING: 
Highly effective methodsb that have low user dependency 
Failure rate of <1% per year when used consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationc 
• Intrauterine device (IUD) 


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE THE 
FOLLOWING: 
• Intrauterine hormone-releasing system (IUS)c 
• Bilateral tubal occlusion 
• Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used. 
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. 
Highly effective methodsb that are user dependent 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationc 
• Oral 
• Intravaginal 
• Transdermal 
• Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
• Oral 
• Injectable 
Sexual Abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the participant. 


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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE THE 
FOLLOWING: 
a Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure 
rates differ from those when used consistently and correctly. 
c Male condoms must be used in addition to hormonal contraception. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and the lactational amenorrhea method (LAM) are 
not acceptable methods of contraception for this study. Male condom and female condom 
should not be used together (due to risk of failure from friction). 
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 Soliqua 100/33. 
• 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 or designee within 24 hours of learning of the partner’s 
pregnancy. The female partner will also be followed up 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 after 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 or designee within 
24 hours of learning of a participant’s pregnancy. 


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• The participant will be followed up 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. 
• Although pregnancy itself is not considered to be an AE or SAE, 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 poststudy pregnancy-related SAE considered reasonably related to the 
investigational product by the investigator will be reported to the sponsor as described in 
Section 6.3.5.5. Although the investigator is not obligated to actively seek this 
information for former study participants, they may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will be 
discontinued from study drug treatment.


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13.8 Appendix: 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 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. In addition, 
current medical records must be available. 
DEFINITION OF SOURCE DATA 
Source Data to Be Found in the Participant’s File 
Evaluations that are reported in the eCRF must be supported by appropriately signed, related, 
and identified source documentation that may include, but is not limited to, the following: 
• Agreement and signature of ICFs (Section 9.3) with the study identification and any 
privacy forms. 
• Study identification (name). 
• Treatment kit number, dates of administration, and doses of Soliqua 100/33 administered. 
• Medical, surgical, and diabetes history, including information on the following: 
o Demography, inclusion, and exclusion criteria. 
o History of alcohol consumption and smoking. 
o Comorbidities. 
o Last participation in a clinical study. 
o Contraception method for WOCBP. 
o Previous and concomitant medications, including treatment for diabetes mellitus. 
o Dates and times of visits and assessments, including examination results. 


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o Vital signs, height, body weight, and clinical laboratory reports. 
o AEs and follow-up. 
• In case of an SAE, the site should file in the source documents, at least, copies of the 
hospitalization reports and any relevant examination reports documenting follow-up of 
the SAE. 
• Date of premature study discontinuation (if any) and reason. 
Source documentation may be found in the following: 
• Participant’s identity (identification card or other verification document of participant 
identity). 
• Medical history. 
• Nursing notes. 
• Physician’s notes. 
• Participant’s eDiary. 
• Glucometer. 
Source Data Verification Requirements for Screen Failures 
For screen failure participants, the following source data must be verified: participant’s 
identification details, the informed consent signed by the participant, the study identification 
(name), dates of study visits, and the main reasons for screen failure. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.


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13.9 Appendix: Eligibility and Analysis Criteria for CGM Measurements 
Eligibility Criteria 
• Participants with less than equivalent of 8 days of evaluable CGM data (not necessarily 
consecutive) of a 14-day period (eg, days of CGM device wear × % time CGM device 
active < 8) during the run-in period will be considered as screen failures (Section 6.2.1). 
• During the run-in period, CGM device reinsertion will be allowed for participants who do 
not meet the equivalent of at least 8 days of evaluable CGM data (not necessarily 
consecutive) over a 14-day period as a result of premature sensor failure (eg, days of 
CGM device wear × % time CGM device active < 8; Table 13-3 and Figure 13–1). 
• During the end of the treatment period, CGM device reinsertion will also be allowed for 
participants who do not meet the equivalent of at least 8 days of evaluable CGM data (not 
necessarily consecutive) over a 14-day period as a result of premature sensor failure 
(eg, days of CGM device wear × % time CGM device active < 8), if data can be captured 
during the 14-day end-of-treatment window (Table 13-3 and Figure 13–1). 
• For participants who discontinue study treatment prematurely, the visit window can be 
extended by 14 days to collect the CGM data before they permanently discontinue the 
treatment. 
 


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Table 13-3 
Criteria for CGM Device Reinsertion 
No. of Days CGM Device 
Worna 
Time CGM Device 
Active (%)a 
Equivalent Days 
8 
100 
8.00 
9 
89 
8.01 
10 
80 
8.00 
11 
73 
8.01 
12 
67 
8.04 
13 
62 
8.01 
14 
57 
7.98 
Abbreviations: AGP, Ambulatory Glucose Profile; CGM, continuous glucose monitoring. 
Note: Any combination of number of days of CGM device worn and % time CGM device is active that results 
in fewer than 8 equivalent days (defined as ineligibility) of evaluable CGM data will require device reinsertion. 
a AGP report. 
Figure 13–1 Criteria for CGM Device Reinsertion 
 
Abbreviation: CGM, continuous glucose monitoring. 
Analysis Criteria 
• Endpoint data will be included in the analysis if at least 10 out of 14 days (not necessarily 
consecutive) have at least ≥80% of evaluable CGM data per 24-hour period during the 
run-in period as well as the end of the treatment period (ie, from Weeks 14 to 16). 

SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
 Sever< 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A 16-Week, Multicenter, Prospective, Open-Label, 
Single-Arm, Phase 4 Study to Evaluate the Effect of 
Soliqua™ 100/33 on the Percentage of Time in Range 
(TIR) from Continuous Glucose Monitoring (CGM) in 
Insulin-Naïve Patients With Very Uncontrolled Type 2 
Diabetes Mellitus 
Protocol number: 
LPS16990 
Compound number 
(INN/Trademark): 
HOE901/AVE0010 
Soliqua 100/33 
Study phase: 
Phase 4 
Short title: 
Soli-CGM 
Statistician: 
Statistical project leader: 
Date of issue: 
27-Apr-2023
Regulatory agency identifier number(s): 
Registry: 
ICTRP 
Enter Registry Name: 
LPS16990 
Total number of pages: 49 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
LIST OF FIGURES .......................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVES AND ENDPOINTS .................................................................................................... 7 
1.2.1 
Estimands ...................................................................................................................................... 10 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 12 
3 
ANALYSIS SETS ........................................................................................................................... 13 
4 
STATISTICAL ANALYSES ........................................................................................................... 14 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 14 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 15 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 16 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 16 
4.3.2 
Main analytical approach ............................................................................................................... 17 
4.3.3 
Sensitivity analyses ........................................................................................................................ 18 
4.3.4 
Supplementary analyses ................................................................................................................ 18 
4.3.5 
Subgroup analyses ........................................................................................................................ 18 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 19 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 19 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 19 
4.4.1.2 
Main analytical approach ............................................................................................................... 20 
4.4.2 
Supportive secondary endpoint(s) ................................................................................................. 20 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 21 
4.5.1 
Definition of endpoint(s) ................................................................................................................. 21 
4.5.2 
Main analytical approach ............................................................................................................... 24 
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4.6 
MULTIPLICITY ISSUES ................................................................................................................ 25 
4.7 
SAFETY ANALYSES ..................................................................................................................... 25 
4.7.1 
Extent of exposure ......................................................................................................................... 26 
4.7.1.1 
Overall exposure ............................................................................................................................ 27 
4.7.2 
Adverse events .............................................................................................................................. 27 
4.7.3 
Hypoglycemia events ..................................................................................................................... 30 
4.7.4 
Additional safety assessments ....................................................................................................... 33 
4.7.4.1 
Laboratory variables and vital signs............................................................................................... 33 
4.7.4.2 
Product complaints......................................................................................................................... 34 
4.8 
OTHER ANALYSES....................................................................................................................... 35 
4.8.1 
Descriptive Analyses ...................................................................................................................... 35 
4.8.2 
Biomarker analyses........................................................................................................................ 35 
4.9 
INTERIM ANALYSES .................................................................................................................... 35 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 36 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 36 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 37 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 37 
5.3.1 
Protocol deviations ......................................................................................................................... 37 
5.3.2 
Demographics and baseline characteristics .................................................................................. 37 
5.3.3 
Medical or surgical history ............................................................................................................. 38 
5.3.4 
Disease characteristics at baseline ................................................................................................ 38 
5.3.5 
Prior and concomitant medication .................................................................................................. 39 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 39 
5.4.1 
Demographic formulas ................................................................................................................... 39 
5.4.2 
Disease characteristics formulas ................................................................................................... 39 
5.4.3 
Reference dates ............................................................................................................................. 39 
5.4.4 
Missing Data .................................................................................................................................. 40 
5.4.5 
Timepoint assessment ................................................................................................................... 40 
5.5 
APPENDIX 5 DEVIATIONS FROM PLANNED STUDY CONDUCT ............................................. 48 
6 
REFERENCES ............................................................................................................................... 49 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for main endpoints ........................................................................ 11 
Table 4 - Analysis Sets .................................................................................................................................. 13 
Table 5 - Sorting of AE tables ....................................................................................................................... 28 
Table 6 - Analyses of adverse events ........................................................................................................... 29 
Table 7 - Selections for AESIs ...................................................................................................................... 30 
Table 8 – Visit Windows for non-CGM data ...................................................................................................... 41 
Table 9 - Major statistical changes from approved version of protocol ......................................................... 48 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................... 7 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study LPS16990 is based on the protocol dated 
18 Aug 2021. This section summarizes major changes to the statistical analysis features in the 
SAP. There are no major changes to the statistical analysis features in this SAP. 
The first participant was enrolled on 27 January 2022. This SAP will be approved before database 
lock. 
Table 1 - Major changes in statistical analysis plan 
SAP 
Version 
Approval Date 
Changes 
Rationale 
1.0 
28-Apr-2023 
Not Applicable  
Original version 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 4, 16 week, prospective, multicenter, interventional, open-label, single-arm study 
in insulin-naïve participants with very uncontrolled type 2 diabetes mellitus (T2DM) using 
blinded continuous glucose monitoring (CGM). The primary endpoint will assess the change of 
time in range (70-180mg/dL) between baseline and week 16 as measured by CGM in participants 
initiated on Soliqua 100/33. Background GLP-1RA (oral or injectable) and DPP-4i therapies will 
be discontinued prior to Soliqua 100/33 administration and sulfonylureas will be down-titrated by 
50% when starting Soliqua 100/33. Continuous glucose monitoring measures will allow clinicians 
to frequently observe changes in glycemic control and variability including measures such as time 
in range (TIR), time below range (TBR) and time above range (TAR) with more granularity than 
the measure of HbA1c% alone. The Freestyle Libre Pro is a flash glucose monitoring device that 
collects glucose values every 15 minutes for up to 14 days. These values are charted into a single 
daily view, irrespective of the numbers of glucose values measured to provide a view of glycemic 
control and variability and assist clinicians for management of patients with diabetes. 
All eligible participants will undergo 14 days of blinded continuous CGM monitoring and a 
mixed-meal tolerance test (MMTT) during the run-in period while on background medications. 
Soliqua 100/33 will be initiated, and dose will be adjusted during the 12-week titration period, at 
the investigator’s discretion, until the desired fasting self-measured plasma glucose (SMPG) value 
(80-100 mg/dL) is achieved. 
In order to attain a target fasting SMPG value of 80 to 100 mg/dL dose of Soliqua 100/33 will be 
adjusted based upon the median SMPG value. If the lowest value from the previous 
3 measurements is from 80 to 100 mg/dL and the other 2 values are well above 100 mg/dL, 
further titration may be implemented at the investigator’s discretion. If the lowest value is 
<70 mg/dL and the other 2 values are near 100 mg/dL, the investigator may stop or temporarily 
reduce the dose if, in their judgment, further titration would be hazardous. Doses will be adjusted 
by 2 to 4 units weekly, or at the investigators discretion to achieve targets. At Week 14, 
participants will again be required to undergo 14 days of blinded continuous CGM monitoring and 
a MMTT (only to derive PPG measures) at week 16. The maximum study duration per participant 
will be 22 weeks. Three site visits, 3 site or home visits, and up to 13 phone contacts are 
scheduled. 
Should a participant not meet the CGM compliance criteria, reinsertion of the CGM device will be 
allowed. 
A detailed description of the assessments performed during each study period and at each visit is 
provided in below figure (Figure 1) 
 
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Figure 1 - Graphical study design 
 
Approximately 100 participants will be enrolled throughout 20 sites in the US. 
Oral Antidiabetic Drugs (OAD)and Glucagon-Like-Peptide 1 Receptor Agonists (GLP-1RA) 
All participants will be allowed to continue their background OADs (except DPP-4i and SU 
down-titration) at stable doses and administration timeframes throughout the study period, unless 
they must be stopped or modified for safety reasons. Any GLP-1RA use (oral or injectable) must 
also be discontinued prior to Soliqua 100/33 administration. 
The analyses of the study will be conducted after completion. 
1.2 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
 
 
 
• 
To demonstrate that in 
participants with T2DM failing 
to achieve glycemic control 
(HbA1c ≥9%-13%) on their 
current regimen of 2+ OADs 
with or without GLP-1RAs, 
introduction of Soliqua 100/33 
exhibits superiority in terms of 
time spent in range (70-180 
mg/dL) at week 16 compared 
with baseline, as measured by 
CGM 
• 
Change in the percentage of TIR (70-
180 mg/dL) from baseline to week 16 
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Objectives 
Endpoints 
Secondary 
 
 
 
Key Secondary Objective 
Key Secondary Endpoints 
 
• 
To evaluate the impact of 
Soliqua 100/33 on measures of 
glycemic control and variability 
in participants with T2DM 
• 
Change (%) from baseline to week 16 
in coefficient of variation (CV) 
• 
Change (mg/dL) from baseline to week 
16 in mean daily blood glucose 
• 
Change (mg/dL) from baseline to week 
16 in the maximum PPG exposure in 
the 4 hours after the breakfast meal 
(using MMTT data) 
• 
Change (%) from baseline to week 16 
in TAR (>180 mg/dL) 
 
Secondary Objective 
Secondary Endpoints 
 
• 
To evaluate the impact of 
Soliqua 100/33 on other 
measures of glycemic control 
and variability in participants 
with T2DM 
• 
Proportion (%) of participants achieving 
CV <36% 
• 
Change (%) from baseline to week 16 
in TIR (70-180 mg/dL) for specific time 
blocks (6 am-12 pm, 12 pm-6 pm, 6 pm 
12 am, 12 am-6 am, and 6 am – 12 
am) 
• 
Proportion (%) of participants achieving 
Glucose Management Indicator (GMI) 
<7% and <9% at week 16 
• 
Change from baseline to week 16 in 
the 4 hour PPG AUC0-4h after start of 
the breakfast meal, including 
associated Tmax  (using MMTT data) 
• 
Proportion (%) of participants at week 
16 who spend <15 minutes/day at a 
glucose level <54 mg/dL 
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Objectives 
Endpoints 
Tertiary/exploratory 
 
 
 
• 
To evaluate the impact of 
Soliqua 100/33 on additional 
measures of glycemic control 
and variability in participants 
with T2DM 
• 
Change (mg/dL) from baseline to week 
16 in mean of daily difference (MODD)  
• 
Change (%) from baseline to week 16 
in TAR (>250 mg/dL) 
• 
Change (%) from baseline to week 16 
in time below range (TBR); <70 mg/dL) 
• 
Correlation of change in the 
percentage of TIR (70-180 mg/dL) and 
change in patient reported outcome 
(PRO) from baseline to week 16 
• 
Correlation of percentage of TIR (70-
180 mg/dL) and HbA1c percentage 
achieved at week 16 
• 
Association of participants reaching 60 
units/day insulin glargine U100 and TIR 
>70% 
• 
Change in HbA1c percentage from 
baseline to week 16 
• 
Change in the percentage from 
baseline to week 16 for Time in Tight 
Range (TITR )(70-140 mg/dL) 
• 
Proportion of participants with TIR (70–
180 mg/dL) > 70% of each day at week 
16 
• 
Proportion of participants with ≥5% 
absolute improvement from baseline to 
week 16 in TIR (70–180 mg/dL) 
• 
Proportion of participants with ≥10% 
absolute improvement from baseline to 
week 16 in TIR (70–180 mg/dL) 
• 
Proportion of participants with 
improvement in HbA1c >0.5% points 
from baseline to week 16 without an 
increase in TBR (<54 mg/dL) of >0.5% 
• 
Proportion of participants with ≥10% 
absolute improvement from baseline to 
week 16 in TIR (70–180 mg/dL) without 
an increase in TBR (<54 mg/dL) of 
>0.5% 
• 
Proportion of participants with TIR (70–
180 mg/dL) > 70% per day and TBR 
(<70 mg/dL) < 4% per day at week 16 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives 
Endpoints 
 
PRO Objective 
PRO Endpoint 
 
• 
To assess participant-
perceived treatment impact on 
health-related quality of life 
(HRQoL) and treatment 
satisfaction 
• 
Change from baseline to week 16 in 
diabetes medication treatment 
satisfaction scores (total score and by 
subscales), using the DM-SAT 
questionnaire 
 
Safety Objective 
Safety Endpoints 
 
• 
To assess the safety and 
tolerability of Soliqua 100/33 
Safety evaluations will include evaluation of the 
following (for 16 weeks): 
• 
Overall hypoglycemia 
• 
Confirmed hypoglycemia 
o 
ADA Level 1: Measurable 
glucose concentration 
<70 mg/dL (3.9 mmol/L) but 
≥54 mg/dL (3.0 mmol/L) 
o 
ADA Level 2: Measurable 
glucose concentration 
<54 mg/dL (3.0 mmol/L) that 
needs immediate action 
o 
ADA Level 3: Severe event 
characterized by altered 
mental and/or physical 
functioning that requires 
assistance* from another 
person for recovery 
• 
Adverse events (AEs), serious adverse 
events (SAEs), and adverse events of 
special interest (AESIs) 
 
1.2.1 Estimands  
The primary estimand defined for main endpoints are summarized in Table 3. More details are 
provided in Section 4.
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Table 3 - Summary of primary estimand for main endpoints 
Endpoint Category 
(estimand) 
Estimands 
Endpoint 
Analysis Set 
Intercurrent event(s) handling 
strategy 
Analysis Set-level summary 
(Analysis and missing data handling) 
Primary objective: To demonstrate that in participants with T2DM failing to achieve glycemic control (HbA1c ≥9%-13%) on their current regimen of 2+ OADs with or without GLP-
1RAs, introduction of Soliqua 100/33 exhibits superiority in terms of time spent in range (70-180 mg/dL) at week 16 compared with baseline, as measured by CGM. 
Primary endpoint  
(treatment policy estimand) 
Mean change in percentage of 
TIR at week 16 from baseline 
Efficacy analysis set 
Treatment policy strategya. 
Mean and 95% (CI) of change in percentage of 
TIR at week 16 from baseline will be calculated for 
subjects who have CGM compliance at baseline 
and week 16. A one sample t-test will be applied to 
test the significance of changes. 
Key Secondary objective: To evaluate the impact of Soliqua 100/33 on measures of glycemic control and variability in participants with T2DM 
Key Secondary endpoint 
(treatment policy estimand) 
Mean percent changes of CV at 
week 16 from baseline 
Efficacy analysis set 
Treatment policy strategya 
Mean and 95% CI will be calculated for subjects 
who have CGM compliance at baseline and week 
16. A one sample t-test will be applied to test the 
significance of changes.  
 
Mean mg/dL change of mean 
daily blood glucose at week 16 
from baseline  
Efficacy analysis set 
Treatment policy strategya 
Mean and 95% CI will be calculated for subjects 
who have CGM compliance at baseline and week 
16. A one sample t-test will be applied to test the 
significance of changes. 
 
Mean mg/dL change in maximum 
PPG exposure in the 4-hour 
period after the breakfast meal at 
week 16 from baseline  
Enrolled analysis set 
Treatment policy strategya 
Mean and 95% CI will be calculated on an overall 
efficacy analysis set. A one sample t-test will be 
applied to test the significance of changes. 
 
Mean percent change in TAR 
>180 mg/dL at week 16 from 
baseline  
Efficacy analysis set 
Treatment policy strategya 
Mean and 95% CI will be calculated for subjects 
who have CGM compliance at baseline and week 
16. A one sample t-test will be applied to test the 
significance of changes. 
a The following intercurrent events for the primary estimand will be handled by the treatment policy strategy: initiation of rescue medication other than the study IMP and discontinuation of IMP 
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2 
SAMPLE SIZE DETERMINATION  
In LPS16990, a total of 100 participants will be enrolled in the study. Sufficient participants will 
be screened from 20 sites to include 100 participants, such that approximately 82 evaluable 
participants complete the study (anticipating that approximately 15% of participants discontinue 
the study before Week 16). 
The sample size is based on the primary objective to demonstrate the significant mean change 
(increase) in the percentage of TIR (70-180 mg/dL) from baseline to week 16 with sufficient 
power. A total sample size of 82 evaluable participants has 95% power to detect an absolute 
increase in TIR means of 10%, assuming a standard deviation (SD) of 25 for the change in TIR, 
with a two-sided type I error of 0.05. Anticipating a 15% loss to follow-up rate, 100 participants 
would need to be enrolled.  
Assumptions for Sample Size Determinations 
• Participants with an HbA1c ≥9% are in range 40% of the time or less (Batellino et al 
2019). 
• Per Vigersky and McMahon, every 10% increase in TIR corresponds to 0.8% HbA1c 
reduction (Vigersky and McMahon 2019). 
• Post hoc analyses from the LixiLan-O study in participants with an HbA1c of ≥9% 
produced an HbA1c reduction of 2.9% at 30 weeks (Davies et al 2019). Therefore, 0.8% 
HbA1c reduction (considered equal to 16% improvement in TIR) at week 16 seems 
reasonable. 
• Assumption for SD is 25. In the AWARD-4 study in participants with T2DM, the increase 
in TIR at Week 26 was 20% to 30%, and the SE was approximately 3.0 (corresponding to 
an SD of approximately 20)  
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3 
ANALYSIS SETS  
The following analysis sets for analyses are defined:  
Table 4 - Analysis Sets  
Analysis Set 
Description 
Screened 
All participants who signed the ICF. 
Enrolled  
All eligible participants who are dispensed Soliqua 100/33 and sign the ICF. 
Efficacy analysis set 
All enrolled participants who receive ≥1 dose of Soliqua 100/33 and have 
complianta CGM data at baseline.   
Safety set  
All enrolled participants who receive ≥1 dose of Soliqua 100/33. 
a. 
CGM compliance is defined as 1) at least 8 out of 14 days (not necessarily consecutive) have 100% of evaluable CGM 
data per 24-hour period (at least 8 days with 96 records minimum per day)  OR 2) at least 9 out of 14 days (not 
necessarily consecutive) have ≥89% of evaluable CGM data per 24-hour period (at least 9 days with 85 records minimum 
per day) OR 3) at least 10 out of 14 days (not necessarily consecutive) have at least ≥80% of evaluable CGM data per 24 
hour period (at least 10 days with 77 records minimum per day) 
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4 
STATISTICAL ANALYSES  
The database lock will be performed when all participants have completed their follow-up phase. 
Final analyses in the clinical study report will be based on all data collected up to this database 
lock. 
4.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), quartile ranges, median, minimum, and maximum. 
All mean, Q1, Q3 and median values will be formatted to one more decimal place than the 
measured value. SD values will be formatted to two more decimal places than the measured value. 
Minimum and maximum will be formatted to the same number of decimal places as the measured 
value. 
Unless otherwise specified below, all confidence intervals (CI) will be two-sided at the 95% 
confidence level and displayed to the same level of precision as the statistic they relate to. If an 
estimate or a CI is not estimable, it will be presented as ‘NE’. If neither an estimate, nor its CI are 
estimable, it will be presented as simply ‘NE’, not displaying ‘NE’ twice. 
The p-values will be two-sided and will be rounded to three decimal places. If a p-value is less 
than 0.001 it will be reported as ‘<0.001’. If a p-value is greater than 0.999 it will be reported as 
‘>0.999’. 
Categorical data will be summarized using the count and percentage of participants. When count 
data are presented, the percentage will be suppressed when the count is zero in order to draw 
attention to the non-zero counts. A row denoted ‘Missing” will be included in count tabulations 
for demographics, baseline characteristics and compliance to account for missing values. No 
percentages will be displayed on the ‘Missing’ rows and the percentages on the other rows will be 
based on the number of non-missing observations. Unless otherwise specified, the denominator 
for all other percentages will be the number of participants in that treatment within the specific 
analysis set of interest. All percentages will be rounded to one decimal place. The number and 
percentage of responses will be presented in the form xx (xx.x), where the percentage is in the 
parentheses. When the numerator is equal to the denominator, the percentage should be presented 
as (100) instead of (100.0), unless otherwise specified. 
The baseline value is defined as the last available value before the first injection of Soliqua 
100/33. Participants enrolled but not treated will have a last available measurement following 
enrollment.  
If multiple valid values of a variable (efficacy or safety) exist within a same day (and the recorded 
times of measurement do not identify which of them is the last assessment), the value measured 
during the scheduled visit will be used as Baseline in the analysis. If none of those values were 
assessed during a scheduled visit, then all these measurements will be used for the analysis and 
the average will be calculated to derive the baseline value. 
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In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from baseline) by scheduled visits will be provided on observed cases (OC; ie, inclusion of only 
participants having non-missing assessments at a specific visit). 
Baseline safety and baseline efficacy results are presented in the safety and efficacy analyses, 
respectively. 
All safety analyses will be performed on the safety analysis set. 
Statistical analysis will be performed using SAS Enterprise software Version 9.4 or higher. 
Observation period  
The observation period will be divided into 3 segments:  
• The pre-treatment period is defined as the period up to first IMP administration. There 
are two periods within pre-treatment period. A 2-week screening period and a 2-week run-
in period. 
• The on-treatment period (ie, treatment-emergent (TE) period) is defined as the period 
from the first IMP administration to the last IMP administration during Visit 7 (Week 16). 
• The post-treatment period is defined as the period from the end of the on-treatment 
period to the end of the 2-week safety period. (Week 18) 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis sets listed in Table 4 will be 
summarized. The participants excluded from the efficacy set will be displayed in a listing. A 
separate listing will be created for those who are excluded from the efficacy set due to technical 
issues from the CGM device.  
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently enrolled (i.e., do not have IMP dispensed subsequently). The number (%) of screen 
failures and reasons for screen failures will be provided in the screened set disposition 
descriptions. 
The number (%) of participants in the following categories will be provided:  
• Screened participants 
• Enrolled participants 
• Enrolled but not exposed participants  
• Enrolled and exposed participants 
• Participants who completed the 16-week study treatment period as per protocol  
• Participants who completed the entire study period as per protocol (22 weeks). 
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• Participants who did not complete the study period as per protocol and did not record a 
main reason for study discontinuation 
• The number (%) of exposed and non-enrolled participants will also be summarized. 
• Final study status 
Additionally, trial impact (disruption) due to COVID-19 will be summarized for the safety set 
using number and percentage. Participants for whom at least one of the following events 
occurred during the study will be presented: 
• Permanent discontinuation of treatment due to COVID-19, defined as participants whose 
“Main Reason for Premature End of Treatment” on End of Treatment eCRF page is 
“Adverse Event”, and a corresponding adverse event of “Covid-19” with “Drug 
withdrawn” as the response to “Action Taken with Study Treatment” on the Adverse 
Events eCRF page. 
• Permanent discontinuation of treatment due to AE related to COVID-19 infection, defined 
as participants whose “Main Reason for Premature End of Treatment” on End of 
Treatment eCRF page is “Adverse Event”, and a corresponding adverse event of “AE 
Term due to Covid-19” with “Drug withdrawn” as the response to “Action Taken with 
Study Treatment” on the Adverse Events eCRF page. 
• Premature end of treatment due to COVID-19 pandemic, defined as participants whose 
“Main Reason for Premature End of Treatment” on the End of Treatment eCRF page is 
“Other”, and in “If Other, specify” beginning the Specify comment following text 
“Covid-19:”. 
• Premature end of study due to COVID-19 pandemic, defined as participants whose 
“Reason for End of Study/follow-up period” on the Completion of End of Study eCRF 
page is “Other”, and in “If Other, specify details” beginning the Specify comment 
following text “Covid-19:” 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint(s)  
The primary endpoint is the difference from baseline to week 16 in the percentage of TIR of 
70-180 mg/dL using 14 days of CGM data at baseline. The percentage of time spent in the 
glycemic target range will be calculated as 100 times the number of recorded measurements in the 
glycemic target range, (70-180 mg/dL) inclusive, divided by the total number of recorded 
measurements. All the efficacy assessments collected during the study will be used, including 
those obtained after IMP discontinuation or introduction of rescue therapy. Regardless of 
intercurrent events at week 16, the value for the mean change in the percentage of TIR will be 
used. 
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CGM data 
CGM compliance is defined as: 
1. at least 8 out of 14 days (not necessarily consecutive) have 100% of evaluable CGM data 
per 24-hour period (total of 768 records on 8 days) OR 
2. at least 9 out of 14 days (not necessarily consecutive) have ≥89% of evaluable CGM data 
per 24-hour period (total of 768 records on 9 days and at least 9 days with 85 records 
minimum) OR 
3. at least 10 out of 14 days (not necessarily consecutive) have at least ≥80% of evaluable 
CGM data per 24-hour period (total of 768 records on 10 days and at least 10 days with 
77 records minimum)  
during baseline (the run-in period) as well as week 16. 
During the run-in period or end of treatment period, CGM device reinsertion will be allowed for 
participants who do not meet the compliance criteria over a 14-day period as a result of premature 
sensor failure. 
Baseline will be defined as the first 14 evaluable days of evaluable CGM data prior to first day of 
treatment and referred to as the run-in period in the graphical study design. An evaluable day is 
defined as a 24-hour period with ≥80% non-missing measurements. Only evaluable days will be 
included in the analysis. Week 16 will be defined as the first 14 evaluable days of evaluable CGM 
data starting at day 95 or later. 
The first day of CGM data will start at time of device insertion and subsequent days will start 
every 24 hours. If the device is re-inserted, device with the most compliant data will be used and 
if neither session is evaluable, the combined data from both sessions will be used as evaluable 
data. For subsequent reinsertions, the day will start at time of reinsertion. 
Unless otherwise specified, outcome variables based on CGM data will use subjects in the 
efficacy analysis set with compliant data at baseline. 
Percent time in the glucose range is defined as the total number of 15-minute increments where a 
participant’s blood glucose falls within range of ≥70 to ≤180 mg/dL (≥3.9 to ≤10 mmol/L) 
divided by the total number of observed 15-minute increments in that period. Percent time in 
range will be calculated for baseline (run-in) and for week 16. 
4.3.2 Main analytical approach  
Mean change (in percentage) from baseline and its associated 95% CI will be calculated using 
subjects in the efficacy analysis set with compliant baseline CGM data. A one-sample t-test will 
be applied to test the significance of changes at week 16 over baseline (run-in). The statistical test 
will be a 2-sided at a nominal 5% significance level. 
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Hypothesis Testing of the Primary Endpoint 
H0: There is no improvement in TIR at week 16 compared with baseline.  
H1: There is an increase in TIR at week 16 compared with baseline. 
A two-sided 95% CI will be presented, superiority versus baseline will be demonstrated if the 
lower bound is above 0. 
Missing data will be handled differently in accordance with the reasons for missing data. If the 
missing data are due to technical issues with the CGM device (ie, CGM data are not evaluable as 
per the CGM compliance rule Section 4.3.1 during the 2-week run-in period [baseline] as well as 
the end of the treatment period [ie, from Weeks 14 to 16], the participant will be excluded from 
the analysis (missing completely at random [MCAR] approach). For all other reasons the 
Week 16 assessment will be imputed with the baseline observation carried forward (BOCF); 
therefore, change from baseline will be 0. 
The MCAR assumption will be non-conclusively evaluated by testing the association between the 
baseline covariates and missing data status at Week 16. Specifically, a contingency table will be 
constructed based on the missing data status at Week 16 and a given categorical baseline 
covariate. If all the expected cell counts exceed 5, the association will be tested by chi-square test; 
otherwise, Fisher’s exact test will be used. 
4.3.3 Sensitivity analyses  
As a sensitivity analysis, the primary analysis will be repeated to include participants with any 
missing data due to discontinuation or non-compliant data at Week 16 by imputing with BOCF. 
The mean and its associated 95% CI will be reported. 
 
As a second sensitivity analysis, the primary analysis will be repeated for all participants in the 
efficacy analysis set. All missing data at Baseline and Week 16 will be excluded and not imputed, 
and only compliant CGM data will be utilized. Mean and its associated 95% CI will be reported. 
4.3.4 Supplementary analyses  
No analysis is planned. 
4.3.5 Subgroup analyses  
The primary analysis will be replicated, if the number of participants in a specific subgroup is at 
least 20, for the following subgroups:  
• Participants using OAD only at baseline 
• Participants using OAD plus GLP-1RA at baseline 
• Participants ≥ 65 years of age 
• Participants < 65 years of age. 
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In these subgroup analyses, mean (SD) and associated 95% CI, as well as minimum, median, and 
maximum will be provided.  
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
4.4.1 Key/Confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
Key Secondary Endpoints: 
• Change (%) from baseline (run-in) to week 16 in glucose total CV. The data for this 
endpoint come from the CGM data using the glucose readings. The endpoint will be 
calculated globally (percent change from the total two weeks baseline CV to the two 
weeks end of treatment week 16 CV). The CV formula used is 𝐶𝑉%𝑡𝑜𝑡𝑎𝑙=
𝑆𝐷𝑡𝑜𝑡𝑎𝑙
𝑥̅
∗100% 
where 𝑆𝐷𝑡𝑜𝑡𝑎𝑙= √∑(𝑥𝑖−𝑥̅)2
𝑛−1
, 𝑥𝑖 is the individual glucose reading value, 𝑥̅ is the 14-day 
mean and n is the number of data points and the % change will be reported.  The 
alternative hypothesis to be tested is that the CV differs between baseline and week 16. A 
two-sided 95% CI will be presented. 
• Change (mg/dL) from baseline (run-in) to week 16 in mean daily blood glucose. These 
data come from the CGM data and will be calculated for each day by using the average 
blood glucose for week 16 compared to the parallel day during the run-in period (baseline) 
[for example, Day 1 of baseline’s average blood glucose will be compared to Day 1 of 
week 16’s average blood]. A global average will be computed to determine the average of 
the mean daily blood glucose for the 14 days at baseline and also at week 16. The global 
average will be used for hierarchal testing and the mg/dL change will be reported. The 
alternative hypotheses to be tested is that mean daily blood glucose differs between 
baseline and week 16. Two-sided 95% CIs will be presented. 
• Change (mg/dL) from baseline (run-in) to week 16 in the maximum PPG exposure in the 
4 hours after the breakfast meal during the mixed-meal tolerance test collected from the 
CRF. The analysis is focused on the 4-hour interval at both baseline (run-in) and week 16 
from t=0 (the timepoint at which glucose measurement is taken immediately preceding 
meal administration) throughout the subsequent 4 hours.  For each participant, the overall 
maximum glucose value (mg/dL) within the described 4-hour period will be determined, 
and the difference between the maximum glucose value at baseline(run-in) and week 16 
will be reported.  The alternative hypothesis to be tested is that the maximum PPG differ 
between baseline and week 16. A two-sided 95% CI will be presented. This analysis will 
be based on participants in the enrolled set who have non-missing outcomes at baseline. 
• Change (%) from baseline (run-in) to week 16 in TAR (>180 mg/dL). The percentage of 
time spent above the glycemic target range will be calculated as 100 times the total 
number of 15-minute increments of CGM data where a participant’s blood glucose falls 
above normal range (>180 mg/dL) in a 14-day period divided by the total number of 
15-minute increments read (up to 1344 15-minute increments). This will be calculated for 
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baseline (run-in) and for week 16 and the change will be reported.  The alternative 
hypothesis to be tested is that the TAR differs between baseline and week 16. A two-sided 
95% CI will be presented. 
4.4.1.2 Main analytical approach  
The key secondary estimand will be estimated based on the efficacy analysis set using 
measurements obtained during the study, regardless of intercurrent events. All four endpoints are 
continuous and will be summarized using the number of observations available, mean, SD, 
minimum, median, and maximum. Mean changes for continuous outcomes will be presented at 
baseline and at the end of the treatment period (Week 16). Mean (SD) and associated 95% CI, as 
well as minimum, median, and maximum values will be provided, and the analysis will be tested 
with 2-sided tests at 5% significance level. 
Key Secondary endpoints will undergo hierarchal testing in the order displayed in Section 4.6, 
using two-sample t-test. The results of the test will be displayed in a summary table. 
Missing data handling of key CGM secondary endpoints will follow the same approach as the 
primary estimand. 
Regarding participants who discontinue treatment early, but complete the early termination visit 
per protocol and have MMTT collected at the EOT visit, their data will be used if collected on 
study day 56 or later; otherwise, the week 16 outcome will be imputed. If the week 16 MMTT 
data were collected prior to day 56 or missed, then the week 16 outcome will be imputed using 
baseline observation carried forward (BOCF).  
4.4.2 Supportive secondary endpoint(s)  
Mean changes for continuous outcomes for other measures of glycemic control and variability: 
• Proportion (%) of participants achieving total CV <36% at week 16. To calculate the 
proportion of participants achieving CV <36%, a sum of the number of participants with 
CV <36% divided by the total number of participants. The endpoint will be calculated 
using all CGM glucose readings available throughout each day for two weeks (week 
14-16). As this is a binary outcome the endpoint will be summarized with proportions and 
95% CI using the Clopper-Pearson exact method.  A two-sided 95% CI will be presented. 
• Change (%) from baseline (run-in) to week 16 in TIR [70-180 mg/dL] for specific time 
blocks [12 am – 6 am, 6 am – 12 pm, 12 pm – 6 pm, 6 pm - 12 am, and 6 am – 12 am]. 
The end point will find the percentage of time spent in the glycemic target range. This is 
calculated as 100 times the number of recorded measurements in the glycemic target 
range, (70-180 mg/dL) inclusive, divided by the total number of recorded measurements 
per time block and comparing the corresponding time blocks from week 16 to baseline in a 
14-day period to determine change. Two-sided 95% CIs will be presented. 
• The proportion (%) of participants achieving Glucose Management Indicator [GMI] <7% 
and <9% at week 16.  The GMI (%) formula used is 3.31 + 0.02392 *(mean glucose in 
mg/dL from CGM data) (Bergenstal et al., 2018); this step is followed by determining the 
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number of participants achieving <7% and <9% at week 16. The endpoint will be 
calculated using all CGM data available throughout each day of the two-week period 
(week 14-16) for derivation of mean glucose. A two-sided 95% CI will be presented. 
• Change from baseline (run-in) to week 16 in the 4-hour PPG area under the concentration 
time curve from 0 to 4 hours (AUC0-4h) after start of the breakfast meal, including 
determination of the time to reach maximum associated concentration (Tmax), are both 
based on MMTT data. Tmax will be calculated by finding the time that corresponds to the 
maximum glucose concentration from t=0 over the 4 hrs. The 4 hour PPG AUC will be 
calculated from the glucose values measured at time 0 (just before the meal), 0.5 hours, 
1.0 hours, 1.5 hours, 2.0 hours, 2.5 hours, 3.0 hours, and 4.0 hours post‑meal utilizing the 
“trapezoidal rule” 𝐴𝑈𝐶= ∑
[𝐶𝑔𝑙𝑢𝑐(𝑖+1)+ 𝐶𝑔𝑙𝑢𝑐(𝑖)]
2
(𝑡𝑖+1 −
4 ℎ𝑟
𝑖=0 ℎ𝑟
𝑡𝑖) where C=concentration, i 
= specified time intervals in the MMTT, and t=time. Differences in (AUC0-4h) from 
baseline (run-in) to week 16 will be reported as well as the corresponding Tmax at baseline 
and week 16.  Two-sided 95% CIs will be presented.  This analysis will be based on 
participants in the enrolled set who have non-missing outcomes at baseline and week 16. 
• Proportion (%) of participants at week 16 who spend < 15 minutes/day at a glucose level 
<54 mg/dL. The endpoint will be summarized based upon CGM data reporting both 
percentages and 95% CI using the Clopper Pearson exact method. A two-sided 95% CI 
will be presented. 
Measures of glycemic control and variability will be presented at baseline and at the end of the 
treatment period (Week 16). The mean (SD) and associated 95% CI, as well as minimum, median, 
and maximum values will be provided.  
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoint(s)  
Mean changes for continuous outcomes for additional measures of glycemic control and 
variability in participants with T2DM:  
• Change (mg/dL) from baseline (run-in) to week 16 in mean of daily difference [MODD] 
of glucose levels. Using the formula: 
∑
|[𝐷𝑎𝑦𝑗+1𝑡− 𝐷𝑎𝑦𝑗𝑡]
𝑡=95
𝑡=0
|
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑝𝑎𝑖𝑟𝑒𝑑 𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡𝑠 where t=time period in the 
24 hour day by 15 minute intervals and j = day to calculate MODD for each participant 13 
times comparing Day 2 to Day 1, up to Day 14 to Day 13 for Baseline and for week 16. 
The average absolute daily differences at each 15-minute interval of CGM data will be 
summarized using descriptive statistics.  Two-sided 95% CI will be presented. 
• Change (%) from baseline (run-in) to week 16 in TAR >250 mg/dL. The percentage of 
time spent above the glycemic target range will be calculated as 100 times the number of 
the total number of 15-minute increments of CGM data where a participant’s blood 
glucose falls above normal range (>250 mg/dL) in a 14-day period divided by the total 
number of 15-minute increments read (1344 number of 15-minute increments). This will 
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be calculated for baseline and for week 16 to report the difference.  A two-sided 95% CI 
will be presented. 
• Change (%) from baseline (run-in) to week 16 in TBR <70 mg/dL. The percentage of time 
spent below the glycemic target range will be calculated as 100 times the number of the 
total number of 15-minute increments from CGM data where a participant’s blood glucose 
falls below normal range (<70 mg/dL) in a 14-day period divided by the total number of 
15-minute increments read (1344 number of 15-minute increments). This will be 
calculated for baseline and for week 16 to report the difference. A two-sided 95% CI will 
be presented. 
• Correlation of change in percentage of TIR [70 – 180 mg/dL] and change in PRO from 
baseline (run-in) to week 16. Analysis will be done between each of the 4 domains (well-
being, medical control, lifestyle, and convenience), PRO overall, and change in TIR. The 
purpose of finding the correlation of change from baseline to week 16 for percentage of 
TIR and PRO is to determine the relationship between those two continuous variables.  
• Correlation of percentage of TIR [70 – 180 mg/dL] and HbA1c percentage achieved at 
week 16. The correlation of percentage of TIR and HbA1c achieved at week 16 will 
estimate the relationship between the two variables. 
• Association of participants reaching 60 units/day insulin glargine U100 and TIR > 70%.  
• Change in HbA1c percentage from baseline (run-in) to week 16. The alternative 
hypothesis to be tested is that the HbA1c will decrease from baseline to week 16. A two-
sided 95% CI will be presented.  This analysis will be based on participants in the enrolled 
set who have non-missing outcomes at baseline and week 16.  
• Change in the percentage from baseline (run-in) to week 16 for TITR (70-140 mg/dL). 
The end point will determine the percentage of time spent in the glycemic tight target 
range. This is calculated as 100 times the number of recorded measurements in the 
glycemic target range, (70-140 mg/dL) inclusive, divided by the total number of recorded 
measurements per time block and comparing week 16 to baseline over a 14-day period to 
determine change. A two-sided 95% CI will be presented. 
• Proportion (%) of participants with TIR (70–180 mg/dL) > 70% each day at week 16. To 
calculate the proportion of participants achieving TIR of >70% each day, a sum of the 
number of participants with more than 67 15-minute intervals with glucose values in range 
per day for all compliant days divided by the total number of participants. The endpoint 
will be calculated using all CGM glucose readings available throughout each day for two 
weeks at the end of study. As this is a binary outcome the endpoint will be summarized 
with proportions and 95% CI using the Clopper Pearson exact method.  A two-sided 95% 
CI will be presented. 
• Proportion (%) of participants with ≥5% absolute improvement from baseline in TIR 
(70-180 mg/dL). Absolute improvement is defined as an increase in TIR from baseline to 
week 16. To calculate the proportion of participants achieving ≥5% in TIR absolute 
improvement from baseline a sum of the number of participants with a positive percent 
change ≥5% will be divided by the total number of participants. The endpoint will be 
calculated using all CGM glucose readings available throughout each day for each two-
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week time blocks. As this is a binary outcome the endpoint will be summarized with 
proportions and 95% CI using the Clopper Pearson exact method.  A two-sided 95% CI 
will be presented. 
• Proportion (%) of participants with ≥10% absolute improvement from baseline in TIR 
(70-180 mg/dL). Absolute improvement is defined as an increase in TIR from baseline to 
week 16. To calculate the proportion of participants achieving ≥10% absolute 
improvement in TIR from baseline a sum of the number of participants with a positive 
percent change ≥10% are divided by the total number of participants. The endpoint will be 
calculated using all CGM glucose readings available throughout each day for each two- 
week time blocks. As this is a binary outcome the endpoint will be summarized with 
proportions and 95% CI using the Clopper Pearson exact method.  A two-sided 95% CI 
will be presented. 
• Proportion (%) of participants with improvement in HbA1c >0.5% points without an 
increase in TBR (<54 mg/dL) of >0.5%. Improvement is defined as an increase in HbA1c 
from baseline to week 16. To calculate the proportion of participants achieving >0.5% 
improvement of HbA1c from baseline and with < 0.5 % change in TBR participants will 
be summed then divided by the total number of participants. The endpoint will be 
summarized based upon CGM data reporting both percentages and 95% CI using the 
Clopper Pearson exact method.  A two-sided 95% CI will be presented. 
• Proportion of participants with ≥10% absolute improvement from baseline in TIR 
(70-180 mg/dL) without an increase in TBR (<54 mg/dL) of >0.5%. Absolute 
improvement is defined as an increase in TIR from baseline to week 16. A sum of 
participants with both ≥10% of improvement from baseline in TIR and no increase in TBR 
of more than 0.5% will be divided by the total number of participants. The endpoint will 
be summarized based upon CGM data reporting both percentages and 95% CI using the 
Clopper Pearson exact method.  A two-sided 95% CI will be presented. 
• Proportion of participants with TIR (70–180 mg/dL) >70% and TBR (<70 mg/dL) <4% at 
Week 16.  To calculate the proportion of participants achieving TIR >70% and TBR <4%, 
a sum of the number of participants with both TIR >70% and TBR <4% divided by the 
total number of participants. The endpoint will be summarized based upon CGM data 
reporting both percentages and 95% CI using the Clopper Pearson exact method.  A two-
sided 95% CI will be presented. 
• Change in diabetes medication treatment-related impact and satisfaction, as measured by 
the DM-SAT, from baseline (run-in) to week 16. The four DM-SAT subscales/domains 
provide a means for the researcher or clinician to understand which component(s) of 
diabetes treatment were most responsive to an intervention, distinguish one treatment 
approach from another, or determine which were appraised more positively or negatively 
by a patient. DM-SAT questionnaire is comprised of 16-item measurements within 
4 subscales/domains: well-being; medical control; lifestyle; convenience 
- 
Well-being – physical symptoms, mood, and energy. 
- 
Medical control – how well the medication(s) keep a participant’s blood sugar where 
the participant thinks it should be, how often are “highs” avoided in a blood sugar test 
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according to the participant, and how much the participant feels in control of their 
diabetes. 
- 
Lifestyle - how easy it is for a participant to have a lifestyle they prefer with the 
diabetes medication they are taking, how much a participant has to plan their social life 
around their diabetes medication(s), how much a participant plans their physical 
activity around their diabetes medication(s), how much a participant has to plan their 
mealtimes because of their diabetes medication(s), and how much time they spend 
each day on their diabetes medication. 
- 
Convenience - how often are “lows” avoided in a blood sugar test according to the 
participant, the convenience of their diabetes medication(s) when they are traveling or 
away from home for more than one day, the way they take their diabetes 
medication(s), the time(s) of day they must take their diabetes medication(s), and the 
overall convenience of their diabetes medication(s). 
The expectation is that the satisfaction scores will increase from baseline to week 16. Two-
sided 95% CIs will be presented.  These analyses will be based on participants in the 
enrolled set who have non-missing outcomes at baseline and week 16. 
4.5.2 Main analytical approach  
The correlation between TIR and participant-reported outcomes (PRO) and TIR and HbA1c at 
week 16 will be assessed using Pearson’s correlation coefficient. A contingency table will be 
constructed based on TIR > 70% and participants requiring 60 units/day of insulin glargine at 
week 16. If all the expected cell counts exceed 5, the association will be tested by chi-square test; 
otherwise, Fisher’s exact test will be used.  
Mean (SD) and associated 95% CI, as well as minimum, median, and maximum values will be 
provided for continuous variables for change from baseline. The correlation endpoint tables 
present “n” being number of participants (xx) and correlation coefficient value (0.xxx). For 
correlation between change in TIR and PRO, a table will present PRO data for overall scores and 
subscale/domain scores and a 95% CI. Participants with non-compliant or missing data at week 16 
will be excluded from the analysis. 
For change in diabetes medication treatment-related impact and satisfaction, as measured by the 
DM-SAT, at baseline (run-in) and week 16, the mean (SD) and associated 95% CI, as well as 
minimum, median, and maximum values will be presented for overall score and by 
subscales/domains. The 16-item questionnaire is measured from 0-10: 0 = Not at all satisfied, 
1-3 = Not too satisfied, 4-6 = Somewhat satisfied, 7-9 = Very satisfied, 10 = Extremely satisfied. 
The score for each the 4 domains/subscales is calculated as follows: lifestyle (sumscore lifestyle 
of 5 questions)/50; medical control (sumscore medical control of 3 questions)/30; convenience 
(sumscore convenience of 5 questions)/50 and well-being (well-being sumscore of 3)/30. The 
overall score will be calculated by: (sumscore overall of 16 questions)/160. If there are more than 
25% missing items for a scale, the scale will be treated as missing. For the greatest measurement 
precision, it is recommended to use the full 16-item DM-SAT total score to assess overall 
treatment satisfaction in research applications, as a study outcome. There will be no reverse 
scoring as it is not applicable to the DM-SAT items. 
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A summary descriptive analysis of TIR, TAR, and TBR will be provided with no imputation for 
missing data. This will be provided under the Descriptive Analyses tables. 
4.6 
MULTIPLICITY ISSUES  
A hierarchical testing procedure will be performed. Key secondary endpoints will be evaluated 
with a one-sample two-sided t-test (𝑡=
𝑥̅−∆
𝑠
√𝑛
) to determine whether there is any change between 
baseline (run-in) and week 16. The overall type-I error rate will be controlled at the two-sided 
0.05 level using a sequential testing procedure.  For any secondary endpoints to be eligible for 
being declared significant, the primary endpoint must be significant at 0.05 significance level. The 
secondary endpoints will be tested following the hierarchical testing procedure with a pre-
specified order, that is, inferential conclusions about successive secondary endpoints require 
statistical significance at 0.05 significance level of the previous one. The following key secondary 
endpoints will be tested in the following order:  
• Change (%) from baseline to week 16 in coefficient of variation  
• Change (mg/dL) from baseline to week 16 in mean daily blood glucose  
• Change (mg/dL) from baseline to week 16 in the maximum PPG exposure in the 4 hours after 
the breakfast meal (MMTT) 
• Change (%) from baseline to week 16 in TAR (>180 mg/dL) 
 If at any step the null statistical hypothesis is not rejected, the endpoints listed after that step will 
be reported at nominal level, otherwise will be technically eligible for being declared significant. 
A summary table will present the mean, 95% CI, p-value, and the statistical significance for the 
primary endpoint and the key secondary endpoints. 
4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the safety set as defined in Section 3, unless otherwise 
specified, using the following common rules: 
• The analysis of the safety variables will be analyzed descriptively, and no testing is 
planned. Planned analysis is described in further detail below.  
The safety endpoints include number of participants with adverse events (AE), serious adverse 
events (SAEs), adverse events of special interest (AESIs), overall hypoglycemia, and confirmed 
hypoglycemia. 
Hypoglycemia rates during 16 weeks of treatment, including the percentage of participants with at 
least 1 hypoglycemia event and number of events per participant year, will be analyzed 
descriptively in a table. Further explanation is described below in hypoglycemia section. 
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4.7.1 Extent of exposure  
The extent of study treatment (specifically, insulin glargine) exposure and adherence will be 
assessed based on the safety set, presented by the following parameters: 
• Duration of treatment; 
• Mean planned dose, i.e., doses documented in CRF Exposure page; 
• Mean actual dose, i.e., doses recorded in diary by participants; 
• Minimum planned dose; 
• Maximum planned dose; 
• Last planned dose, i.e., the planned dose documented in CRF at the last visit; 
• Number of participants whose planned dose reached at least 60 units/mL. 
The lixisenatide dose will not be presented; instead, a footnote that states the ratio of insulin 
glargine (in unit/mL) to lixisenatide (in µg/mL) equals 3:1 will be included wherever applicable. 
Duration of IMP exposure 
The duration of IMP exposure will be calculated as date of the last IMP injection – date of the 
first IMP injection + 1. If the date of the last dose of IMP (in the eCRFs) is missing, the duration 
of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively using descriptive statistics and 
categorically as below:  
• ≤ 8 weeks  
• > 8 weeks to ≤ 16 weeks  
• >16 weeks  
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of days of the duration of treatment exposure for all participants divided by 365.25, and will be 
expressed in participant years. 
A summary of the number and percentage of subjects with any visit impacted by the COVID-19 
pandemic may be produced, if applicable.  The summary will include the number of visits and 
assessments impacted, as well as the reasons for the impacted visits/assessments. 
Treatment adherence 
A given administration will be considered nonadherent if the participant did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for participants with 
missing or incomplete data.  
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The adherence rate for a participant will be defined as the total number of days with a Soliqua 
100/33 injection divided by planned number of days with Soliqua 100/33 injection multiplied by 
100. 
Treatment adherence will be summarized using the mean, SD, median, minimum, maximum and 
range, using the safety set. In addition, the percentage of participants who have <60%, ≥60% to 
<80%, ≥80% to ≤100%, and >100% adherence will be summarized. 
4.7.1.1 Overall exposure  
The exposure information will be assessed by the following variable(s): 
• Duration of IMP exposure (in weeks) is defined as (Last day of exposure – first day of 
exposure +1)/7. 
4.7.2 Adverse events  
All AEs will be collected from the signing of the ICF until the follow-up visit. 
General common rules for adverse events 
All adverse events (AEs) will be coded to a lower-level term (LLT), preferred term (PT), high-
level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. 
The AEs (which are recorded on the AE eCRF page, including hypoglycemia events qualifying as 
AEs) will be categorized as: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period, defined as the time from the signed informed consent date up to the first 
administration of the IMP. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period defined as the time from the first 
administration of the IMP (on Day 1) to the last administration of the IMP + 3 days. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period defined as the time starting 1 day after the end of the TEAE period up to 
the end of the study follow-up (2 weeks after the end of treatment period) 
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
Pre-treatment safety data will be analyzed using the Screening Analysis Set.  Treatment-emergent 
and post-treatment safety data will be analyzed using the Safety Analysis Set.  
The primary focus of AE reporting will be on TEAEs, and AESIs.  Pre-treatment and post-
treatment AEs will be described separately.  
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An AE with incomplete or missing date/time of onset (occurrence, worsening or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, the AE will be assumed to be 
related to IMP within summary tables. If the severity is missing for one of the treatment-emergent 
occurrences of an AE, the severity will be imputed with the maximal severity of the other 
occurrences within the PT. If the severity is missing for all the occurrences, the severity will be 
left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase.  
An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or 
spontaneously notified by the participant and defined as at least twice the intended dose within the 
intended therapeutic interval (planned treatment period), adjusted according to the tested drug. 
Cases of symptomatic overdoses will constitute AESIs and will be listed as such. 
The AE tables will be sorted as indicated in Table 5.  
Table 5 - Sorting of AE tables 
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
a Sorting will be based on the mg dose intervention group/overall incidence. 
b Within each table the sorting will be by the internationally agreed SOC order and decreasing frequency of PTs; in case of tie for PT, the 
sorting will be alphabetical. 
Analysis of all AEs 
The overview of TEAE with the details below will be generated (number and percentage of 
participants) in a table: 
• Any TEAE  
• Any treatment emergent SAE 
• Any treatment emergent AESI 
- 
Pregnancy. 
- 
Symptomatic overdose. 
- 
Increase in ALT (>3 × ULN). 
• TEAE leading to death (death as an outcome of the AE as reported in the AE page) 
• Any TEAE leading to temporary IMP discontinuation.  
• Any TEAE leading to permanent IMP discontinuation 
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• Any treatment-related TEAE 
• Any TEAE leading to study discontinuation 
The overview summary for TEAEs will be provided on the safety set and will be repeated on the 
subgroup of safety participants according to trial impact (disruption) due to the COVID-19 
pandemic. 
Individual listings (AEs, SAEs, AEs leading to death, TEAEs leading to permanent IMP 
discontinuation, AESI, AEs for Treated and not enrolled participants) will be provided to support 
the summary tables based on the safety set. 
A listing of all participants who died during the study will be provided. 
The AE summaries of Table 6 will be generated with number (%) of participants experiencing at 
least one event.  
Table 6 - Analyses of adverse events 
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HGLT, HLT and PT 
Common TEAE (≥5%)  
Primary SOC and PT 
TEAE related to IMP  
Primary SOC, and PT 
TEAE by maximal severity 
Primary SOC and PT  
Treatment emergent SAE 
Primary SOC and PT 
TEAE leading to study discontinuation 
Primary SOC and PT 
TEAE leading to permanent discontinuation of IMP 
Primary SOC and PT 
TEAE leading to death 
Primary SOC and PT 
Pre-treatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment SAE 
Primary SOC and PT 
 
a Will include the following AE categories: any AEs, any serious AEs, any, any AEs leading to death, any AEs leading to permanent IMP 
discontinuation and be repeated for participants impacted by COVID-19 
Analysis of adverse events of special interest (AESIs)  
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
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interest may be added, modified, or removed during a study by protocol amendment. All AESIs 
will be reported to the Sponsor in the same timeframe as SAEs (within 24 hours). 
Adverse events of special interest (AESIs) are defined by the protocol and will be documented in 
eCRF: 
• Pregnancy of a female participant enrolled in the study as well as pregnancy occurring in a 
female partner of a male participant enrolled in the study with IMP/NIMP. 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP. 
• Increase in ALT (>3 × ULN). 
Adverse events of special interest (AESIs) will be selected for analyses as indicated in Table 7. 
The number (%) of participants experiencing at least one event will be provided for each event of 
interest. Tables will be sorted as indicated in Table 5.  
Table 7 - Selections for AESIs  
AESIs  
Selection 
Symptomatic overdose 
eCRF specific tick box on the AE page 
ALT Increase 
eCRF specific tick box on the AE page 
Pregnancy  
eCRF specific tick box on the AE page 
4.7.3 Hypoglycemia events  
During the study, participants are to be instructed to document any hypoglycemic episodes in their 
e-diary. Hypoglycemia will be reported on the specific eCRF page with onset date and time, 
symptoms and/or signs, the glucose measurement obtained at the time of the event before 
countermeasures, the collection date and time of glucose measurement, and the treatment of 
hypoglycemia. Hypoglycemia meeting the definition of an adverse event will be documented, in 
addition, on the AE form in the eCRF. 
The following hypoglycemia events are the categories of interest:  
• Any Hypoglycemia Event: Any event recorded in Hypoglycemic Event Information 
Library eCRF page that has “Yes” as the response to the question “Were any 
hypoglycemic events experienced”, regardless of the plasma glucose measurements. 
• ADA Level 1 Hypoglycemia: A measurable glucose concentration of <70 mg/dL 
(3.9 mmol/L) but ≥54 mg/dL (3.0 mmol/L) that can alert a person to take action. A blood 
glucose concentration of 70 mg/dL (3.9 mmol/L) has been recognized as a marker of 
physiologic hypoglycemia in humans. Recurrent episodes of hypoglycemia lead to 
increased hypoglycemia unawareness, Therefore, glucose levels <70 mg/dL (3.9 mmol/L) 
are clinically important, independent of the severity of acute symptoms. The event will be 
captured if the Glucose Measurement in the Hypoglycemic Event Information Library 
eCRF page falls within the described blood glucose concentration levels. 
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• ADA Level 2 Hypoglycemia: A measurable glucose concentration of <54 mg/dL 
(3.0 mmol/L) that needs immediate action. At approximately 54 mg/dL (3.0 mmol/L), 
neurogenic and neuroglycopenic hypoglycemia symptoms begin to occur, ultimately 
leading to brain dysfunction at levels <50 mg/dL (2.8 mmol/L). Neuroglycopenic 
symptoms, including behavioral changes, visual changes, seizure, and loss of 
consciousness, are the result of central nervous system neuronal glucose deprivation. The 
event will be captured if the Glucose Measurement in the Hypoglycemic Event 
Information Library eCRF page falls within the described blood glucose concentration 
levels. 
• ADA Level 3 Hypoglycemia: A severe event characterized by altered mental and/or 
physical functioning that requires assistance from another person for recovery due to 
participant’s inability to help themselves. Severe hypoglycemia captures events during 
which the symptoms associated with hypoglycemia affect a participant such that the 
participant requires assistance from others.  The event will be captured if the Glucose 
Measurement in the Hypoglycemic Event Information Library eCRF page falls within the 
described blood glucose concentration levels and if “Required Assistance because subject 
was not capable of helping self was selected. 
• Documented Hypoglycemia: (<70 mg/dL): a glucose level of <70 mg/dL (or 
<3.9 mmol/L) (with or without symptoms). 
- 
Documented Symptomatic Hypoglycemia (<70 mg/ dL): defined as an event during 
which typical symptoms of hypoglycemia are accompanied by a measured plasma 
glucose concentration less than 70 mg/dL (3.9 mmol/L). Clinical symptoms that often 
result from a hypoglycemic episode can include (but not necessarily limited to) 
increased sweating, nervousness, asthenia/weakness, tremor, dizziness, increased 
appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, 
or coma.  
- 
Documented Symptomatic Hypoglycemia will be identified in the Hypoglycemic 
Event Information Library eCRF page in those who indicated “symptoms were 
present” with a measured plasma glucose value <70 mg/dL (or <3.9 mmol/L) 
- 
Documented Serious Symptomatic Hypoglycemia: defined as an event where the 
participant also requires assistance from another person for recovery due to 
participant’s inability to help themselves, i.e., identified in the Hypoglycemic 
Event Information Library eCRF page, as “Required assistance because subject 
was not capable of helping self”. 
- 
Documented Non-serious Symptomatic Hypoglycemia: defined as an event where 
the participant does not require assistance from another person for recovery, i.e., 
identified in the Hypoglycemic Event Information Library eCRF page, with a “No 
Assistance” response or “Received Assistance but Subject Was Capable of Helping 
Self”.  
 
- 
Documented Asymptomatic Hypoglycemia: asymptomatic hypoglycemia is defined as 
an event not accompanied by typical symptoms of hypoglycemia but with a measured 
plasma glucose concentration < 70 mg/dL (or <3.9 mmol/L) i.e., identified in the 
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Hypoglycemic Event Information Library eCRF page with a “No” response to “Were 
symptoms present”.  
• Symptomatic Hypoglycemia: defined as any symptomatic hypoglycemia recorded on 
Hypoglycemic Event Information Library eCRF page responding that symptoms were present 
with the plasma glucose measurements of < 70 mg/dL (or <3.9 mmol/L). 
• Pseudohypoglycemia: defined as any symptomatic hypoglycemia recorded on Hypoglycemic 
Event Information Library eCRF page responding that symptoms were present with the 
plasma glucose measurements of ≥ 70 mg/dL (or ≥3.9 mmol/L).  
Hypoglycemia events categorized by time of day at which the event occurred by ADA levels, will 
be provided in a table: 
• Nocturnal Hypoglycemia Defined by Time of the Day: Any hypoglycemia event that 
occurs between 00:00 and 05:59, regardless of whether the participant was awake or woke 
up because of the event.  
• Nocturnal Hypoglycemia Defined by Sleep Status: Any hypoglycemia event that wakes 
the participant from sleep between bedtime and rising in the morning, i.e., before the 
morning assessment of fasting prebreakfast SMPG and before any insulin injection. The 
participant wakes up because of the event.  
• Daytime Hypoglycemia Defined by Time of the Day: Any hypoglycemia event that occurs 
between 06:00 and 23:59.  
• Daytime Hypoglycemia Defined by Awake Status: Any hypoglycemia event that occurs 
between the participant waking up and going to sleep.  
Hypoglycemia observation periods 
• Pre-treatment hypoglycemia events are events that developed or worsened or became 
serious from the signed informed consent date up to first administration of the IMP.  
• Treatment-emergent hypoglycemia events are those that developed or worsened or became 
serious during the on-treatment period arising from the time of the first IMP 
administration (on Day 1) up to 1 day after the last IMP injection.  
• Post-treatment hypoglycemia events are events that developed or worsened or became 
serious during the post-treatment period arising 1 day after the end of the TEAE period up 
to the end of the study follow-up (2 weeks after the end of treatment period) 
Descriptive analysis will summarize hypoglycemia events in a table (repeat for subgroups 
[i.e., OAD only at baseline, OAD plus GLP-1 RA at baseline, ≥ 65 years of age, < 65 years of 
age]):  
• Overall number and percentage of participants with at least 1 hypoglycemia event (for 
overall and each observation period) and number of hypoglycemic events (for overall and 
each observation period) 
• Number and percentage of participants with at least 1 hypoglycemia event and number of 
hypoglycemic events, by ADA classification levels  
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• Number and percentage of participants with at least 1 hypoglycemia event and number of 
hypoglycemic events, by observation periods 
• Documented Hypoglycemia 
- 
Documented symptomatic hypoglycemia 
- 
Documented serious symptomatic hypoglycemia 
- 
Documented non-serious symptomatic hypoglycemia 
- 
Asymptomatic Hypoglycemia 
• Symptomatic Hypoglycemia 
• Pseudohypoglycemia 
• Nocturnal Hypoglycemia Defined by Time of the Day, overall and by ADA levels 
• Nocturnal Hypoglycemia Defined by Sleep Status, overall and by ADA levels 
• Daytime Hypoglycemia Defined by Time of the Day: overall and by ADA levels 
• Daytime Hypoglycemia Defined by Awake Status, overall and by ADA levels 
In addition, rate of on-treatment symptomatic hypoglycemic events (Overall, and by time of 
day per ADA levels) will be summarized in a table whereas 
Hypoglycemic events rate per participant year = Number with hypoglycemic events/Total 
Person Years 
If there are multiple events from an individual participant, all events will be counted. 
where Total PY is calculated as below: 
Observation 
period 
Total Person Years 
Time to event 
(days) 
Censoring time 
(days)  
On-treatment (cumulative total time to event 
date for participants with event 
+ cumulative total of censoring 
time for participants without 
event) 
date of event -first 
dose date +1 
(last dose 
date+1) -first 
dose date +1 
Participants with symptomatic hypoglycemia events, and participants with severe hypoglycemia 
events will be displayed in listings. A figure will be provided showing the time to the first severe 
or documented ADA Level 3 symptomatic hypoglycemia during on-treatment period. 
4.7.4 Additional safety assessments  
4.7.4.1 Laboratory variables and vital signs  
The following laboratory variables and vital signs will be converted into standard international 
units and analyzed from screening to week 16 per the schedule of events. Analysis will distinguish 
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between early end of treatment and week 16 end of treatment. Glucose values will be analyzed 
using conventional units. 
• Hematology:  
- 
Red blood cells and platelets: erythrocytes, platelet count, leukocytes, hemoglobin, 
hematocrit  
• Clinical chemistry: 
- 
Metabolism: lipase, amylase 
- 
Electrolytes: sodium, potassium  
- 
Renal function: creatinine, uric acid 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total bilirubin (if >ULN , then the direct and indirect subfractions must be 
measured) 
• Calcitonin 
• Urinalysis: 
- 
Urinalysis for quantitative analysis: pH, ketones, leukocytes, blood/hemoglobin, 
protein and glucose  
• Vital signs: pulse rate, systolic and diastolic blood pressure, weight 
Specified in the study protocol, all clinical safety laboratory assessments will be performed by a 
central laboratory. Additional tests may be performed at a local or central laboratory at any time 
during the study as determined necessary by the investigator or required by local regulations. If 
they are used to evaluate an AE (diagnostic, follow-up, outcome), the results must be entered into 
the eCRF. A urine pregnancy test will be performed at each schedule of event timepoint and 
treated as an AESI and not reported in the laboratory analysis tables. 
Quantitative analyses 
Descriptive statistics will be used for results and changes from baseline will be provided for each 
planned visit, during the on-treatment period. Laboratory values below the lower limit of 
quantification (LLOQ ) will be set to one half of the LLOQ. 
4.7.4.2 Product complaints  
Any defect in the IMP device must be reported as soon as possible by the investigator to the 
monitoring team, who will complete a product complaint form within the required timelines. 
Appropriate information (eg, samples, labels, or documents like pictures or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered. The 
investigator will assess whether the quality issue must be reported in association with an AE or 
SAE. 
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All product complaint summaries during the on-treatment period (see Section 4.1) will be 
generated using the safety set and will include the number (%) of participants experiencing at 
least one event, the number of events, and the event rate per participant-year. 
The event rate per participant-year will be defined as the number of events divided by the 
cumulative duration of all participants’ exposure expressed in years. 
The overview of product complaints with the details below will be generated: 
• Any product complaint 
• Any product complaint related to AEs 
In addition, the analysis below will be conducted. 
• Any product complaint categorized by type of complaint 
• AE(s) leading to product complaints by primary SOC and PT 
4.8 
OTHER ANALYSES  
4.8.1  Descriptive Analyses   
Other summary descriptive analyses will be provided based upon the efficacy assessments. This 
includes a summary descriptive analysis of TIR, TAR, TBR, fasting plasma glucose, and two 
analyses based on fasting self-monitoring plasma glucose value (SMPG) taken in the mornings 
3-4 times per day, 3 days before visit to determine titration. This information is provided from the 
eDiary. The analyses for fasting SMPG will be based on data from week -2 to week 16 showing a 
descriptive analysis of both lowest and average SMPG of each.  
4.8.2 Biomarker analyses  
β-cell biomarker analyses fall outside this SAP. β-cell markers (glucose, insulin, and C-peptide) 
will be collected at baseline only during the MMTT at specific timepoints during Visit 3.1. These 
values will be utilized to model β-cell function by an external clinician once the trial is completed 
and the data are available. 
4.9 
INTERIM ANALYSES  
No interim analysis is planned. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
AESI: 
adverse events of special interest 
AUC0-4h: 
 area under the concentration versus time curve from time 0 to 4 hours 
CGM: 
continuous glucose monitoring 
CI: 
confidence interval 
CV: 
coefficient of variation 
DM-SAT: 
Diabetes Medication Satisfaction Tool 
DPP-4i: 
dipeptidyl peptidase-4 inhibitor 
eCRF: 
electronic case report form 
GLP-1RA: 
glucagon-like peptide 1 receptor agonist 
GMI: 
Glucose Management Indicator 
HbA1c: 
glycated hemoglobin 
HLGT: 
high level group term 
HLT: 
high level term 
HRQoL: 
health related quality of life 
ICF: 
informed consent form 
IMP: 
investigational medicinal product 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
MCAR: 
missing completely at random 
MedDRA: 
medical dictionary for regulatory activities 
MMTT: 
mixed-meal tolerance test 
MODD: 
mean of daily difference 
OAD: 
oral antidiabetic drug 
OC: 
observed cases 
PPG: 
postprandial glucose 
PRO: 
patient reported outcome 
PT: 
preferred term 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SMPG: 
self-measured plasma glucose 
SOC: 
system organ class 
SU: 
sulfonylurea 
T2DM: 
type 2 diabetes mellitus 
TAR: 
time above range, time above range 
TBR: 
time below range 
TE: 
treatment emergent 
TEAE: 
treatment-emergent adverse event 
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TIR: 
time in range 
TITR: 
 Time in Tight Range 
Tmax: 
time to reach maximum concentration 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
There are no changes to protocol-planned analyses. 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
5.3.1 Protocol deviations  
Significant protocol deviations, including drug dispensing irregularities, will be summarized in 
the enrolled analysis set. Protocol deviations due to the COVID-19 pandemic will be categorized 
as such. Protocol deviations will come from the clinical trial management system and will be 
categorized according to the rules document for protocol deviations.  
A listing of participants with at least one significant protocol deviation will be provided with 
comprehensive information related to each deviation identified. 
5.3.2 Demographics and baseline characteristics  
Treatment adherence, demographics, and baseline characteristics will be summarized in 
descriptive tables. Continuous data will be summarized using the number of observations 
available, mean, SD, quartile ranges, minimum, median, and maximum. Categorical data will be 
summarized using count and percentage. 
Baseline safety and efficacy parameters will be presented along with the safety and efficacy 
summaries. 
The following demographics and baseline characteristics will be summarized: 
• age in years as continuous variable and in categories of 65 ≤ and > 65 
• gender (Male, Female) 
• race: White, Black or African American, Asian (will subgroup Asian with Chinese, 
Japanese, Asian Indian, Korean, Other Asian Origin, Multiple Asian Origin, Asian Origin 
Not Reported, Asian Origin Unknown), Other, Multiple, Not Reported, Unknown.  
• ethnicity (Hispanic or Latino, not Hispanic or Latino, Not Reported, Unknown, Other 
Ethnicity) 
• weight (kg) 
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• height (cm) 
• BMI in kg/m2 as documented in eCRF and in categories BMI ≤ 30 (kg/m²) and BMI > 30 
(kg/m²) 
• OAD status (OAD with GLP-1RA or OAD without GLP-1RA) 
5.3.3 Medical or surgical history  
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the participant. Medical and surgical history will be coded to a LLT, PT, HLT, HLGT, 
and associated primary SOC using the MedDRA version currently in effect at Sanofi at the time 
of database lock. 
Specific disease history, including gestational diabetes, will be reported in the summary. 
Comorbidities will be summarized separately. Comorbid disease will be summarized from eCRF 
pages on the physical exam page completed by investigators based on participant report. Body 
system will be examined as assessment and defined as normal, abnormal, or not done.  
Medical and surgical history will be summarized for enrolled participants and by SOC and PT, 
sorted by internationally agreed order of SOC and by the decreasing frequency of PT within SOC.  
5.3.4 Disease characteristics at baseline  
The following baseline disease characteristics will be summarized (see Section 5.4.1 for 
calculation details): 
• HbA1c background % 
• Renal Function (measured in creatinine and uric acid) 
• Background medication. 
• Duration of diabetes 
• Age at onset T2DM 
Any technical details related to computation, dates, and imputations for missing dates are 
described in Section 5.4.2. 
Continuous data will be summarized using the number of observations, mean, standard deviation 
(SD), median, minimum, and maximum for enrolled participants. Categorical and ordinal data 
will be summarized using the number and percentage of enrolled participants. 
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5.3.5 Prior and concomitant medication  
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant used prior to first IMP administration.  Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any interventions received by the participant concomitantly 
to the IMP during the on-treatment period/from the first administration of IMP to the last 
IMP administration + 1 day. 
• Post-treatment medications are those the participant took in the timeframe spanning the 
last IMP administration +2 days (week 16) up to the end of the study (Week 18).  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as a post-treatment medication. If it cannot be determined whether a 
given medication was taken prior or concomitantly or post, it will be considered as prior, 
concomitant, and post-treatment medication. 
The prior and concomitant and post-treatment medications will be summarized for the enrolled 
set, by anatomic and therapeutic level. The summaries will be sorted by decreasing frequency of 
anatomic category (ATC) based on incidence. In case of equal frequency, alphabetical order will 
be used. Participants will be counted once each ATC category (anatomic or therapeutic) linked to 
the medications. 
Use of all concomitant medications will be recorded in the participant’s eCRF. This includes all 
prescription drugs, herbal products, vitamins, minerals, and OTC medications. Any changes in 
concomitant medications will also be recorded in the participant’s eCRF.  
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
5.4.1 Demographic formulas  
Age (years) = (Year of informed consent date – Year of birth) 
5.4.2 Disease characteristics formulas  
Duration of diabetes (years)= (Date of informed consent – Date of diagnosis of diabetes + 
1)/365.25 
Age at diagnosis of diabetes (years)= Year of diagnosis of diabetes – Year of birth 
5.4.3 Reference dates  
For efficacy analyses, Day 1 reference date is a participant’s enrollment date. For safety 
assessments, the Day 1 reference date is a participant’s first treatment date. 
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5.4.4 Missing Data  
For categorical variables, participants with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of participants with missing 
data is presented. 
Medication missing/partial dates  
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior and a concomitant medication. 
Adverse events and Hypoglycemic events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment, the adverse event will be classified as treatment emergent. These data imputations are 
for categorization purpose only and will not be used in listings. No imputation is planned for 
date/time of adverse event resolution. 
Missing date and time of first IMP administration 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after first dose day defined by the eCRF should be considered as treatment-emergent 
adverse events. 
The exposure duration should be kept as missing. 
Missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event within 
data collection per MedDRA PT, the maximal severity on the remaining occurrences will be 
considered. If the severity is missing for all the occurrences, a “missing” category will be added in 
the summary table. 
5.4.5 Timepoint assessment  
Diary Timepoint Definitions 
At Visit 3.1 (Day -1), participants on OADs or an oral or injectable GLP-1RA will be required to 
take their dose after the blood sample for fasting plasma glucose (FPG) and HbA1c is collected 
and 30 minutes before administration of the meal during the MMTT and measures for both β-cell 
function and PPG analyses will be captured. β-cell function (plasma glucose, insulin, and 
C-peptide) will be collected at baseline and only plasma glucose will be collected at week 16.  
Participants on a weekly GLP-1RA should have their baseline MMTT conducted within 7 (± 3) 
days after their last dose and administer their last weekly GLP-1RA dose 7 (± 2) days before the 
first dose of Soliqua 100/33. During Visit 3.1(on the morning of Day –1, the day before the first 
dose of Soliqua 100/33), the last doses of daily DPP-4i and daily GLP-1RA should be 
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administered. Down-titration of SU dose to 50% should occur at Visit 3.2 (when starting Soliqua 
100/33).  
Participants are enrolled into the trial at Visit 3.2, which is considered Day 1. The first dose of 
Soliqua 100/33 is administered at this visit (Visit 3.2). 
Visit windows 
All post-baseline data (e.g. CGM data, MMTT data, patient reported outcome data, laboratory 
data, physical exam data, and vital signs data) will use windowing to determine the analysis visit. 
The visit windows will consider nominal visits and unscheduled visits within the window. If there 
are two visits within a window, then the visit closest to the target day will be used. 
Table 8 – Visit Windows for non-CGM data 
Week 
Target Day 
Days 
Week -4 
-28 
informed consent date to -15 
Week -2 
-15 
-14 to -1 
First treatment 
1 
1 
Week 8 
57 
2 to 60 
Week 14 
99 
61 – 102 
Week 16 
113 
103 – 116 
 
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Schedule of Events 
 
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Abbreviations: ADA, American Diabetes Association; AE, adverse event; AESI, adverse event of special interest; BMI, body mass index; BP, blood pressure; CGM, continuous glucose 
monitoring; DM-SAT, Diabetes Medications Satisfaction Questionnaire; DPP-4i, dipeptidyl peptidase-4 inhibitor; DTP, direct-to-patient; eDiary, electronic diary; FPG, fasting plasma glucose; 
GLP-1RA, glucagon-like peptide-1 receptor agonist; Hb, hemoglobin; HbA1c, glycated hemoglobin; HCP, healthcare provider; IMP, investigational medicinal product; MMTT, mixed-meal 
tolerance test; OAD, oral antidiabetic drug; PPG, postprandial glucose; SAE, serious adverse event; SMPG, self-measured plasma glucose; SU, sulfonylurea.  
a For participants who discontinue study treatment prematurely, the visit window can be extended by 14 days to collect the CGM data, followed by MMTT data, before they permanently 
discontinue the treatment. Before permanent discontinuation of treatment regardless of the reason or as soon as possible after the decision for discontinuation has been made, if possible, the 
participant will undergo all procedures planned for the last dosing day with Soliqua 100/33 and the follow-up visit (ie, Visit 7 and above).  
b During the titration period, the dose of IMP will be adjusted upwards or downwards by 2 to 4 units every week, or at the investigator’s discretion, based on the participant’s blood glucose 
monitoring results, with the objective of safely attaining a fasting SMPG value of 80 to 100 mg/dL, as well as other glycemic goals, while minimizing the risk of hypoglycemia and 
hyperglycemia. The duration of the titration period and number of phone contacts to safely meet the study goals will also be at the discretion of the investigator.  
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c Participants will have the choice to have Visits 2, 5, and 6 performed at the study site or at home. This choice is to be determined at the screening visit. Participants who opt for site visits should 
be encouraged not to change to home visits during the study period. However, if this is unavoidable, the home health provider and the sponsor-approved courier company for IMP shipment will 
need at least 72 hours’ notice from the investigator to arrange a home visit and DTP IMP supply, if required.  
d Participants on weekly GLP-1RA should administer their last dose 7 (± 2) days before the first dose of Soliqua 100/33, whereas the last dose of daily DPP-4i and daily GLP-1RA (oral or 
injectable) should be administered on the morning of Day –1, the day before the first dose of Soliqua 100/33.  
e It is the first day of Soliqua 100/33 administration and includes a phone contact to ALL participants to ensure that all administration procedures were successfully executed and to answer any 
questions. The first day of Soliqua 100/33 administration (ie, Visit 3.2, Day 0) for participants on weekly GLP-1RA will depend on their administration schedule and may not be the day 
immediately following Visit 3.1. Soliqua 100/33 administration for these participants should be 7 (± 2) days after their last weekly GLP-1RA dose. A phone contact should be made to 
participants on weekly GLP-1RA on the day before Soliqua 100/33 initiation, to remind them of the next morning’s injection and to provide instructions for SoloStar pen use. The participants 
will provide their concomitant medication details to the site personnel over the phone.  
f Doses of SU should be down-titrated by 50% when Soliqua 100/33 is started on Day 0.  
g Weekly phone contacts for dose adjustments will be continued at the investigator’s discretion until the desired fasting SMPG value is achieved.  
h If the desired fasting SMPG value is not achieved in the first 8 weeks of treatment; the investigator has the option to continue weekly dose titration phone contacts for an additional 4 weeks (until 
Week 12) for the purpose of achieving glycemic targets.  
i At the end of the study, participants should discuss with the investigator, in collaboration with their HCP, whether to continue on the Soliqua 100/33 treatment regimen or transition to an alternate 
antihyperglycemic therapy.  
j An unscheduled visit can be planned anytime during the treatment period if IMP resupply is required. This can be a site visit or via phone contact with DTP IMP delivery. If DTP Soliqua 100/33 
supply is required, the sponsor-approved courier company will need at least 72 hours’ notice to collect Soliqua 100/33 treatment kits from a study site.  
k Visit 2 will be performed at Day –15 for ALL participants, including those on weekly GLP-1RA, who will administer their last dose 7 (± 2) days before the first dose of Soliqua 100/33; those 
taking daily SU (dose will be down-titrated by 50% on the morning of Soliqua 100/33 initiation); and those taking daily DPP-4i, and daily GLP-1RA (oral or injectable; their last dose will be 
administered on the morning of Day –1, the day before the first dose of Soliqua 100/33).  
l Body weight and height will be recorded during the screening period for the calculation of BMI (metric: BMI = weight (kg)/height [m2]) and only body weight will be recorded during the 
baseline and at the end of the treatment period.  
m Participants are required to measure fasting SMPG values before breakfast at least 3 to 4 times per week throughout the study period (to inform each dose adjustment) and record the results in 
the eDiary. During the titration period, fasting SMPG should be performed on each of the 3 to 4 days before each dose adjustment.  
n HbA1c will be measured during the screening and run-in periods, and at Visit 3.1 (before administration of the meal) at the central laboratory, to determine study eligibility, and at the end of the 
16-week treatment period (Visit 7), to determine change in glycemic control.  
o Blinded CGM will be performed for 14 continuous days. The baseline CGM measure will be captured before discontinuing the daily (oral or injectable) or weekly GLP-1RA, DPP-4i, or down-
titration of SU by 50%, and before initiation of Soliqua 100/33 treatment. During the run-in period, CGM device reinsertion will be allowed for participants who do not meet the CGM compliance 
criteria. During the end of the treatment period, CGM device reinsertion will also be allowed for participants who do not meet the CGM compliance criteria. 
p The MMTT includes a standardized meal (ie, Boost Very High Calorie) that contains approximately 530 kcal and is composed of 19% carbohydrates, 44% protein, and 33% fat. The composition 
and the quantity of the standardized meal must be identical throughout the study period. Baseline MMTT is to be performed before discontinuation of daily (oral or injectable) or weekly GLP-
1RA, DPP-4i, or down-titration of SU medications. Participants on weekly GLP-1RA should have their baseline MMTT conducted within 7 (± 3) days after their last dose. During the baseline 
(Visit 3.1), blood samples will be collected at the following time points: premeal (30 min) and just before administration of OADs or GLP-1RA (oral or injectable) (baseline); time 0 (just before 
meal administration); 10 min; 20 min; and 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal for plasma glucose, C-peptide, and insulin levels. At Visit 3.1, participants on OADs or an oral or 
injectable GLP-1RA will be required to take their dose after blood sample for FPG and HbA1c is collected and 30 minutes before administration of the meal during the MMTT (during which 
measures for both β-cell function and PPG analyses will be captured). Soliqua 100/33 should be administered 30 minutes before administration of the meal during the MMTT at Visit 7 (during 
which only measures for PPG analyses will be captured). At the end of the treatment period (Visit 7), blood samples will be collected for plasma glucose levels, as follows: premeal (30 min) and 
just before administration of Soliqua 100/33; and time 0 (just before meal administration); 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, and 4.0 hours post-meal. These values will be used for PPG analyses with the 
goal of deriving reduction in maximum glucose exposure in the 4-hour period after the breakfast meal after Soliqua 100/33 administration at Week 16 compared with baseline.  
q At baseline, the CGM device will be removed and the data will be downloaded on Day –1 at their next site visit (ie, Visit 3.1), after collection of C-peptide, insulin, and plasma glucose data from 
the MMTT. Downloaded CGM data will be reviewed by the investigator to determine participants’ study eligibility. At the end of the treatment period, the CGM device will be removed and the 
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data will be downloaded on the fifteenth day after CGM placement (ie, Visit 7; after collection of only plasma glucose data from the MMTT). Downloaded CGM data will be verified by the 
investigator at the site to determine participants’ study completion.  
r Participants who do not meet CGM compliance criteria at baseline will be considered screen failures.  
s Participants will undergo the MMTT to assess maximum PPG exposure in the 4-hour period after the breakfast meal with biomarkers of β-cell function (plasma glucose, insulin, and C-peptide) 
measured at Visit 3.1 (ie, site visit during the baseline period), whereas only plasma glucose will be assessed at Visit 7 (ie, end of the treatment period).  
t Participants should discontinue GLP-1RA, DPP-4i, or down-titrate SU medications after all baseline assessments have been completed. SU doses should be down-titrated by 50% when starting 
Soliqua 100/33, whereas the last dose of daily DPP-4i and daily GLP-1RA (oral or injectable) should be administered on the morning of Day –1, the day before the first dose of Soliqua 100/33. 
Participants on weekly GLP-1RA should administer their last dose 7 (± 2) days before the first dose of Soliqua 100/33.  
u Soliqua pen instructions will be given to all participants at Visit 3.1. A phone contact should be made to participants on weekly GLP-1RA on the day before Soliqua 100/33 initiation, to 
remind them of the next morning’s injection and to provide instructions for SoloStar pen use.  
v For the scheduled site visits, participants are required to arrive fasting without administering the Soliqua 100/33 injection. Fasting is defined as no food intake in the 8 hours before blood 
sampling, except water.  
w Baseline DM-SAT should be completed before discontinuation or down-titration of baseline therapies. The questionnaire should be completed at the start of the visit before any other study tests 
or procedures are performed or Soliqua 100/33 is administered.  
x The following hypoglycemia categories of interest will be presented: overall hypoglycemia and confirmed hypoglycemia (ADA Levels 1, 2, and 3; Section 6.3.2).  
y Urinalysis: pH, glucose, ketones, leukocytes, blood/Hb, protein.  
z Only for women of childbearing potential; urine pregnancy test. 
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5.5 
APPENDIX 5 DEVIATIONS FROM PLANNED STUDY CONDUCT  
This section summarizes major statistical changes in the current protocol version. 
Table 9 - Major statistical changes from approved version of protocol 
Protocol 
Version 
Protocol 
Version 
Date 
Deviations from Protocol 
Rationale 
1.0 
18-Aug-2022 
changing the endpoint to Correlation 
of Change in the Percentage of TIR 
(70 180 mg/dL) and Patient 
Reported Outcome (PRO) from 
Baseline to Week 16 
TIR is subject level and LS means of the 
PRO is not subject level, it is best not to use 
correlation 
 
 
Updating endpoint correlation of 
participants reaching 60 units/day 
insulin glargine U100 and TIR >70% 
to reaching 60 units and TIR > 70% 
and testing as a chi-square test 
instead of a correlation analysis. 
Association 60 units and TIR > 70% are 
binary variables 
 
 
Update CGM compliance definition 
to include 8 days with 100% data 
available in a 24- hour period and 9 
days with 89% of data available in a 
24-hour period for both baseline and 
week 16. 
The decision to update compliance rule is to 
allow the best opportunity for participants to 
be included in the efficacy analysis set to 
ensure we meet the best power available for 
sample size.   
 
 
 
 
 
 
VV-CLIN-0646625 1.0


Statistical Analysis Plan  
27-Apr-2023 
HOE901/AVE0010-LPS16990 - Soliqua 100/33 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 49 
6 
REFERENCES  
1. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose 
monitoring data interpretation: recommendations from the International Consensus on 
Time in Range. Diabetes Care. 2019;42(8):1593-603. 
 
2. Vigersky RA, McMahon C. The relationship of hemoglobin A1c to time-in-range in patients 
with diabetes. Diabetes Technol Ther. 2019;21(2):81-5. 
 
3. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 
2018. A consensus report by the American Diabetes Association (ADA) and the European 
Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41(12):2669-701. 
 
4. Jendle J, Testa MA, Martin M, et al. Continuous glucose monitoring in patients with type 2 
diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with 
prandial insulin lispro: an AWARD-4 substudy. Diabetes Obes Metab. 2016;18(10):999-1005. 
 
5. Richard M. Bergenstal, Roy W. Beck, Kelly L. Close, George Grunberger, David B. 
Sacks, Aaron Kowalski, Adam S. Brown, Lutz Heinemann, Grazia Aleppo, Donna B. 
Ryan, Tonya D. Riddlesworth, William T. Cefalu; Glucose Management Indicator (GMI): 
A New Term for Estimating A1C From Continuous Glucose Monitoring. Diabetes Care 1 
November 2018;41(11):2275–80. https://doi.org/10.2337/dc18-1581. 
 
6. Battelino, T, Alexander, C, Amiel S, et al. Continuous glucose monitoring and metrics for 
clinical trials: an international consensus statement.  Lancet Diabetes Endocrinology 
2023;11:42-57. 
 
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