Clinical trial NCT05552859
Conditions: Type 2 Diabetes Mellitus Renal Impairment
Sponsor: Sanofi
Start date: 2022-12-05; Completion date: 2023-08-04
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The TRENT trial is designed to confirm the efficacy and safety of Gla-300 compared with IDeg-100 in insulin-naïve patient (participants who have not tried insulin) with Type 2 Diabetes Mellitus (T2DM) and renal impairment. It will test the hypothesis that Gla-300 is non-inferior to IDeg-100 with glucose control. If achieved, the trial will also test for the superiority of Gla-300 compared with IDeg-100 in Hemoglobin A1c (HbA1c) reduction, without an increased potential risk of hypoglycemia.

Detailed description:
The trial will consist of the following periods:

* A screening period of up to 2 weeks,
* A 24-week, open-label treatment period, including a titration period and a maintenance period.
* A 7-day, post-treatment, safety follow-up period after the last dose of the study drug or after premature/permanent discontinuation from study drug treatment. This will be a phone contact, but could be a site visit if ongoing or new AEs emerge during the post-treatment period, if necessary.

Arms: arm 1: Gla-300 will be administered once daily for 24 weeks arm 2: Ideg-100 will be administered once daily for 24 weeks
Interventions: intervention 1: Insulin glargine 300 U/mL intervention 2: Insulin degludec 100 U/mL
Intervention descriptions: intervention 1: Insulin glargine 300 U/mL in the SoloStar pen, self-administered once daily for 24 weeks. intervention 2: Insulin degludec 100 U/mL will be self- administered once daily for 24 weeks.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
Universal Trial Number: U1111-1272-6776 
EudraCT Number: 2022-001485-35 
A 24-Week, Multicenter, Randomized, Open-Label, Parallel-Group Trial 
Comparing the Efficacy and Safety of Insulin Glargine 300 U/mL (Gla-300) 
and Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve People with 
Type 2 Diabetes Mellitus and Renal Impairment: TRENT Trial 
LPS17007 
Short Title: 
Gla-300 and IDeg-100 in Insulin-Naïve People with 
Type 2 Diabetes Mellitus and Renal Impairment 
Compound Number: 
HOE901-U300 (Insulin Glargine 300 U/mL) 
Trial Phase: 
Phase 4 
Sponsor: 
Sanofi-Aventis Recherche & Développement 
1 Avenue Pierre Brossolette 
91380 Chilly-Mazarin Cedex, France 
Sponsor Contact: 
 
 
 
 
 
Medical Monitor: 
 
  
Version of Protocol:  
Original, Version 1.0 
Date of Protocol:  
28 Apr 2022 
CCI
PPD


 
 
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 trial will be conducted according to the International Council for Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
28 April 2022
PPD


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Declaration of Investigator 
I have read and understood all sections of the protocol titled A 24-Week, Multicenter, 
Randomized, Open-Label, Parallel-Group Trial Comparing the Efficacy and Safety of Insulin 
Glargine 300 U/mL (Gla-300) and Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve 
People with Type 2 Diabetes Mellitus and Renal Impairment: TRENT Trial” and the 
accompanying product label. 
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 28 Apr 2022, 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-Aventis Recherche & Développement or implement protocol changes without 
independent ethics committee approval except to eliminate an immediate risk to patients.  
I agree to administer study drug only to patients under my personal supervision or the 
supervision of a sub-investigator. 
I will not supply the study drug to any person not authorized to receive it. Confidentiality 
will be protected. Patient identity will not be disclosed to third parties or appear in any trial 
reports or publications. 
I will not disclose information regarding this clinical investigation or publish results of the 
investigation without authorization from Sanofi-Aventis Recherche & Développement. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 


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Table of Contents 
Table of Contents .......................................................................................................................5 
List of Tables ............................................................................................................................10 
List of Figures ..........................................................................................................................10 
Protocol Synopsis..................................................................................................................... 11 
List of Abbreviations................................................................................................................36 
1 
Introduction ......................................................................................................................39 
1.1 
Background Information .........................................................................................39 
1.2 
Rationale .................................................................................................................40 
1.3 
Benefit-Risk Assessment ........................................................................................42 
2 
Trial Objectives, Estimands, and Endpoints .....................................................................44 
2.1 
Primary Objectives, Estimands, and Endpoints ......................................................44 
2.2 
Secondary Efficacy Objectives and Endpoints .......................................................45 
2.3 
Safety and Exploratory Objectives and Endpoints .................................................45 
3 
Investigational Plan ..........................................................................................................48 
3.1 
Trial Design .............................................................................................................48 
3.1.1 
Rationale For Trial Design .......................................................................54 
3.1.2 
Duration of Trial Participation for Each Patient ......................................54 
3.1.3 
End of Trial Definition .............................................................................55 
4 
Selection of Trial Population and Discontinuation/Withdrawal .......................................56 
4.1 
Inclusion Criteria ....................................................................................................56 
4.2 
Exclusion Criteria ...................................................................................................57 
4.3 
Screen Failure .........................................................................................................60 
4.4 
Discontinuation From Study Drug and/or Withdrawal From the Trial ...................60 
4.4.1 
Discontinuation From Study Drug Treatment .........................................60 
4.4.1.1 
Permanent Discontinuation ......................................................................61 
4.4.1.2 
Temporary Discontinuation .....................................................................61 
4.4.2 
Lost to Follow-Up ....................................................................................61 
4.4.3 
Handling of Withdrawals .........................................................................62 
4.4.4 
Replacements ...........................................................................................63 


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5 
Trial Treatments ................................................................................................................64 
5.1 
Study Drug ..............................................................................................................64 
5.2 
Non-Investigational Medicinal Product ..................................................................65 
5.2.1 
Background Noninsulin Antidiabetic Drug(s) .........................................65 
5.2.2 
Rescue Therapy ........................................................................................65 
5.3 
Storage and Dispensing ..........................................................................................67 
5.4 
Method of Assigning Patients to Treatment Arms ..................................................67 
5.5 
Treatments Administered ........................................................................................69 
5.5.1 
Dose Modifications ..................................................................................69 
5.6 
Identity of Study Drug ............................................................................................71 
5.7 
Management of Clinical Supplies ...........................................................................71 
5.7.1 
Study Drug Packaging and Storage .........................................................71 
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; 
For the CGM Substudy) ...........................................................................73 
5.8 
Overdose Management ...........................................................................................74 
5.8.1 
Treatment of Overdose ............................................................................74 
5.9 
Blinding ..................................................................................................................75 
5.9.1 
Compensation for Lack of Blinding ........................................................75 
5.10 Study Drug Accountability and Adherence.............................................................75 
5.11 Prior and Concomitant Therapy ..............................................................................76 
6 
Trial Assessments and Procedures ....................................................................................78 
6.1 
Efficacy Assessments ..............................................................................................78 
6.1.1 
HbA1c Measurements .............................................................................78 
6.1.2 
FPG Measurements ..................................................................................78 
6.1.3 
7-Point SMPG Profile ..............................................................................79 
6.1.4 
Fasting SMPG ..........................................................................................79 
6.1.5 
SMPG During Symptomatic Hypoglycemia ...........................................79 
6.1.6 
CGM Measures (For the CGM Substudy) ...............................................80 
6.2 
Safety Assessments .................................................................................................81 
6.2.1 
Physical Examination ..............................................................................81 


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6.2.2 
Hypoglycemia Events ..............................................................................81 
6.2.3 
Local Tolerability at the Injection Site and Hypersensitivity Reactions ..83 
6.2.4 
Vital Signs ................................................................................................84 
6.2.4.1 
Body Weight ............................................................................................84 
6.2.5 
Clinical Safety Laboratory Assessments..................................................85 
6.2.6 
Adverse Events ........................................................................................86 
6.2.6.1 
Suspected Unexpected Adverse Events ...................................................87 
6.2.6.2 
Adverse Events of Special Interest ..........................................................87 
6.2.6.3 
Pregnancy ................................................................................................88 
6.2.6.4 
Eliciting and Documenting AEs ..............................................................89 
6.2.6.5 
Reporting AEs ..........................................................................................89 
6.2.6.6 
Assessment of Severity ............................................................................90 
6.2.6.7 
Assessment of Causality ..........................................................................90 
6.2.6.8 
Follow-Up of Patients Reporting AEs .....................................................90 
6.2.7 
Safety Monitoring Committee .................................................................91 
6.2.8 
Guidelines for Reporting Product Complaints ........................................91 
6.3 
Sample Collections .................................................................................................91 
6.4 
Use of Biological Samples and Data For Future Research .....................................91 
7 
Trial-Specific Committees ................................................................................................93 
7.1 
Steering Committee ................................................................................................93 
8 
Statistical Considerations .................................................................................................95 
8.1 
Estimands and Intercurrent Events .........................................................................95 
8.1.1 
Intercurrent Events ...................................................................................95 
8.1.2 
Estimands .................................................................................................95 
8.2 
Statistical Hypothesis ..............................................................................................96 
8.3 
Sample Size Determination.....................................................................................97 
8.4 
Analysis Sets ...........................................................................................................97 
8.5 
Description of Subgroups to be Analyzed ..............................................................98 
8.6 
Disposition, Demographics, and Baseline Characteristics .....................................98 
8.7 
Statistical Analysis Methodology ...........................................................................99 
8.7.1 
General Considerations ............................................................................99 
8.7.2 
Overview of Statistical Methods: Estimation of Primary Estimands and 
Sensitivity Analyses ...............................................................................100 


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8.7.3 
Analysis of Primary Endpoints ..............................................................103 
8.7.3.1 
Main Estimation of Primary Estimand ..................................................103 
8.7.3.2 
Sensitivity Analysis of Primary Estimand .............................................104 
8.7.3.3 
Main Estimation of Supplementary Estimand .......................................105 
8.7.3.4 
Supportive Analysis of Supplementary Estimand .................................105 
8.7.4 
Analysis of Secondary Endpoints ..........................................................105 
8.7.5 
Analyses of Exploratory Endpoints .......................................................106 
8.7.6 
Analysis of Safety Evaluation ...............................................................106 
8.7.6.1 
Analysis of AEs .....................................................................................107 
8.7.6.2 
Hypoglycemia ........................................................................................108 
8.7.6.3 
Other Safety Analyses ............................................................................109 
8.7.7 
Other Analyses .......................................................................................109 
8.8 
Handling of Missing Data .....................................................................................109 
8.9 
Interim Analyses ...................................................................................................109 
8.10 Data Quality Assurance......................................................................................... 110 
8.10.1 
Data Management .................................................................................. 110 
9 
Ethics .............................................................................................................................. 112 
9.1 
Independent Ethics Committee or Institutional Review Board ............................ 112 
9.2 
Ethical Conduct of the Trial .................................................................................. 112 
9.3 
Patient Information and Consent .......................................................................... 112 
10 Investigator’s Obligations .............................................................................................. 114 
10.1 Confidentiality ...................................................................................................... 114 
10.2 Data Protection ..................................................................................................... 114 
10.3 Financial Disclosure and Obligations ................................................................... 117 
10.4 Investigator Documentation .................................................................................. 118 
10.5 Trial Conduct ........................................................................................................ 118 
10.6 Adverse Events and Trial Report Requirements ................................................... 119 
10.7 Investigator’s Final Report ................................................................................... 119 
11 Trial Management ..........................................................................................................120 
11.1 Monitoring ............................................................................................................120 
11.1.1 
External Data Monitoring Committee ...................................................120 
11.1.2 
Monitoring of the Trial ..........................................................................120 


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11.1.3 
Inspection of Records ............................................................................120 
11.2 Management of Protocol Amendments and Deviations........................................121 
11.2.1 
Modification of the Protocol ..................................................................121 
11.2.2 
Protocol Deviations ...............................................................................121 
11.3 Trial Termination ..................................................................................................122 
11.4 Final Report ..........................................................................................................122 
11.5 Records Retention .................................................................................................122 
11.6 Publication Policy, Disclosure, and Clinical Trial Registration ............................123 
11.6.1 
Publication Policy and Disclosure .........................................................123 
11.6.2 
Clinical Trial Registration ......................................................................123 
11.6.3 
Clinical Trial Results Disclosure ...........................................................123 
12 Reference List.................................................................................................................125 
13 Appendices .....................................................................................................................129 
13.1 Appendix: Details Specific to the CGM Substudy ...............................................129 
13.2 Appendix: Schedule of Events for the Main Trial ................................................132 
13.3 Appendix: Patient eDiary Information..................................................................136 
13.4 Appendix: Clinical Safety 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, Including AESIs ....................................................145 
13.6 Appendix: Contraceptive and Barrier Guidance ...................................................146 
13.7 Appendix: Liver Safety .........................................................................................151 
13.8 Appendix: Source Documents ..............................................................................153 


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List of Tables 
Table 2-1 
Primary Objectives, Estimands, and Endpoints .............................................. 44 
Table 2-2 
Secondary Objectives and Endpoints .............................................................. 45 
Table 2-3 
Safety and Exploratory Objectives and Endpoints ......................................... 45 
Table 5-1 
Overview of Study Drug To Be Administered ................................................ 65 
Table 5-2 
Recommended Dose-Adjustment Algorithm .................................................. 70 
Table 8-1 
Intercurrent Events .......................................................................................... 95 
Table 8-2 
Primary and Supplementary Estimands .......................................................... 95 
Table 13-1 
Schedule of Events for the CGM Substudy .................................................. 129 
Table 13-2 
Criteria for CGM Device Reinsertion ........................................................... 130 
Table 13-3 
Schedule of Events for the Main Trial .......................................................... 132 
Table 13-4 
Protocol-Required Safety Laboratory Assessments ...................................... 138 
 
List of Figures 
Figure 3-1 
Graphical Trial Design (Main Trial) ............................................................... 50 
Figure 3-2 
Graphical Trial Design (CGM Substudy) ....................................................... 52 
Figure 13-1 
Criteria for CGM Device Reinsertion ........................................................... 131 
 
 
 


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Protocol Synopsis 
Protocol 
Number: 
LPS17007 
Universal Trial 
Number: 
U1111-1272-6776 
EudraCT 
Number: 
2022-001485-35 
Compound 
Number: 
HOE901-U300 (insulin glargine 300 U/mL) 
Title: 
A 24-Week, Multicenter, Randomized, Open-Label, Parallel-Group 
Trial Comparing the Efficacy and Safety of Insulin Glargine 300 U/mL 
(Gla-300) and Insulin Degludec 100 U/mL (IDeg-100) in 
Insulin-Naïve People with Type 2 Diabetes Mellitus and Renal 
Impairment: TRENT Trial 
Short Title: 
Gla-300 and IDeg-100 in Insulin-Naïve People with Type 2 Diabetes 
Mellitus and Renal Impairment 
Sponsor: 
Sanofi-Aventis Recherche & Développement 
1 Avenue Pierre Brossolette 
91380 Chilly-Mazarin Cedex, France 
Trial Phase: 
Phase 4 
Trial Sites: 
Approximate number of sites: 74 
Indication: 
Type 2 diabetes mellitus and renal impairment 
Rationale: 
Due to profoundly altered glucose and insulin metabolism, people with 
diabetes and chronic kidney disease (CKD) are generally at increased 
risk of hypoglycemia and other short- and long-term complications 
(Galindo et al 2020).  
Second-generation basal insulin analogs, such as insulin glargine 
300 U/mL (Gla-300) and insulin degludec 100 U/mL (IDeg-100), have 
more stable and prolonged pharmacokinetic (PK)/pharmacodynamic 
(PD) profiles compared with insulin glargine 100 U/mL (Gla-100; 
Rosenstock et al 2018; Haluzík et al 2020), a first-generation analog. 
The EDITION and BEGIN clinical trial programs demonstrated 
similar glycemic control and reduced hypoglycemia risk with Gla-300 
or IDeg-100 when compared to Gla-100, with both achieving a ~1.4% 
decrease in glycated hemoglobin (HbA1c) in insulin-naïve people with 
type 2 diabetes mellitus (T2DM; Riddle et al 2014; Bolli et al 2015; 
Yki-Järvinen et al 2015; Roussel et al 2018; Haluzík et al 2020).  
Furthermore, when individual basal insulins were compared, Gla-300 
mimicked the typical physiological effects on glucose and lipid 


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metabolism, and suppressed glucagon, with lower within-day 
variability than Gla-100 (Haluzík et al 2020). A subanalysis of data in 
insulin-naïve people with uncontrolled T2DM and renal impairment 
(estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m2) in 
the BRIGHT trial (a multicenter, open-label, parallel-group, 24-week, 
non-inferiority trial) showed that Gla-300 treatment resulted in 
significantly greater improvement in HbA1c than IDeg-100, without 
increasing the occurrence of hypoglycemic events (Haluzík et al 
2020). 
While the clinical benefits of basal insulin in people with T2DM have 
been documented in several clinical trials (Riddle et al 2014; Bolli et al 
2015; Yki-Järvinen et al 2015; Roussel et al 2018; Rosenstock et al 
2018; Haluzík et al 2020), to date there have been no dedicated 
randomized clinical trials comparing basal insulins in insulin-naïve 
people with T2DM experiencing CKD. 
The TRENT trial is designed to confirm the efficacy and safety of 
Gla-300 compared with IDeg-100 in insulin-naïve patients with T2DM 
and renal impairment. It will test the hypothesis that Gla-300 is 
non-inferior to IDeg-100 with glucose control. If achieved, the trial 
will also test for the superiority of Gla-300 compared with IDeg-100 in 
HbA1c reduction, without an increased potential risk of hypoglycemia. 
A substudy will also be conducted in the North American sites to 
evaluate the effects of treatment with Gla-300 compared with 
IDeg-100 on metrics derived from blinded continuous glucose 
monitoring (CGM) at Week 12 and Week 24 in patients with T2DM 
and renal impairment. 
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Objectives and 
Endpoints: 
Objectives 
Endpoints 
Primary Objective 
Primary Endpoint 
• To demonstrate non-inferiority 
(with a margin of 0.3%) and, if 
achieved, to demonstrate the 
superiority in the efficacy of 
Gla-300 compared with IDeg-100 
in terms of change in HbA1c from 
baseline to Week 24 in 
insulin-naïve patients with T2DM 
and renal impairment who have 
glycemic levels above target with 
oral antidiabetic drugs (OADs) with 
or without glucagon-like peptide 1 
receptor agonist (GLP-1 RA) 
• HbA1c: Change from baseline to 
Week 24 (Gla-300 vs IDeg-100)  
Secondary Objectives 
Secondary Endpoints 
Secondary Efficacy Objective 
Secondary Efficacy Endpoints 
• To evaluate the effects of treatment 
with Gla-300 compared with IDeg-
100 on clinical parameters 
• Fasting plasma glucose (FPG): 
Change from baseline to Week 24 
• Fasting SMPG: Change from 
baseline to Week 24 
• 7-point SMPG profiles: Change 
from baseline to Week 24, per time 
point within 24-hour period 
• Percentage (%) of patients reaching 
HbA1c target of <7.0% at Week 24 
Safety Objective 
Safety Endpoints 
• To assess the safety and tolerability 
of Gla-300 and IDeg-100 
• Safety evaluations of the following 
(during the 24-week treatment 
period, during the titration period, 
and during the maintenance period): 
o 
All hypoglycemia events (see 
Section 6.2.2) 
o 
The frequency of and diurnal 
distribution (all day, daytime, 
and nocturnal) of 
hypoglycemia by category 
(symptomatic, asymptomatic, 
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severe) per the American 
Diabetes Association 
(ADA)/European Association 
for the Study of Diabetes 
(EASD) hypoglycemia 
classification 
o 
Local tolerability at injection 
site 
o 
Hypersensitivity reactions 
o 
Adverse events (AEs) and 
serious adverse events (SAEs), 
including adverse events of 
special interest (AESIs), and 
other safety evaluations, 
including vital signs and body 
weight 
Exploratory Objectives 
Exploratory Endpoints 
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Patient 
Population: 
Key Inclusion Criteria 
Each patient must meet all of the following criteria to be enrolled in 
this trial: 
1. Is an adult aged ≥18 years at screening. 
2. Was diagnosed with T2DM of >1-year duration and had glycemic 
levels above target with OADs with or without GLP-1 RA (oral or 
injectable) at stable doses for ≥3 months before the screening 
period. 
3. Has an HbA1c ≥7.5% and ≤10.5% at screening. 
4. Has renal impairment, as defined by an eGFR of 
<60 mL/min/1.73m2 and ≥15 mL/min/1.73m2 (using the Chronic 
Kidney Disease Epidemiology Collaboration [CKD-EPI] equation; 
National Kidney Foundation 2022).  
5. Has adequately controlled blood pressure with stable 
antihypertensive therapy at trial inclusion. 
6. Is insulin-naïve, except for short use of insulin not exceeding 
15 days during the last year before the screening period. 
7. Is capable of understanding the written informed consent, and 
provides signed written informed consent.  
8. Is willing and able to complete the electronic diary (eDiary) and 
agrees to comply with protocol requirements. 
9. Is willing and able to fast without having administered study drug 
for scheduled site visits. (Note: Fasting is defined as no intake of 
food or drink, except water, in the 8 hours before blood sampling.) 
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Key Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from 
the trial: 
1. Has initiated treatment with potential novel therapies like dual 
glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 
RA. 
2. Has a body mass index (BMI)* >45 kg/m² during the screening 
period. 
*Body weight and height will be recorded during the screening period 
for the calculation of BMI (BMI = weight [kg]/[height (m)]2). 
3. Has a history of hypoglycemia unawareness (defined as the onset 
of neuroglycopenia before the appearance of autonomic warning 
symptoms [eg, 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).  
4. Has a history of 2 or more episodes of severe hypoglycemia and/or 
2 or more episodes of diabetic ketoacidosis within the 6 months 
before the day of screening. 
5. Has been exposed to other investigational drug(s) within 1 month 
or  
5 half-lives from screening, whichever is longer. 
Trial Design: 
This is a multicenter, multinational, randomized, open-label, 
parallel-group clinical trial comparing the efficacy and safety of 
Gla-300 and IDeg-100 in insulin-naïve patients with T2DM and renal 
impairment who have glycemic levels above target with OADs with or 
without GLP-1 RA (oral or injectable), defined as an HbA1c level of 
≥7.5% and ≤10.5% and an eGFR of <60 mL/min/1.73m2 and 
≥15 mL/min/1.73m2 at screening. The trial will attempt to represent 
the diversity of the patient population with T2DM (eg, race, ethnicity) 
and renal impairment (ie, <45 mL/min/1.73m2) through site 
recruitment efforts. 
At the screening visit, diet and lifestyle recommendations will be 
provided to patients, if needed, at the investigator’s discretion. 
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Compliance with the diet and lifestyle recommendations will be 
discussed with the patient throughout the trial, if needed, and more 
specifically if glucose levels are above target. 
The trial will be conducted in approximately 630 patients. Patients will 
be randomly assigned in a 1:1 ratio to 1 of the 2 treatment arms: 
Gla-300 arm or IDeg-100 arm (Figure 1). 
At baseline (Day 0, Visit 2), all eligible participants will be randomly 
assigned to the Gla-300 arm or the IDeg-100 arm and will initiate their 
study drug treatment (Figure 1). They will be allowed to continue their 
current treatment with OADs with or without GLP-1 RA (oral or 
injectable; with stable doses for ≥3 months) throughout the trial period 
unless such treatments have to be stopped or modified for safety 
reasons (Section 5.2.1). 
During the titration period (ie, from Week 1 through Week 12), the 
doses of Gla-300 and IDeg-100 will be adjusted using a recommended  
dose-adjustment algorithm (Table 1). After randomization, the dose 
will be titrated at least weekly (but no more than every 3 days), until 
the patient reaches a target fasting SMPG value of 80 to 100 mg/dL 
(4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes. 
Thereafter, until the end of the trial, the doses of Gla-300 and 
IDeg-100 will be adjusted to maintain this glycemic target if deemed 
appropriate by the investigator. Dose adjustments will be based on a 
median of fasting SMPG values from the last 3 measurements, 
including the value on the day of titration, measured by the patient 
using glucose meters and accessories supplied by the sponsor through 
a vendor. Best efforts should be made to reach the glycemic target by 
8–12 weeks after randomization. 
Other efficacy parameters, including HbA1c, FPG, and 7-point SMPG, 
will be assessed at the time points specified in the schedule of events 
(SoE; Table 2). Adverse events and SAEs, including AESIs, and other 
safety evaluations, will be assessed at the time points specified in the 
SoE (Table 2). Physical examination findings, hypoglycemia events, 
and vital signs will also be recorded to evaluate the safety of the study 
drug (Table 2). 
The trial will consist of the following periods: 
• A screening period of up to 2 weeks, 
• A 24-week, open-label treatment period, including a titration 
period and a maintenance period. 
• A 7-day, post-treatment, safety follow-up period after the last dose 
of the study drug or after premature/permanent discontinuation 
from study drug treatment. This will be a phone contact, but could 


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be a site visit if ongoing or new AEs emerge during the 
post-treatment period, if necessary.  
At the end of the trial, patients should discuss with the investigator, in 
collaboration with their HCP, whether to continue on the Gla-300 or  
IDeg-100 treatment regimen or transition to an alternate 
antihyperglycemic therapy. Discussions and final decisions made 
should be clearly documented in the patients’ source documents. 
Estimated Trial 
Duration: 
The maximum trial duration per patient will be 27 weeks. Five site 
visits and at least 13 phone contacts are scheduled, as well as an 
unscheduled phone contact (during the treatment period) for study 
drug resupply, if required. A patient will be considered to have 
completed the trial if they have completed all phases of the trial, 
including the last visit (Week 25 follow-up phone contact). 
Efficacy 
Assessments: 
The SoE (for the main trial) is provided in Table 2. Details related to 
trial assessments and procedures for the CGM substudy are provided 
in Table 3. 
The efficacy assessments are as follows: 
• HbA1c measurements 
• FPG measurements 
• 7-point SMPG profile 
• Fasting SMPG 
• SMPG during symptomatic hypoglycemia 
HbA1c Measurements 
Blood samples will be collected to measure HbA1c at the different 
time points specified in the SoE (Table 2) at the central laboratory. 
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FPG Measurements 
Blood samples will be collected to measure FPG levels at the time 
points specified in the SoE (Table 2) at the central laboratory. For 
scheduled site visits, patients will be required to arrive having fasted 
without administering the study drug. Fasting is defined as no intake of 
food or drink, except water, in the 8 hours before blood sampling.  
7-Point SMPG Profile 
Patients will be supplied with a glucose meter and an eDiary during 
the screening period. Site staff will provide appropriate training to the 
patients on the proper use of the glucose meter and eDiary completion. 
The 7-point SMPG profile will be measured (and recorded in the 
patient’s eDiary) at the following 7 points: preprandial and 2 hours 
after starting breakfast, lunch, and dinner, and at bedtime. The time 
points are specified in the SoE (Table 2). 
Fasting SMPG 
Fasting SMPG values will be used to titrate and adjust study drug 
doses and monitor glycemic levels (Table 2). Patients will be required 
to measure fasting SMPG values (using the glucose meter supplied 
during the screening period) before breakfast and before 
administration of the study drug once daily throughout the treatment 
period; the results will be recorded in the eDiary.  
SMPG During Symptomatic Hypoglycemia 
Whenever patients experience hypoglycemia symptoms, they  
(or others, if applicable) should measure plasma glucose (using the 
glucose meter supplied during the screening period), if possible. 
Patients will be instructed to measure plasma glucose levels before 
carbohydrate intake/administration of glucose whenever symptomatic 
hypoglycemia is suspected (Section 6.2.2), unless safety 
considerations necessitate immediate carbohydrate/glucose rescue 
before confirmation with the SMPG values. 
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Safety 
Assessments: 
The safety assessments are as follows: 
• AEs and SAEs, including AESIs 
• Hypoglycemia events 
• Local tolerability at the injection site and hypersensitivity reactions 
• Physical examination 
• Vital signs 
• Clinical safety laboratory assessments 
Adverse Events and Serious Adverse Events, including Adverse Events 
of Special Interest 
All AEs (serious or nonserious) will be recorded from the signing of 
the informed consent form (ICF) until the safety follow-up visit, the 
patient’s permanent discontinuation from the trial, or loss to follow-up 
(Table 2). 
The definitions of AEs and SAEs are provided in Section 13.5.  
The definition of an AESI is provided in Section 6.2.6.2. 
The following AEs will be considered as AESIs in this trial: 
• Pregnancy of a female patient enrolled in the trial, as well as 
pregnancy occurring in a female partner of a male patient enrolled 
in the trial with study drug/non-investigational medicinal product 
(NIMP). 
o A urine pregnancy test (only for woman of childbearing 
potential [WOCBP]) will be performed at the time points 
specified in the SoE (Table 2). 
o Any female patient who becomes pregnant while participating 
in the trial will be discontinued from study drug treatment. 
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• Symptomatic overdose (serious or nonserious) with study 
drug/NIMP. 
• Increase in alanine aminotransferase (ALT; >3 × upper limit of 
normal [ULN]). 
Hypoglycemia Events 
Hypoglycemia events will be assessed at the time points specified in 
the SoE (Table 2). 
During the trial, patients will be instructed to document any 
hypoglycemia events (including any possible reasons for 
hypoglycemia [eg, physical exercise, skipped meal]) in their eDiary. 
This will be reported in the specific hypoglycemia event information 
form in the electronic case report form (eCRF). The information 
recorded will include onset date and time; symptoms and/or signs; the 
SMPG value, if available; and the treatment, with documentation of 
whether the patient required outside assistance to achieve neurologic 
recovery. A hypoglycemia event that fulfills the seriousness criteria 
will also be documented on the SAE form in the eCRF. 
Hypoglycemia events will be evaluated based on the categories of 
interest listed in Section 6.2.2. 
Local Tolerability at the Injection Site and Hypersensitivity Reactions 
If the investigator or the patient recognizes any signs of local 
intolerability at the study drug injection site or hypersensitivity 
reactions, the event should be recorded in the AE page in the eCRF. 
Physical Examination 
A physical examination will be performed, per standard of care, to 
assess the health status of patients at the time points specified in the 
SoE (Table 2).  
Vital Signs 
Vital signs (including body weight, heart rate, systolic blood pressure 
[SBP], and diastolic blood pressure [DBP]) will be recorded at the 
time points specified in the SoE (Table 2). Height and body weight 
measurements at screening will be used to calculate BMI. 
Body Weight: Body weight will be measured to assess the change from 
baseline to Week 24. Self-reported weights are not acceptable. 
Clinical Safety Laboratory Assessments 
All clinical safety laboratory assessments (ie, hematology, clinical 
chemistry, urinalysis) will be performed by the central laboratory.  
The list of clinical safety laboratory tests to be performed is provided 


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in Section 13.4. The timing and frequency of sample collection are 
provided in the SoE (Table 2).  
Additional tests may be performed at a local or central laboratory at 
any time during the trial, as deemed necessary by the investigator or 
required by local regulations. If a test is used to evaluate an AE 
(diagnostic, follow-up, outcome), the results (including, notably, the 
disease progression of CKD) must be entered into the eCRF. 


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Study Drug, 
Dosage, and 
Route of 
Administration: 
The study drugs are Gla-300 or IDeg-100 and will be supplied as 
prefilled, disposable pens (Gla-300 as a SoloStar® pen and IDeg-100 
as a FlexTouch® pen). 
• Formulation:  
o Gla-300 will be supplied as a sterile, nonpyrogenic, clear, 
colorless solution in a SoloStar prefilled (disposable) pen for 
subcutaneous (SC) injection. 
o IDeg-100 will be supplied as a sterile, nonpyrogenic, clear, 
colorless solution in a FlexTouch prefilled (disposable) pen for 
SC injection. 
• Unit dose strength(s)/Dosage level(s):  
o Gla-300: Each Gla-300 SoloStar pen contains 450 U of insulin 
glargine (1.5 mL of 300 U/mL insulin glargine solution). 
o IDeg-100: Each IDeg-100 FlexTouch pen contains 300 U of 
insulin degludec (3 mL of 100 U/mL insulin degludec solution). 
• Route of administration: The study drug will be administered via 
SC self-injection into the abdominal area, thigh, or upper arm 
using the SoloStar pen or FlexTouch pen. Injection sites should be 
rotated within the same region from 1 injection to the next to 
reduce the risk of lipodystrophy.  
• Time of administration: Gla-300 or IDeg-100 should be 
self-administered once daily between 6:00 PM and 8:00 PM 
throughout the treatment period. The investigator and patient will 
discuss and agree upon the injection time at Visit 2 
(baseline/randomization). 
Starting Dose 
Per the product label, in insulin-naïve patients with T2DM, the 
recommended starting dose of Gla-300 is 0.2 U/kg of body weight 
once daily and the recommended starting dose of IDeg-100 is 10 U 
once daily. 
Dose Modifications 
During the trial, the dose of study drug will be titrated to achieve 
glycemic targets without hypoglycemia using the recommended  
dose-adjustment algorithm (Table 1). 
• After randomization, the dose will be titrated at least weekly (but 
no more than every 3 days) until the patient reaches a target fasting 
SMPG value of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while 
avoiding hypoglycemia episodes.  


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• Thereafter, until the end of the trial, the doses of Gla-300 and 
IDeg-100 will be adjusted to maintain this glycemic target, if 
deemed appropriate by the investigator. 
Best efforts should be made to reach the glycemic target by 
8-12 weeks after randomization. 
Table 1 
Recommended Dose-Adjustment Algorithm  
Mediana of Fasting SMPG Values From 
the Last 3 Measurements 
Gla-300 and IDeg-100 Dose 
Adjustmentb 
>140 mg/dL (>7.8 mmol/L) 
+6 U  
>120 to ≤140 mg/dL (>6.7 to 
≤7.8 mmol/L) 
+4 U 
>100 to ≤120 (>5.6 to ≤6.7 mmol/L) 
+2 U 
Glycemic target: ≥80 to ≤100 mg/dL 
(≥4.4 to ≤5.6 mmol/L) 
No change 
<80 mg/dL (<4.4 mmol/L) or occurrence of 
≥1 confirmed symptomatic hypoglycemia 
event(s) in the preceding week 
–2 U or –10% of the previous dose, 
or at the discretion of the 
investigator or any qualified 
designee 
Abbreviations: Gla-300, insulin glargine 300 U/mL; IDeg-100, insulin degludec 
100 U/mL; SMPG, self-measured plasma glucose. 
a 
Median refers to an intermediate SMPG value (ie, the value between the lowest 
and the highest SMPG values when the values are ranked in a growing order). 
b 
Dose adjustment should not occur more than every 3 days. 
Non-Investigational Medicinal Product 
The protocol-allowed background noninsulin antidiabetic drug(s) and 
rescue therapies used to treat hyperglycemia are considered NIMPs. 
Background noninsulin antidiabetic drug(s) (ie, OADs and GLP-1 RA 
[oral or injectable]) that patients are receiving before screening will be 
continued during the treatment period unless the treatments have to be 
stopped or modified for safety reasons. 
Rescue Therapy 
“Rescue therapy,” adding a new antidiabetic drug or increasing the 
dose of an existing antihyperglycemic, non-study drug that is part of 
the patient’s current regimen, if needed, should be based on the 
investigator’s decision and local labeling documents. 
Statistical 
Methods: 
Sample Size Determination 
This trial is designed with a primary objective of demonstrating that 
Gla-300 is non-inferior to IDeg-100 regarding change from baseline to 
Week 24 in HbA1c level, with a non-inferiority margin of 0.3%, a 
2.5% alpha risk (1-sided), and 90% power, assuming an SD of 1.1 and 
10% dropouts.  


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A sample size of 566 randomized patients (283 per treatment arm with 
a 1:1 allocation ratio) is expected to ensure that the upper bound of the 
2-sided 95% CI for the difference in the mean change from baseline to 
Week 24 in HbA1c level between Gla-300 and IDeg-100 would not 
exceed the non-inferiority margin of 0.3% with approximately 90% 
power. This calculation assumes a common SD of 1.1% with a 1-sided 
test at the 2.5% significant level and that the true difference in the 
mean change between Gla-300 and IDeg-100 is 0. Assuming a 10% 
dropout rate, a total of 630 patients will be randomized (315 per 
treatment arm). 
Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
• Safety set: The safety set will consist of all patients who receive at 
least 1 dose of study drug treatment. All analyses using the safety 
set will be done according to the treatment actually received. 
• Intention-to-treat (ITT) set: The ITT set will consist of all patients 
who sign the ICF and are randomized into the trial. All analyses 
using the ITT set will group patients according to randomized 
treatment.  
• Per protocol set (PPS): The PPS will consist of all randomized 
patients who complete the trial without major protocol deviations. 
The ITT set will be used for the primary efficacy analyses, the PPS 
will be used for a supportive analysis for non-inferiority, and the safety 
analyses will be based on the safety set. Patients’ disposition will be 
presented for the ITT set. 
Statistical analyses will be performed using SAS software Version 9.4 
or higher. Continuous variables will be summarized using the mean, 
SD, median, minimum, and maximum. Categorical variables will be 
summarized using frequency counts and percentages.  
All CIs presented will be 2-sided 95% CIs, unless otherwise specified. 
For the primary efficacy endpoint, non-inferiority will be established if 
the 2-sided 95% CI of the difference in the mean change from baseline 
to Week 24 in HbA1c level between Gla-300 and IDeg-100 lies 
entirely below 0.3% (equivalent to a 1-sided test at the 2.5% 
significance level). If non-inferiority is demonstrated, superiority of 
Gla-300 to IDeg-100 will also be considered and established if the 
95% CI lies entirely below 0%. 
The primary efficacy endpoint will be analyzed using an analysis of 
covariance (ANCOVA) model including baseline HbA1c value as a 
covariate, and study treatment and stratification factors at 


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randomization (other than the categorized HbA1c) as fixed factors.  
A multiple imputation (MI) strategy will be employed for handling 
missing data. 
Safety data will be descriptively summarized using the safety set. 
Details of the analysis plans will be specified in a separate statistical 
analysis plan (SAP). 
Date of 
Protocol: 
28 Apr 2022 


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Figure 1 
Graphical Trial Design (Main Trial) 
 
Abbreviations: AE, adverse event; CGM, continuous glucose monitoring; DTP, direct-to-patient; Gla-300, insulin glargine 300 U/mL; HCP, healthcare provider; 
IDeg-100, insulin degludec 100 U/mL; IMP, investigational medicinal product; SMPG, self-measured plasma glucose. 
a 
An unscheduled visit can be planned anytime during the treatment period if study drug resupply is required. This will be via phone contact with DTP-IMP 
delivery. The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial site. All patients who withdraw from 


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the trial prematurely will, as soon as possible, undergo all end-of-trial and follow-up assessments/procedures at a visit that should be identified as “the early 
trial discontinuation visit.” 
b 
During the titration period, the doses of Gla-300 and IDeg-100 will be adjusted using a recommended dose-adjustment algorithm (Table 1). After 
randomization, the dose will be titrated at least weekly (but no more than every 3 days) until the patient reaches a target fasting SMPG value of  
80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes. Thereafter, until the end of the trial, the doses of Gla-300 and IDeg-100 will be 
adjusted to maintain this glycemic target, if deemed appropriate by the investigator. Dose adjustments will be based on a median of fasting SMPG values 
from the last 3 measurements, including the value on the day of titration, measured by the patient using glucose meters and accessories supplied by the 
sponsor through a vendor. Best efforts should be made to reach the glycemic target by 8–12 weeks after randomization. 
c 
d 
At the end of the trial, patients should discuss with the investigator, in collaboration with their HCP, whether to continue on the Gla-300 or IDeg-100 
treatment regimen or transition to an alternate antihyperglycemic therapy. 
e 
This will be a phone contact, but could be a site visit if ongoing or new AEs emerge during the post-treatment period, if necessary. 
 
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Table 2 
Schedule of Events for the Main Trial 
Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography (including 
height) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Current medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Study drug dispensing 
 
X 
 
X 
 
Xg 
 
X 
 
 
 
X 
 
SoloStar or FlexTouch pen 
instructionh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient eDiary setup 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient eDiary completion 
<----------------------------------------------------------------------------------------------X-------------------------------------------------------------------> 
 
Collection of eDiary 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
Glucose meter (dispensing 
and instruction) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of glucose meter 
(if mandatory by local 
regulation) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Daily dosing of Gla-300 or 
IDeg-100i 
 
<--------------------------------------------------------------------------------------X----------------------------------------------------------------> 
 
Study drug dose 
adjustments 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


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Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study drug adherence and 
accountability 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
HbA1c 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
FPGj 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Fasting SMPGk 
 
<-----------------------------------------------------------------------------X--------------------------------------------------> 
 
 
7-point SMPGl 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Hypoglycemia eventsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Recording of AEs and 
SAEs (including AESIs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Product complaints 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (including body 
weight)n 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Clinical chemistryo 
Xp 
 
 
 
 
 
 
 
 
 
Xp 
 
 
Hematologyo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysiso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine albumin: 
creatinine ratio 
Xp 
 
 
 
 
 
 
 
 
 
Xp 
 
 
Pregnancy testq 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; BMI, body mass index; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney 
Disease Epidemiology Collaboration; cr, creatinine; DBP, diastolic blood pressure; DTP, direct-to-patient; eDiary, electronic diary; eGFR, estimated glomerular filtration rate; FPG, fasting plasma 
glucose; Gla-300, insulin glargine 300 U/mL; HbA1c, glycosylated hemoglobin; HCP, healthcare provider; IDeg-100, insulin degludec 100 U/mL; IMP, investigational medicinal product; 
SAE, serious adverse event; SBP, systolic blood pressure; Scr, serum creatinine; SMPG, self-measured plasma glucose; WOCBP, women of childbearing potential. 
a 
During the titration period, the doses of Gla-300 and IDeg-100 will be adjusted using a recommended dose-adjustment algorithm (Table 1). After randomization, the dose will be titrated at least 
weekly (but no more than every 3 days) until the patient reaches a target fasting SMPG value of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes. Thereafter, until the 
end of the trial, the doses of Gla-300 and IDeg-100 will be adjusted to maintain this glycemic target, if deemed appropriate by the investigator. Dose adjustments will be based on a median of 


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Protocol: LPS17007 (Original, Version 1.0) 
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fasting SMPG values from the last 3 measurements, including the value on the day of titration, measured by the patient using glucose meters and accessories supplied by the sponsor through a 
vendor. Best efforts should be made to reach the glycemic target by 8–12 weeks after randomization. 
c 
At the end of the trial, patients should discuss with the investigator, in collaboration with their HCP, whether to continue on the Gla-300 or IDeg-100 treatment regimen or transition to an alternate 
antihyperglycemic therapy. All patients who withdraw from the trial prematurely will, as soon as possible, undergo all end-of-trial and follow-up assessments/procedures at a visit that should be 
identified as “the early trial discontinuation visit.” 
d 
An unscheduled visit can be planned anytime during the treatment period if study drug resupply is required. This will be a site visit or via phone contact with DTP-IMP delivery. The 
sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial site. 
e 
This will be a phone contact, but could be a site visit if ongoing or new AEs emerge during the post-treatment period, if necessary. 
f 
A physical examination will be performed per standard of care to assess the health status of patients. A list of assessments is provided in Section 6.2.1. 
g 
Study drug resupply at Visit 10 will be via phone contact with DTP-IMP delivery. The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial 
site. 
h 
All patients will be trained by trial staff on how to use the pen correctly, how to store it, and how to change the needle to ensure that each patient is able to perform self-injection. An instruction 
leaflet will be provided to patients that explains how to use the disposable pen and needles. Training will be repeated during the treatment period as often as deemed necessary by site staff. 
i 
Gla-300 or IDeg-100 should be self-administered once daily between 6:00 PM and 8:00 PM throughout the treatment period. The investigator and patient will discuss and agree upon the injection 
time. Gla-300 or IDeg-100 will be administered after the fasting blood sample draw during site visits. The need for dose adjustment will be assessed at each visit. 
j 
For scheduled site visits, patients will be required to arrive having fasted without administering the study drug. Fasting is defined as no intake of food or drink, except water, in the 8 hours before 
blood sampling. 
k 
Fasting SMPG values will be used to titrate and adjust study drug doses and monitor glycemic levels. Patients will be required to measure fasting SMPG values (using the glucose meter supplied 
during the screening period) before breakfast and before administration of study drug once daily throughout the treatment period and to record the results in the eDiary.  
l 
The 7-point SMPG profile will be measured (and recorded in the patient’s eDiary) at the following 7 points: preprandial and 2 hours after starting breakfast, lunch, and dinner, and at bedtime. The 
7-point SMPG profile will be performed over a single, 24-hour period, on at least 2 days within the week before selected site visits. 
m 
Hypoglycemia events will be evaluated based on the categories of interest described in Section 6.2.2. 
n 
This includes body weight, heart rate, SBP, and DBP. Height and body weight measurements at screening will be used to calculate BMI. 
o 
The list of clinical safety laboratory tests to be performed is provided in Section 13.4). Additional tests may be performed at a local or central laboratory at any time during the trial as deemed 
necessary by the investigator or required by local regulations. The central laboratory should calculate eGFR using the CKD-EPI equation: eGFRcr = 142 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.200 × 
0.9938Age × 1.012 [if female] (National Kidney Foundation 2022). 
p 
Creatinine and eGFR (clinical chemistry) and spot urine albumin: creatinine ratio will be measured for CKD monitoring. 
q 
This is only for WOCBP and is a urine pregnancy test. 
 
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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 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
BP 
blood pressure 
BMI 
body mass index 
CFR 
Code of Federal Regulations 
CGM 
continuous glucose monitoring 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CNIL 
Commission Nationale de l’Informatique et des Libertés 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
CSR 
clinical study report 
CV 
coefficient of variation 
CVD 
cardiovascular disease 
DBP 
diastolic blood pressure 
DTP 
direct-to-patient 
EASD 
European Association for the Study of Diabetes 
eCRF 
electronic case report form 
EDC 
electronic data collection 
eDiary 
electronic diary 
eGFR 
estimated glomerular filtration rate 
FDA 
Food and Drug Administration 
FPG 
fasting plasma glucose 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 


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Abbreviation 
Definition 
GIP 
glucose-dependent insulinotropic polypeptide 
Gla-100 
insulin glargine 100 U/mL 
Gla-300 
insulin glargine 300 U/mL 
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  
HRT 
hormonal replacement therapy 
IB 
investigator’s brochure 
ICE 
intercurrent event 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IDeg-100 
insulin degludec 100 U/mL 
IEC 
independent ethics committee 
IR 
Investigator Registry 
IRB 
institutional review board 
ITT 
intention-to-treat 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IVRS 
interactive voice response system 
IWRS 
interactive web response system 
LAM 
lactational amenorrhea method 
LS 
least-squares 
MAR 
missing at random 
MCMC 
Markov chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
multiple imputation 
MMRM 
mixed-effect model with repeated measures 
MNAR 
missing not at random 
NIMP 
non-investigational medicinal product 
NYHA 
New York Heart Association 


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Abbreviation 
Definition 
OAD 
oral antidiabetic drug 
OR 
odds ratio 
OTC 
over-the-counter 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PPS 
per protocol set 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SC 
subcutaneous 
SGLT-2i 
sodium-glucose co-transporter-2 inhibitor 
SIP 
Shared Investigator Platform 
SMPG 
self-measured plasma glucose 
SOC 
system organ class 
SoE 
schedule of events 
SU 
sulfonylureas 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TAR 
time above range 
TBR 
time below range 
TEAE 
treatment-emergent adverse event 
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 
Chronic kidney disease (CKD) affects approximately 20% to 40% of people with diabetes 
and is an independent risk factor for both cardiovascular disease (CVD) and the occurrence 
of hypoglycemia (Rabkin 2003; Alsahli and Gerich 2014; Papademetriou et al 2015; 
Haluzík et al 2020). Glycemic control is vital to slowing the progression of CKD in people 
with type 2 diabetes mellitus (T2DM); however, lowering glycated hemoglobin (HbA1c) in 
severe or stage 4 CKD is not only challenging due to various patient and pharmacological 
factors but is also unlikely to completely arrest CKD progression (Cherney et al 2021). 
Hypoglycemia is a key issue for people with diabetes and CKD, as it is associated with 
increased morbidity and mortality, particularly in relation to CVD. Additionally, comorbid 
CKD increases the difficulty of managing diabetes because some treatment options, such as 
metformin, sulfonylureas (SUs), α-glucosidase inhibitors, and sodium-glucose 
co-transporter-2 inhibitors (SGLT-2i) are contraindicated or not recommended as renal 
function deteriorates because of the risk of hypoglycemia, drug accumulation, or lack of 
glycemic efficacy (Haluzík et al 2020). Hence, there is a need for therapies that are 
well-tolerated and effective in lowering glucose levels in people with T2DM and CKD, 
which will allow them to achieve glycemic targets while minimizing hypoglycemia. 
Insulin is being used increasingly to treat people with T2DM experiencing CKD, but current 
treatment guidelines have not provided specific guidance for insulin brand administration in 
this patient population (Association of British Clinical Diabetologists and The Renal 
Association 2021; Navaneethan et al 2021). While people with T2DM and renal impairment 
(early to most advanced stages of CKD) on basal and/or rapid-acting insulin continue to 
experience the clinical outcome benefits from optimized glycemic control, CKD puts them at 
increased risk of hypoglycemia compared to those with normal renal function. Moreover, 
because of the reduced renal insulin catabolism and impaired hypoglycemia counter-
regulation in CKD, more careful titration of insulin is required in patients with reduced renal 
function, to minimize the risk of hypoglycemia. Therefore, it would be valuable to identify 
insulin options with more desirable safety profiles for people with T2DM and CKD 
(Haluzík et al 2020). 


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1.2 Rationale 
Due to profoundly altered glucose and insulin metabolism, people with diabetes and CKD are 
generally at increased risk of hypoglycemia and other short- and long-term complications 
(Galindo et al 2020).  
Second-generation basal insulin analogs, such as insulin glargine 300 U/mL (Gla-300) and 
insulin degludec 100 U/mL (IDeg-100), have more stable and prolonged pharmacokinetic 
(PK)/pharmacodynamic (PD) profiles compared with insulin glargine 100 U/mL (Gla-100; 
Rosenstock et al 2018; Haluzík et al 2020), a first-generation analog. The EDITION and 
BEGIN clinical trial programs demonstrated similar glycemic control and reduced 
hypoglycemia risk with Gla-300 or IDeg-100 when compared to Gla-100, with both 
achieving a ~1.4% decrease in glycated hemoglobin (HbA1c) in insulin-naïve people with 
T2DM (Riddle et al 2014; Bolli et al 2015; Yki-Järvinen et al 2015; Roussel et al 2018; 
Haluzík et al 2020). 
Furthermore, when individual basal insulins were compared, Gla-300 mimicked the typical 
physiological effects on glucose and lipid metabolism, and suppressed glucagon, with lower 
within-day variability than Gla-100 (Haluzík et al 2020). A subanalysis of data in 
insulin-naïve people with uncontrolled T2DM and renal impairment (estimated glomerular 
filtration rate [eGFR] <60 mL/min/1.73m2) in the BRIGHT trial (a multicenter, open-label, 
parallel-group, 24-week, non-inferiority trial) showed that Gla-300 treatment resulted in 
significantly greater improvement in HbA1c than IDeg-100, without increasing the 
occurrence of hypoglycemic events (Haluzík et al 2020). Recent Tresiba studies have been 
conducted in people with T2DM who were at increased risk for hypoglycemia  
(Goldenberg et al 2021). 
While the clinical benefits of basal insulin in people with T2DM have been well documented 
in several clinical trials (Riddle et al 2014; Bolli et al 2015; Yki-Järvinen et al 2015; Roussel 
et al 2018; Rosenstock et al 2018; Haluzík et al 2020), to date there have been no dedicated 
randomized clinical trials comparing basal insulins in insulin-naïve people with T2DM 
experiencing CKD. 
The TRENT trial is designed to confirm the efficacy and safety of Gla-300 compared with 
IDeg-100 in insulin-naïve patients with T2DM and renal impairment. It will test the 
hypothesis that Gla-300 is non-inferior to IDeg-100 with glucose control. If achieved, the 
trial will also test for the superiority of Gla-300 compared with IDeg-100 in HbA1c 


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reduction, without an increased potential risk of hypoglycemia. The study will also determine 
if potential treatment differences can be explained based on the ease of titration of Gla-300 as 
well a more stable PK/PD profile compared with IDeg-100. 
A substudy will also be conducted in the North American sites to evaluate the effects of 
treatment with Gla-300 compared with IDeg-100 on metrics derived from blinded continuous 
glucose monitoring (CGM) at Week 12 and Week 24 in patients with T2DM and renal 
impairment.  
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1.3 Benefit-Risk Assessment 
The safety and effectiveness of Gla-300 and IDeg-100 in people with T1DM and T2DM have 
been well established. Post-marketing experience with Gla-300 and IDeg-100 has 
demonstrated that their safety profiles are similar to those of other products in this 
therapeutic class. Overall, based on a review of the safety and efficacy data, the benefit-risk 
balance of Gla-300 and IDeg-100 under the currently approved conditions of use remains 
favorable; no new risks have been identified for the patient population to be included in the 
TRENT trial. 
The starting doses of Gla-300 and IDeg-100 used in this trial are per the approved product 
label (ie, 0.2 U/kg body weight once daily and 10 U once daily, respectively)  
(TOUJEO 2020; Toujeo 300 2020; TRESIBA® 2019; Tresiba 100 2021). During the titration 
period of the trial, doses of Gla-300 or IDeg-100 will be titrated using the same 
dose-adjustment algorithm that was used in the BRIGHT trial (Rosenstock et al 2018). All 
eligible participants will benefit from medical care and monitoring of their glucose level. 
Therefore, the risk for patients participating in this trial is considered acceptable. 
The important identified risks for Gla-300 and IDeg-100 are hypoglycemia or hyperglycemia 
associated with alterations in the insulin dosing regimen, medication errors (eg, accidental 
mix-ups between basal insulin products and other insulins, particularly rapid-acting), fluid 
retention and heart failure (when concomitantly used with peroxisome proliferator-activated 
receptor-gamma agonists), and adverse reactions, such as hypoglycemia, hypersensitivity and 
allergic reactions, and hypokalemia (TOUJEO 2020; Toujeo 300 2020; TRESIBA® 2019; 
Tresiba 100 2021). 
The patients with T2DM included in this trial will be insulin-naïve, will have uncontrolled 
glucose levels with their current therapy (as evident from an HbA1c level of ≥7.5% and 
≤10.5%), and will have renal impairment (as evident from an eGFR of <60 mL/min/1.73m2 
and ≥15 mL/min/1.73m2). Consequently, the expected improvement of glycemic control and 
the additional measures to improve diabetes management are considered to outweigh any 
potential risk associated with Gla-300 or IDeg-100 treatment.  
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Overall, the benefit-to-risk ratio for patients with T2DM and renal impairment who 
participate in this trial is considered favorable. 


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2 Trial Objectives, Estimands, and Endpoints 
2.1 Primary Objectives, Estimands, and Endpoints 
The primary objectives and estimands (including endpoints) are presented in Table 2-1. 
Table 2-1 
Primary Objectives, Estimands, and Endpoints 
Primary Objective 
Estimand Description (Including Endpoints) 
• 
To demonstrate non-inferiority (with a margin of 
0.3%) and, if achieved, to demonstrate the 
superiority in the efficacy of Gla-300 compared 
with IDeg-100 in terms of change in HbA1c 
from baseline to Week 24 in insulin-naïve 
patients with T2DM and renal impairment who 
have glycemic levels above target with OADs 
with or without GLP-1 RA 
• 
Estimand 1a (Primary): Difference in the mean 
change from baseline to Week 24 in HbA1c 
level (Gla-300 vs IDeg-100) in insulin-naïve 
patients with T2DM and renal impairment who 
have glycemic levels above target with OADs 
with or without GLP-1 RA, regardless of 
discontinuation of study drug treatment due to 
any reasons and use of rescue therapies 
(treatment policy strategy) 
 
• 
Estimand 1b (Supplementary): Difference in the 
mean change from baseline to Week 24 in 
HbA1c level (Gla-300 vs IDeg-100) in 
insulin-naïve patients with T2DM and renal 
impairment who have glycemic levels above 
target with OADs with or without GLP-1 RA, 
assuming no discontinuation of study drug 
treatment due to any reasons and use of rescue 
therapies (hypothetical strategy). This 
supplementary estimand will only be estimated 
for supporting the non-inferiority analysis 
Abbreviations: Gla-300, insulin glargine 300 U/mL; IDeg-100, insulin degludec 100 U/mL; GLP-1 
RA, glucagon-like peptide 1 receptor agonist; HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug; 
T2DM, type 2 diabetes mellitus. 


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2.2 Secondary Efficacy Objectives and Endpoints 
The secondary efficacy objectives and endpoints (including those for the 
) are 
presented in Table 2-2. 
Table 2-2 
Secondary Objectives and Endpoints 
Secondary Efficacy Objective 
Endpoints 
• 
To evaluate the effects of treatment with Gla-
300 compared with IDeg-100 on the clinical 
parameters 
• 
FPG: Change from baseline to Week 24 
• 
Fasting SMPG: Change from baseline to 
Week 24 
• 
7-point SMPG profiles: Change from baseline to 
Week 24, per time point within 24-hour period 
• 
Percentage (%) of patients reaching HbA1c 
target of <7.0% at Week 24 
• 
 
Abbreviations: FPG, fasting plasma glucose; Gla-300, insulin glargine 300 U/mL; HbA1c, glycated 
hemoglobin; IDeg-100, insulin degludec 100 U/mL; SMPG, self-measured plasma glucose. 
2.3 Safety and Exploratory Objectives and Endpoints 
The safety and exploratory objectives and endpoints are presented in Table 2-3. 
Table 2-3 
Safety and Exploratory Objectives and Endpoints 
Safety and Exploratory Objectives 
Endpoints 
Safety 
 
• 
To assess the safety and tolerability of Gla-300 
and IDeg-100 
• 
Safety evaluations of the following (during the 
24-week treatment period, during the titration 
period, and during the maintenance period): 
o 
All hypoglycemia events (see 
Section 6.2.2). 
o 
The frequency of and diurnal distribution 
(all day, daytime, and nocturnal) of 
hypoglycemia by category (symptomatic, 
asymptomatic, severe) per the ADA/EASD 
hypoglycemia classification 
o 
Local tolerability at injection site 
o 
Hypersensitivity reactions 
o 
AEs and SAEs, including AESIs, and other 
safety evaluations, including vital signs and 
body weight 
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Safety and Exploratory Objectives 
Endpoints 
Exploratory 
 
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Safety and Exploratory Objectives 
Endpoints 
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3 Investigational Plan 
3.1 Trial Design 
This is a multicenter, multinational, randomized, open-label, parallel-group clinical trial 
comparing the efficacy and safety of Gla-300 and IDeg-100 in insulin-naïve patients with 
T2DM and renal impairment who have glycemic levels above target with oral antidiabetic 
drugs (OADs) with or without glucagon-like peptide 1 receptor agonist (GLP-1 RA [oral or 
injectable]), defined as an HbA1c level of ≥7.5% and ≤10.5% and an eGFR of 
<60 mL/min/1.73m2 and ≥15 mL/min/1.73m2 at screening. The trial will attempt to represent 
the diversity of the patient population with T2DM (eg, race, ethnicity) and renal impairment 
(ie, <45 mL/min/1.73m2) through site recruitment efforts. 
At the screening visit, diet and lifestyle recommendations will be provided to patients, if 
needed, at the investigator’s discretion. Compliance with the diet and lifestyle 
recommendations will be discussed with the patient throughout the trial, if needed, and more 
specifically if glucose levels are above target. 
The trial will be conducted in approximately 630 patients. Patients will be randomly assigned 
in a 1:1 ratio to 1 of the 2 treatment arms: Gla-300 arm or IDeg-100 arm (Figure 3-1). 
At baseline (Day 0, Visit 2), all eligible participants will be randomly assigned to the  
Gla-300 arm or the IDeg-100 arm and will initiate their study drug treatment (Figure 3-1). 
They will be allowed to continue their current treatment with OADs with or without GLP-1 
RA (oral or injectable; with stable doses for ≥3 months) throughout the trial period unless 
such treatments have to be stopped or modified for safety reasons (Section 5.2.1). 
During the titration period (ie, from Week 1 through Week 12), the doses of Gla-300 and 
IDeg-100 will be adjusted using a recommended dose-adjustment algorithm (Table 5-2). 
After randomization, the dose will be titrated at least weekly (but no more than every 3 days), 
until the patient reaches a target fasting SMPG value of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) 
while avoiding hypoglycemia episodes. Thereafter, until the end of the trial, the doses of 
Gla-300 and IDeg-100 will be adjusted to maintain this glycemic target if deemed 
appropriate by the investigator. Dose adjustments will be based on a median of fasting SMPG 
values from the last 3 measurements, including the value on the day of titration, measured by 
the patient using glucose meters and accessories supplied by the sponsor through a vendor. 
Best efforts should be made to reach the glycemic target by 8–12 weeks after randomization. 


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Other efficacy parameters, including HbA1c, fasting plasma glucose (FPG), and 7-point 
SMPG, will be assessed at the time points specified in the schedule of events (SoE; 
Section 13.2). Adverse events (AEs) and serious adverse (SAEs), including adverse events of 
special interest (AESIs), and other safety evaluations will be assessed at the time points 
specified in the SoE (Section 13.2). Physical examination findings, hypoglycemia events, and 
vital signs will also be recorded to evaluate the safety of the study drug (Section 13.2). 
The maximum trial duration per patient will be 27 weeks. Five site visits and at least 
13 phone contacts are scheduled, as well as an unscheduled phone contact (during the 
treatment period) for study drug resupply, if required. A patient will be considered to have 
completed the trial if they have completed all phases of the trial, including the last visit 
(Week 25 follow-up phone contact). 
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Figure 3-1 
Graphical Trial Design (Main Trial) 
 
Abbreviations: AE, adverse event; CGM, continuous glucose monitoring; DTP, direct-to-patient; Gla-300, insulin glargine 300 U/mL; HCP, healthcare provider; 
IDeg-100, insulin degludec 100 U/mL; IMP, investigational medicinal product; SMPG, self-measured plasma glucose. 
a 
An unscheduled visit can be planned anytime during the treatment period if study drug resupply is required. This will be via phone contact with DTP-IMP 
delivery. The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial site. All patients who withdraw from 


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the trial prematurely will, as soon as possible, undergo all end-of-trial and follow-up assessments/procedures at a visit that should be identified as “the early 
trial discontinuation visit.” 
b 
During the titration period, the doses of Gla-300 and IDeg-100 will be adjusted using a recommended dose-adjustment algorithm (Table 5-2). After 
randomization, the dose will be titrated at least weekly (but no more than every 3 days) until the patient reaches a target fasting SMPG value of  
80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes. Thereafter, until the end of the trial, the doses of Gla-300 and IDeg-100 will be 
adjusted to maintain this glycemic target, if deemed appropriate by the investigator. Dose adjustments will be based on a median of fasting SMPG values 
from the last 3 measurements, including the value on the day of titration, measured by the patient using glucose meters and accessories supplied by the 
sponsor through a vendor. Best efforts should be made to reach the glycemic target by 8–12 weeks after randomization. 
d 
At the end of the trial, patients should discuss with the investigator, in collaboration with their HCP, whether to continue on the Gla-300 or IDeg-100 
treatment regimen or transition to an alternate antihyperglycemic therapy. 
e 
This will be a phone contact, but could be a site visit if ongoing or new AEs emerge during the post-treatment period, if necessary. 
 
 
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3.1.1 Rationale For Trial Design  
This trial is designed to demonstrate non-inferiority and superiority in the efficacy of Gla-300 
compared with IDeg-100 in terms of change in HbA1c from baseline to Week 24 in 
insulin-naïve patients with T2DM and renal impairment who have glycemic levels above 
target with OADs with or without GLP-1 RA (oral or injectable). 
The design chosen for this trial (ie, randomized, open-label, parallel-group) is a classical 
design used to assess a causal relationship between the trial outcome and the intervention. 
Previously, the BRIGHT trial followed a similar treatment pattern (ie, patients were 
randomly assigned in a 1:1 ratio to evening dosing of Gla-300 or IDeg-100)  
(Rosenstock et al 2018). 
As discussed in Section 1.2, although previous randomized clinical trials have demonstrated 
the efficacy and safety of Gla-300 and/or IDeg-100 in people with T1DM and T2DM, to date 
there are no dedicated prospective trials in people with T2DM and CKD. Hence, the TRENT 
trial is the first intended to demonstrate non-inferiority and superiority in the efficacy of 
Gla-300 compared with IDeg-100 in the above-mentioned patient population.  
3.1.2 Duration of Trial Participation for Each Patient 
The trial will consist of the following periods (further details are provided in the graphical 
trial design [Figure 3-1] and the SoE in Section 13.2): 
• A screening period of up to 2 weeks. 
• A 24-week, open-label treatment period, including a titration period and a maintenance 
period. 
• A 7-day, post-treatment, safety follow-up period after the last dose of the study drug or 
after premature/permanent discontinuation from study drug treatment. This will be a 
phone contact, but could be a site visit if ongoing or new AEs emerge during the 
post-treatment period, if necessary.  
At the end of the trial, patients should discuss with the investigator, in collaboration with 
their HCP, whether to continue on the Gla-300 or IDeg-100 treatment regimen or transition to 
an alternate antihyperglycemic therapy. Discussions and final decisions made should be 
clearly documented in the patients’ source documents. 


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The maximum trial duration per patient will be 27 weeks. A detailed description of the 
assessments performed during each trial period and at each visit is provided in Section 13.2. 
3.1.3 End of Trial Definition 
The end of the trial is defined as the date of the last visit of the last patient in the trial 
globally. 
A patient will be considered to have completed the trial if they completed all visits of the 
trial, including the safety follow-up visit, or resolution/stabilization of all SAEs and AEs with 
prespecified monitoring. 
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4 Selection of Trial Population and Discontinuation/Withdrawal 
Approximately 630 patients will be enrolled at approximately 74 sites. Patients will be 
assigned to 1 of the 2 treatment arms 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 patient must meet all of the following criteria to be enrolled in this trial: 
1. Is an adult aged ≥18 years at screening. 
2. Was diagnosed with T2DM of >1-year duration and had glycemic levels above target 
with OADs with or without GLP-1 RA (oral or injectable) at stable doses for ≥3 months 
before the screening period. 
3. Has an HbA1c ≥7.5% and ≤10.5% at screening. 
4. Has renal impairment, as defined by an eGFR of <60 mL/min/1.73m2 and 
≥15 mL/min/1.73m2 (using the Chronic Kidney Disease Epidemiology Collaboration 
[CKD-EPI] equation; National Kidney Foundation 2022).  
5. Has adequately controlled blood pressure with stable antihypertensive therapy at trial 
inclusion. 
6. Is insulin-naïve, except for short use of insulin not exceeding 15 days during the last year 
before the screening period. 
7. Is capable of understanding the written informed consent, and provides signed written 
informed consent.  
8. Is willing and able to complete the electronic diary (eDiary) and agrees to comply with 
protocol requirements. 


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9. Is willing and able to fast without having administered study drug for scheduled site 
visits. (Note: Fasting is defined as no intake of food or drink, except water, in the 8 hours 
before blood sampling.) 
10. If female, is not pregnant or breastfeeding and satisfies one of the following conditions: 
o Is a woman of nonchildbearing potential (WONCBP), as defined in the Contraceptive 
and Barrier Guidance section (Section 13.6). 
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 the 
Contraceptive and Barrier Guidance section (Section 13.6), during the trial treatment 
period (to be effective before starting the study drug treatment).  
 A WOCBP must have a negative urine pregnancy test during the screening 
period. (Note: If a urine test cannot be confirmed as negative [eg, an ambiguous 
result], a serum pregnancy test is required. In such cases, the patient must be 
excluded from participation if the serum pregnancy result is positive.) 
4.2 Exclusion Criteria 
Patients meeting any of the following criteria will be excluded from the trial: 
1. Has initiated treatment with new glucose-lowering medications and/or used weight loss 
drugs (including over-the-counter [OTC] and herbal medications), other than those stated 
in the inclusion criteria, within 3 months before the screening period. 
2. Has initiated treatment with potential novel therapies like dual glucose-dependent 
insulinotropic polypeptide (GIP) and GLP-1 RA. 
3. Has a body mass index (BMI)* >45 kg/m² during the screening period. 
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*Body weight and height will be recorded during the screening period for the calculation of 
BMI (BMI = weight [kg]/[height (m)]2). 
4. Has a history of hypoglycemia unawareness (defined as the onset of neuroglycopenia 
before the appearance of autonomic warning symptoms [eg, 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). 
5. Has a history of 2 or more episodes of severe hypoglycemia and/or 2 or more episodes of 
diabetic ketoacidosis within the 6 months before the day of screening. 
6. Has been exposed to other investigational drug(s) within 1 month or 5 half-lives from 
screening, whichever is longer. 
7. Has uncontrolled (treated/untreated) hypertension (systolic blood pressure [SBP] 
>180 mmHg and/or diastolic blood pressure [DBP] >95 mmHg) during the screening 
period. 
8. Has a history of myocardial infarction, stroke, or heart failure requiring hospitalization 
within the 3 months before the screening period. 
9. Has proliferative retinopathy or maculopathy with ongoing or anticipated requirement for 
active treatment prior to randomization; and/or peripheral vascular disease with ongoing 
or anticipated requirement for active intervention. 
10. Has any of the following associated conditions/situations: 
o Conditions/concomitant diseases making them non-evaluable for the primary efficacy 
endpoint (eg, hemoglobinopathy or hemolytic anemia, receipt of blood or plasma 
products) within the 3 months before the screening period or planned to receive 
transfusion of blood or plasma products during the screening period. 
o Severe or unstable hepatic, gastrointestinal, cardiovascular (including congestive 
heart failure, according to New York Heart Association [NYHA] Functional 
Classification III/IV [The Criteria Committee of the New York Heart Association 
1994]), respiratory, neurological, psychiatric, hematological, endocrine, 


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dermatological disease, active malignant tumor, other major systemic disease, or 
short life expectancy. 
o Any disorder, except for conditions associated with T2DM, which in the 
investigator’s opinion, might jeopardize the patient’s safety or compliance with the 
protocol requirements. 
o Acute or chronic kidney conditions with an underlying etiology, aside from diabetic 
nephropathy, that may require immunosuppressive treatment, or is on dialysis (eGFR 
of <15 mL/min/1.73m2; verified on 2 occasions) or has planned dialysis during the 
screening period. 
o Has a history of renal transplant. 
11. Is receiving or anticipated initiation or change in concomitant medications (for 
>14 consecutive days) known to affect weight or glucose metabolism (eg, treatment with 
orlistat, thyroid hormones, or corticosteroids, excluding topical application or inhaled 
forms).  
12. Has active liver disease or laboratory tests indicating liver damage (alanine 
aminotransferase [ALT] or aspartate aminotransferase [AST] >3 × upper limit of normal 
[ULN], total bilirubin >1.5 × ULN), except for documented Gilbert’s syndrome, during 
the screening period. 
13. Has nightshift working hours. 
14. Is likely to require nonpermitted medications during the treatment period (Section 5.11). 
15. Is currently in an institution because of a regulatory or legal order (ie, is a prisoner or a 
patient who is legally institutionalized).  
16. Is an employee of the site or an immediate family member of the investigator or site 
personnel. 
17. Is involved in a specific situation during trial implementation or the course of the trial 
that may raise ethics considerations. 


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18. Has hypersensitivity to any of the study drugs, or any of its excipients that, in the opinion 
of the investigator, contraindicates participation in the trial.  
4.3 Screen Failure 
Screen failures are defined as patients who provide signed written informed consent to 
participate in the clinical trial but are not subsequently enrolled as they do not meet all 
required criteria. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure patients to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information is defined as demography, screen failure reasons, eligibility criteria, and 
any SAEs, including AESIs. 
Patients can be rescreened once before randomization in case of non-evaluable exclusion 
criteria or in cases where original screen failure was due to reasons expected to change at 
rescreening and based upon the investigator’s clinical judgment. Patients can be rescreened 
for any other reasons or situations, if deemed necessary, at the investigator’s discretion. 
Rescreened patients will repeat the screening visit procedures/assessments, including signing 
of a new informed consent form (ICF) and allocation of a new patient number. 
4.4 Discontinuation From Study Drug and/or Withdrawal From the Trial 
4.4.1 Discontinuation From Study Drug Treatment 
All efforts should be made to keep patients on the study drug treatment. If the study drug is 
stopped, it should be determined whether the discontinuation can be made temporarily; 
permanent study drug discontinuation should be the last resort. Any study drug 
discontinuation should be fully documented in the electronic case report form (eCRF). 
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4.4.1.1 Permanent Discontinuation 
In rare instances, it may be necessary for a patient to permanently discontinue the study drug.  
Patients will be followed up according to the trial procedures specified in this protocol up to 
the scheduled date of trial completion, or up to recovery or stabilization of any AE, 
whichever comes last. 
If possible, and after the permanent discontinuation of study drug treatment, patients will be 
assessed using the procedure normally planned for the last dosing day with the study drug. 
See the SoE (Section 13.2) for data to be collected at the time of study drug discontinuation 
and follow-up and for any further evaluations that need to be completed. 
All cases of permanent study drug discontinuation must be recorded by the investigator in the 
appropriate pages of the 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 patient. 
Temporary study drug discontinuation may be considered by the investigator because of 
suspected AEs or for other reasons (eg, other medical issues). If study drug treatment is 
interrupted due to an AE, treatment will be reinitiated under close and appropriate 
clinical/and or laboratory monitoring if the investigator deems the relationship of the event to 
study drug as unlikely and if the trial 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 
Patients will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and are unable to be contacted by the site. 
The following actions must be taken if a patient fails to return to the clinic for a required trial 
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• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible. The patient should be counselled on the importance of maintaining the assigned 
visit schedule and asked whether they wish to and/or should continue in the trial. 
• Before a patient is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the patient. The methods to contact the patient include 
2 phone calls or local equivalent methods (eg, sending an email to patient’s last known 
email address). These contact attempts should be documented in the patient’s source 
documents. 
If the patient continues to be unreachable, they will be considered to have withdrawn from 
the trial. 
4.4.3 Handling of Withdrawals 
Patients are free to withdraw from the trial at any time upon request. Their participation in 
the trial may be stopped at any time at the discretion of the investigator or at the request of 
the sponsor. 
If the patient 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 patient withdraws from the trial, they may request destruction of any samples taken and 
not tested, and the investigator must document this in the site trial records. 
Patients who permanently discontinue the study drug or active participation in the trial will 
no longer receive the study drug. When a patient withdraws from the trial, the reason(s) for 
withdrawal shall be recorded by the investigator on the relevant page of the eCRF.  
A patient may withdraw from the trial or study drug treatment for circumstances that include, 
but are not limited to, the following: 
• The patient intends to become pregnant. 
• The patient may be withdrawn at the discretion of the investigator due to noncompliance 
or due to a safety concern. 


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• The patient will be withdrawn if they are starting any drugs that interfere with glucose 
metabolism (eg, systemic glucocorticoid therapy). 
• If the fasting or the mean SMPG value 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 patient may be withdrawn. 
• The patient has recurrent severe hypoglycemia or recurrent nocturnal hypoglycemia 
during the treatment period that poses a potential risk to the patient, as judged by the 
investigator. 
• The patient needs dialysis, as judged by the investigator. 
• The patient is unable to comply with the trial protocol, at the investigator’s discretion. 
All patients who discontinue study drug treatment will be followed up per the methods 
specified in this protocol. All patients who withdraw from the trial prematurely will, as soon 
as possible, undergo all end-of-trial and follow-up assessments/procedures at a visit that 
should be identified as “the early trial discontinuation visit.” Patients who fail to return for 
final assessments will be contacted by the site in an attempt to have them comply with the 
protocol requirements. 
Patients who withdraw from study drug 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 and in the source documents. 
It is vital to obtain follow-up data on any patients who withdrew because of an AE or SAE. 
In every case, all efforts must be made to return the patient to the site as soon as possible to 
perform protocol-specified, safety follow-up procedures (Section 13.2). 
4.4.4 Replacements 
Patients who discontinue the trial will not be replaced. 


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5 Trial Treatments 
5.1 Study Drug 
The study drugs are Gla-300 or IDeg-100 and will be supplied as prefilled, disposable pens 
(Gla-300 as a SoloStar® pen and IDeg-100 as a FlexTouch® pen). The details are provided in 
Table 5-1.  
An instruction leaflet will be provided to patients that explains how to use the disposable pen 
and needles. All patients will be trained by site staff at Visit 2 (baseline/randomization) on 
how to use the pen correctly, how to store it, and how to change the needle and to ensure 
patients are able to self-inject (eg, set correct dose, change the needle, identify the correct 
injection area, complete the injection, know the appropriate storage conditions, conduct 
simple troubleshooting). The patient’s family member or usual caregiver, if applicable, is 
highly encouraged to attend the training with the patient, as they play a key role and are able 
to support the patient with trial-related procedures during the trial. Training will be repeated 
during the treatment period as often as deemed necessary by site staff. These 
training/re-training details should be documented in the patient’s source documents. 
For the duration of treatment, patients will be required to use the same type of disposable 
pens and needles. The pen and leaflet that patients will need to use during the treatment 
period will be dispensed at the time points specified in the SoE (Section 13.2). Each patient 
will be supplied with the appropriate number of pens according to the dispensing scheme 
indicated in the SoE (Section 13.2). 
Injection pens should never be shared with others, even if the needle is changed. Patients 
must always use a new needle for each injection to help ensure sterility and prevent blocked 
needles. 


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Table 5-1 
Overview of Study Drug To Be Administered 
Formulation 
Gla-300 
IDeg-100 
Dosage formulation 
Gla-300 will be supplied as a sterile, 
nonpyrogenic, clear, colorless 
solution in a SoloStar prefilled 
(disposable) pen for SC injection.  
IDeg-100 will be supplied as a 
sterile, nonpyrogenic, clear, colorless 
solution in a FlexTouch prefilled 
(disposable) pen for SC injection. 
Unit dose 
strength(s)/Dosage level(s) 
Each Gla-300 SoloStar pen contains 
450 U of insulin glargine (1.5 mL of 
300 U/mL insulin glargine solution). 
Each IDeg-100 FlexTouch pen 
contains 300 U of insulin degludec 
(3 mL of 100 U/mL insulin degludec 
solution). 
Route of administration 
The study drug will be administered via SC self-injection into the abdominal 
area, thigh, or upper arm using the SoloStar pen or FlexTouch pen. Injection 
sites should be rotated within the same region from 1 injection to the next to 
reduce the risk of lipodystrophy. (Note: The injection sites for study drug and 
NIMP, if taken, should be different so that any injection site reactions can be 
attributed specifically to the study drug or NIMP [eg, GLP-1 RA].)  
Abbreviations: Gla-300, insulin glargine 300 U/mL; GLP-1 RA, glucagon-like peptide-1 receptor agonist; 
IDeg-100, insulin degludec 100 U/mL; NIMP, non-investigational medicinal product; SC, subcutaneous. 
5.2 Non-Investigational Medicinal Product  
The protocol-allowed background noninsulin antidiabetic drug(s) (Section 5.2.1) and rescue 
therapies used to treat hyperglycemia (Section 5.2.2) are considered non-investigational 
medicinal products (NIMPs). 
5.2.1 Background Noninsulin Antidiabetic Drug(s) 
Background noninsulin antidiabetic drug(s) (ie, OADs and GLP-1 RA [oral or injectable]) 
that patients are receiving before screening will be continued during the treatment period 
unless the treatments have to be stopped or modified for safety reasons. Formulation and 
route(s) of administration of background antidiabetic therapy will be defined per local 
labeling. 
5.2.2 Rescue Therapy 
Routine fasting SMPG, central laboratory FPG measurements, and central laboratory alerts 
on HbA1c are set up to ensure that glycemic parameters remain under predefined threshold 
values. The threshold values for rescue are defined as follows: 
• After Week 12 (ie, end of the titration period): FPG >200 mg/dL (11 mmol/L) and/or 
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If the patient’s FPG and/or HbA1c level is above the threshold, the investigator has to ensure 
that no reasonable explanation exists for glycemic levels above target, and in particular that: 
• Plasma glucose was actually measured in fasting condition (ie, after at least 8 hours of 
fasting). 
• The study drug is being properly titrated according to the protocol. 
• There is no intercurrent disease that may jeopardize glycemic levels (eg, infection). 
• Compliance to study drug treatment, diet, and lifestyle is appropriate. 
If any of the above can reasonably explain the glycemic levels being above target, the 
investigator should undertake appropriate action, ie,: 
• Titrate basal insulin dose according to the protocol. 
• Initiate an evaluation and treatment of any intercurrent disease (to be reported in 
AE/SAE/concomitant medication parts of the eCRF and the medical record). 
• Stress the absolute need to comply with study drug treatment, and the advantages of 
following diet and lifestyle recommendations. 
• Schedule an HbA1c and/or FPG assessment at the next visit (if the next visit is a phone 
call, it should be replaced by a site visit). 
If none of the above reasons can be found, and/or appropriate actions fail, it is recommended 
that rescue therapy be initiated.  
“Rescue therapy,” adding a new antidiabetic drug or increasing the dose of an existing 
antihyperglycemic, non-study drug that is part of the patient’s current regimen, if needed, 
should be based on the investigator’s decision and local labeling documents. Adding prandial 
insulin may be the preferred option. The addition of a new antidiabetic drug or an increase in 
the dose of a background antidiabetic drug (“rescue”) should not be decided based on a 
single FPG or HbA1c value, but rather on a thorough evaluation of the patient’s glycemic 
levels. It is expected that the initiation of any rescue therapy will be deferred until the study 
drug has been optimally titrated to target (ie, Week 12 of the treatment period). 


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The reason for initiating rescue therapy, the type of rescue therapy, and the day of starting 
rescue therapy along with the dose will be documented on the appropriate pages of the eCRF. 
Note: Short-term (ie, 10 consecutive days) uses of short- or rapid-acting insulin therapy 
(eg, due to acute illness or surgery) will not be considered as rescue therapy. All such uses of 
short- or rapid-acting insulin therapy must be reported in the eCRF and patient record. 
All assessments for the primary and secondary efficacy and safety parameters planned at the 
end of the treatment period (Week 24; Section 13.2) should be performed before initiating the 
rescue therapy. The patient will remain in the trial and continue to administer the study drug 
(including background antidiabetic therapy). The planned visits and assessments should be 
performed until the last scheduled visit. 
5.3 Storage and Dispensing 
Investigators or other authorized persons (eg, pharmacists, study drug managers) are 
responsible for storing the study drug in a secure and safe place in accordance with local 
regulations, labeling specifications, policies, and procedures. Control of study drug storage 
conditions, especially control of temperature (eg, refrigerated storage) and information on 
in-use stability and instructions for handling the compounds 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 drugs received, and any discrepancies must be reported 
and resolved before use of the study drug. 
The expiry date is presented on the study drug labels, and storage conditions are written on 
the study drug labels and in the instruction leaflet. Patients are responsible for the correct 
storage of “unused” and “in-use” pens after being dispensed at the site. 
5.4 Method of Assigning Patients to Treatment Arms 
Global Clinical Supply Manager from PPD, a clinical research organization contracted by the 
sponsor, will provide the treatment kit number list, and the biostatistician assigned to the trial 
will provide the randomization scheme to the interactive voice response system 
(IVRS)/interactive web response system (IWRS). Then, the IVRS/IWRS will generate the 
patient randomization list according to which the patients are allocated to the treatment arms. 


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The study drugs will be provided in open-label boxes, and each type of kit will be identified 
with a treatment number. 
At the screening visit, the investigator or designee will contact the IVRS/IWRS center to 
receive the patient number. The patient number will be composed of a 12-digit number 
containing the 3-digit country code, the 4-digit center code, and the 5-digit patient 
chronological number (which is 00001 for the first patient screened in a center, 00002 for the 
second patient screened in the same center, etc.). 
Patients will be randomized to receive Gla-300 or IDeg-100 during the 24-week comparative 
efficacy and safety period. The randomization ratio will be 1:1, and randomization will be 
stratified by HbA1c value at screening (<8.5%, ≥8.5%), SU use (Yes, No), and eGFR 
(<45 mL/min/1.73m2, ≥45 mL/min/1.73m2). 
The treatment kits will be allocated using a centralized treatment allocation system 
(IVRS/IWRS). At Visit 2, after assessment results are reviewed and baseline assessments are 
completed, the IVRS/IWRS center will be contacted by the investigator or designee for 
randomization and the first treatment kit(s) allocation. The investigator or designee will have 
to call the IVRS/IWRS center to provide some information (such as patient number provided 
by IVRS/IWRS at screening visit, date of birth, etc.). The IVRS/IWRS will be contacted 
again each time new treatment kit(s) allocation is necessary (Section 13.2). The IVRS/IWRS 
will allocate treatment kit(s) using their treatment number. 
A randomized patient is defined as a patient who is registered and assigned with a 
randomized treatment arm from the IVRS/IWRS, as documented from IVRS/IWRS log file 
regardless of whether the treatment kit was used or not. 
A patient cannot be randomized more than once. 


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5.5 Treatments Administered 
The following treatments will be administered in the trial: 
• Gla-300 arm: Insulin glargine 300 U/mL 
• IDeg-100 arm: Insulin degludec 100 U/mL 
• Time of administration:  
o Gla-300 or IDeg-100 should be self-administered once daily between 6:00 PM and 
8:00 PM throughout the treatment period. The investigator and patient will discuss 
and agree upon the injection time at Visit 2 (baseline/randomization).  
o The first dose of Gla-300 or IDeg-100 will be administered on the evening of Day 0 
(Visit 2).  
Starting Dose 
Per the product label, in insulin-naïve patients with T2DM, the recommended starting dose of 
Gla-300 0.2 U/kg of body weight once daily and the recommended starting dose of IDeg-100 
is 10 U once daily. 
5.5.1 Dose Modifications 
During the trial, the dose of study drug will be titrated to achieve glycemic targets without 
hypoglycemia using the recommended dose-adjustment algorithm (Table 5-2).  
• After randomization, the dose will be titrated at least weekly (but no more than every 
3 days) until the patient reaches a target fasting SMPG value of 80 to 100 mg/dL  
(4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes.  
• Thereafter, until the end of the trial, the doses of Gla-300 and IDeg-100 will be adjusted 
to maintain this glycemic target, if deemed appropriate by the investigator. 
• Dose adjustments will be based on a median of fasting SMPG values from the last 
3 measurements, including the value on the day of titration, measured by the patient using 
glucose meters and accessories supplied by the sponsor through a vendor. 


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Best efforts should be made to reach the glycemic target by 8–12 weeks after randomization. 
Table 5-2 
Recommended Dose-Adjustment Algorithm  
Mediana of Fasting SMPG Values From the Last 
3 Measurements 
Gla-300 and IDeg-100 Dose Adjustmentb 
>140 mg/dL (>7.8 mmol/L) 
+6 U  
>120 to ≤140 mg/dL (>6.7 to ≤7.8 mmol/L) 
+4 U 
>100 to ≤120 (>5.6 to ≤6.7 mmol/L) 
+2 U 
Glycemic target: ≥80 to ≤100 mg/dL (≥4.4 to 
≤5.6 mmol/L) 
No change 
<80 mg/dL (<4.4 mmol/L) or occurrence of ≥1 confirmed 
symptomatic hypoglycemia event(s) in the preceding 
week 
–2 U or –10% of the previous dose or at the 
discretion of the investigator or any qualified 
designee 
Abbreviations: Gla-300, insulin glargine 300 U/mL; IDeg-100, insulin degludec 100 U/mL; 
SMPG, self-measured plasma glucose. 
a 
Median refers to an intermediate SMPG value (ie, the value between the lowest and the highest SMPG 
values when the values are ranked in a growing order). 
b 
Dose adjustment should not occur more than every 3 days. 
Sound clinical judgment is to be exercised during titration, and investigators may adjust or 
stop titration, or temporarily reduce the dose if they believe that further titration would result 
in patients experiencing any AEs (eg, hypoglycemia, AESIs). 
Patients will be educated about the titration schedule so that they can monitor it with the 
assistance of the investigator or medically qualified designee. All discussions must be 
properly documented in the patient’s record. If needed, additional contacts will be made 
available for patients to discuss dose adjustments in between the scheduled visits. It is at the 
discretion of the investigator to allow well-trained patients to make study drug dose 
adjustments in between scheduled visits without prior consultation of the site personnel. 
Data relevant for study drug titration (eg, fasting SMPG, daily insulin dose, hypoglycemia 
occurrence) will be regularly reviewed by dedicated, qualified persons to identify patients 
whose basal insulin dose was not titrated according to the recommended dose-adjustment 
algorithm. If needed, site staff (including the investigator) can be retrained on titration 
procedures. The details on insulin titration monitoring will be provided in separate 
documents. 


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5.6 Identity of Study Drug 
Gla-300 and IDeg-100 are sterile, nonpyrogenic, clear, colorless solutions provided in 
SoloStar and FlexTouch prefilled (disposable) pens, respectively, for subcutaneous (SC) 
injection. 
Adequate supplies of the Gla-300 and IDeg-100 treatment kits to the sites will be made by 
PPD through appropriate channels. 
The following drug supplies will be used in the trial:  
Product 
Supplied As 
Gla-300 
SoloStar pen (containing 450 U of insulin glargine 
[1.5 mL of 300 U/mL insulin glargine solution]) 
IDeg-100 
FlexTouch pen (containing 300 U of insulin 
degludec [3 mL of 100 U/mL insulin degludec 
solution]) 
Abbreviations: Gla-300, insulin glargine 300 U/mL; IDeg-100, insulin degludec 100 U/mL. 
5.7 Management of Clinical Supplies 
5.7.1 Study Drug Packaging and Storage 
Gla-300 is a sterile, nonpyrogenic, clear, colorless solution in a 1.5 mL SoloStar prefilled 
(disposable), single-patient-use pen injector and is supplied by PPD. Gla-300 SoloStar pens 
will be supplied as open-label treatment kits containing 5 pens. 
IDeg-100 is a sterile, nonpyrogenic, clear, colorless solution in a 3 mL FlexTouch prefilled 
(disposable), single-patient-use pen injector and is supplied by PPD. IDeg-100 FlexTouch 
pens will be supplied as open-label treatment kits containing 5 pens. 
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 treatment kits (including pen needles as ancillary supplies) will be 
dispensed to provide patients with study drug coverage up to the next site visit or phone 
contact with direct-to-patient (DTP) study drug delivery (Section 13.2). Storage conditions 
and use-by end date (ie, expiry date) are part of the Gla-300 and IDeg-100 label text. 


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Treatment labels will indicate the treatment number used for treatment allocation.  
The investigator’s name, patient number, visit number, and box number will be entered 
manually by the site staff on the treatment box label before dispensing. 
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 patient in 
the trial. The investigator or other personnel designated by the investigator will also be 
responsible for controlling the site stocks of the study drug and requesting any resupply, if 
required. Reasons for departure from the expected dispensing regimen must also be recorded. 
At the completion of the trial, to satisfy regulatory requirements regarding drug 
accountability, all remaining study drug will be reconciled and retained or destroyed 
according to applicable regulations. 
All treatment kits will be dispensed with the investigator’s oversight. The investigator is also 
responsible for ensuring that accurate records are maintained of treatment kits being issued 
and returned. 
Any quality issue noticed with the receipt or use of study drug (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 6.2.8).  
A potential defect in the quality of the study drug 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 study drug and eliminate potential hazards. 
Further details regarding product complaint management will be provided in a study-specific 
pharmacy manual. 
Under no circumstances will the investigator supply the study drug to a third party, allow the 
study drug to be used other than as directed by this clinical trial protocol, or dispose of the 
study drug. 


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5.7.3 Other Supplies 
5.7.3.1 Blood Glucose Meter Kit 
Each patient will be provided with a blood glucose meter kit, in order to perform SMPG 
assessments. Site staff will provide appropriate training to the patients related to proper use 
of the glucose meter. The blood glucose meter kit will include a blood glucose meter, a 
lancing device, test strips, sterile lancets, a storage box, a control solution, and instructions 
for use.  
The training will be repeated as often as necessary at the site visits and documented in the 
patient’s source documents. Patients will be instructed to bring their glucose meters with 
them to each site visit. 
The glucose meters should be calibrated according to the instructions for use, and the site 
should also check the glucose meters regularly using the provided control solutions for data 
validity. 
The SMPG values stored in the glucose meter memory will be downloaded, printed out, 
dated, signed, and filed into the patient file. If the patient has more than one SMPG reading at 
the same time point, the investigator or site staff should work with the patient to identify the 
appropriate value to be recorded in the patient eDiary and in the eCRF. This information will 
help the investigator to assess treatment effects, adjust insulin doses, and assess compliance. 
Note: The SMPG values to be entered in the eCRF must be checked for consistency with the 
information from the glucose meter. If there is inconsistency, the reason for this has to be 
documented. If needed, the resulting action (eg, training of the patient on correct 
documentation of the values) will also be documented. The confirmed values will be entered 
in the eCRF based on the glucose meter output values. 
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5.8 Overdose Management 
An overdose (accidental or intentional) with the study drug/NIMP is an event suspected by 
the investigator or spontaneously reported by the patient. This 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 the eCRFs by 
the sites, who will then notify 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. 
5.8.1 Treatment of Overdose 
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe 
and sometimes prolonged and life-threatening hypoglycemia and hypokalemia. Mild 
episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug 
dosage, meal patterns, or physical activity (eg, exercise) level may be needed. More severe 
episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with 
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intramuscular/SC glucagon or concentrated intravenous glucose. Sustained carbohydrate 
intake and observation may be necessary because hypoglycemia may recur after apparent 
clinical recovery. Hypokalemia must be corrected appropriately. 
5.9 Blinding 
As Gla-300 and the control drug, IDeg-100 are distinguishable, this trial is an open-label 
design, and no attempt will be made to blind administration. 
5.9.1 Compensation for Lack of Blinding 
Despite the open-label administration of the study drug, assessment of outcomes will be 
based on objectively collected data, which are assessments for the efficacy variable (HbA1c, 
FPG) by a central laboratory blinded to treatment arms. 
As Gla-300 and IDeg-100, the control drug, are distinguishable in terms of initial dose and 
subsequent doses during the first weeks of the trial, a process will be applied to blind this 
information at the trial-team level. 
Selected trial team members will be blinded to the treatment arm and dose of study drug of 
individual patients throughout the trial up to the database lock. All analyses and data review 
before database lock will be performed blindly, except for the study drug titration review, 
which will be performed by dedicated qualified persons.  
The insulin titration review will be performed by examining the data related to fasting 
SMPG, hypoglycemia events, and study drug dose titration by dedicated, qualified persons.  
The first statistical analysis plan (SAP) will be written before the first patient is randomized 
in the trial and will be finalized before database lock. 
5.10 Study Drug Accountability and Adherence 
Study drug accountability and adherence will be monitored at the time points specified in the 
SoE (Section 13.2). 
Measures taken to ensure and document study drug accountability and adherence include the 
following: 


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• The treatment kit number should be properly recorded as required on the appropriate 
eCRF page, for accounting purposes. 
• All treatment kits (whether empty or unused) are to be returned by the patient at each 
visit when treatment kit dispensing is planned. 
• Patients will record their daily dose details in an eDiary (Section 13.3). 
• The investigator (or their delegate) will track study drug 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 the 
number of treatment kits provided versus the number of treatment kits returned (whether 
empty or unused). 
• The monitor in charge of the trial will check the data entered on the study drug 
administration page in the eCRF and compare them with the study drug that has been 
returned and the patient’s treatment log form. 
5.11 Prior and Concomitant Therapy  
A concomitant medication is any treatment received by the patient concomitantly to the study 
drug. Recording of prior and concomitant medications will be done at the time points 
specified in the SoE (Section 13.2). 
Use of all concomitant medications will be recorded in the patient’s eCRF. The minimum 
requirement is that the drug name and the dates of administration are 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 patient’s eCRF. 
Dose changes and any treatments in addition to the study drug should be kept to a minimum 
during the study. However, if these are considered necessary for the patient’s welfare and are 
unlikely to interfere with the study drug, they may be given at the discretion of the 
investigator, with a stable dose (when possible). It is the responsibility of the investigator to 
ensure that details regarding the concomitant medication are recorded in full in the eCRF. 
The Gla-300 and IDeg-100 labels should be consulted for any additional information 
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The following medication(s) are not permitted during the screening and randomized, 
open-label treatment periods of the trial: 
• Any type of glucose-lowering agents other than the study drug, protocol-allowed 
background noninsulin antidiabetic drug(s) (Section 5.2.1), and when applicable, rescue 
therapy (Section 5.2.2) are to be used. (Note: Short-term [≤10 days] use of short- or 
rapid-acting insulin therapy [eg, due to acute illness or surgery] is allowed.) 
• Potential novel therapies like dual GIP and GLP-1 RA. 
• Noninsulin antidiabetic drugs, which are not approved for combination with insulin 
according to local labeling/local treatment guidelines. 
• Insulin pump therapy. 
• Weight loss drugs (including OTC and herbal medications). 
o Patients who have initiated weight loss drugs (including OTC and herbal medications) 
within 3 months before the screening period should be excluded from the trial. 
• Use of systemic glucocorticoids (excluding topical application or inhaled forms) for 
>14 consecutive days. 
• Other medications are allowed as needed; however, doses of chronically administered 
medicines should be kept fixed during the trial if at all possible. 
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6 Trial Assessments and Procedures 
Before performing any procedures, all potential participants will sign an ICF (Section 9.3). 
They will have the opportunity to have any questions answered before signing the ICF. The 
investigator must address all questions raised by the patient. The investigator will also sign 
the ICF. 
The SoE is provided in Section 13.2. 
6.1 Efficacy Assessments 
6.1.1 HbA1c Measurements 
The primary efficacy endpoint and some secondary and exploratory endpoints will be 
assessed by HbA1c measurement. Blood samples will be collected to measure HbA1c at the 
different time points specified in the SoE (Section 13.2) at the central laboratory. 
For the eligibility assessment, HbA1c levels will be measured during the screening period 
(Week –2, Visit 1). For the efficacy assessments of the trial, HbA1c levels will be measured 
at baseline/randomization, at the end of the titration period (Week 12; Visit 14), and at the 
end of the treatment period (Week 24, Visit 17; Section 13.2). If a patient needs to receive 
rescue antidiabetic therapy, the HbA1c assessment should be performed before they are 
introduced. In addition, in case of study drug treatment discontinuation, patients will be 
followed up per protocol. In case of trial discontinuation, HbA1c assessment will be 
performed at the time of withdrawal, if possible. 
6.1.2 FPG Measurements 
Blood samples will be collected to measure FPG levels at the time points specified in the SoE 
(Section 13.2) at the central laboratory. For scheduled site visits, patients will be required to 
arrive having fasted without administering the study drug. Fasting is defined as no intake of 
food or drink, except water, in the 8 hours before blood sampling.  
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6.1.3 
7-Point SMPG Profile 
Patients will be supplied with a glucose meter and an eDiary during the screening period.  
Site staff will provide appropriate training to the patients on the proper use of the glucose 
meter and eDiary completion. The 7-point SMPG profile will be measured (and recorded in 
the patient’s eDiary) at the following 7 points: preprandial and 2 hours after starting 
breakfast, lunch, and dinner, and at bedtime. The time points are specified in the SoE 
(Section 13.2). 
The 7-point SMPG profile will be performed over a single 24-hour period, on at least 2 days 
within the week before selected site visits (Section 13.2). 
6.1.4 Fasting SMPG 
Fasting SMPG values will be used to titrate and adjust study drug doses and monitor 
glycemic levels (Section 13.2). Patients will be required to measure fasting SMPG values 
(using the glucose meter supplied during the screening period) before breakfast and before 
administration of the study drug once daily throughout the treatment period; the results will 
be recorded in the eDiary.  
During the trial period, additional glucose measurements can be done at the investigator’s 
discretion. 
6.1.5 SMPG During Symptomatic Hypoglycemia 
Whenever patients experience hypoglycemia symptoms, they (or others, if applicable) should 
measure plasma glucose (using the glucose meter supplied during the screening period), if 
possible. Patients will be instructed to measure plasma glucose levels before carbohydrate 
intake/administration of glucose whenever symptomatic hypoglycemia is suspected 
(Section 6.2.2), unless safety considerations necessitate immediate carbohydrate/glucose 
rescue before confirmation with the SMPG values.  
Patients must contact the investigator as soon as possible after hypoglycemia events 
(especially, severe hypoglycemia events) for review and so that a decision can be made 
regarding any necessary actions. Patients should be instructed to again measure plasma 
glucose levels (using the glucose meter supplied during the screening period) once the event 
has resolved. 


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6.2 Safety Assessments 
6.2.1 Physical Examination 
A physical examination will be performed, per standard of care to assess the health status of 
patients at the time points specified in the SoE (Section 13.2). Physical examination will 
include, at a minimum, assessment of the followings: general appearance, head, ears, eyes, 
nose, throat, neck, respiratory system, cardiovascular system, gastrointestinal system 
(including mouth), musculoskeletal system, central and peripheral nervous system, and skin. 
6.2.2 Hypoglycemia Events 
Hypoglycemia events will be assessed at the time points specified in the SoE (Section 13.2). 
During the trial, patients will be instructed to document any hypoglycemia events (including 
any possible reasons for hypoglycemia [eg, physical exercise, skipped meal]) in their eDiary. 
Hypoglycemia will be reported in the specific hypoglycemia event information form in the 
eCRF. The information recorded will include onset date and time; symptoms and/or signs; 
the SMPG value, if available; and the treatment, with documentation of whether the patient 
required outside assistance to achieve neurologic recovery. A hypoglycemia event that fulfills 
the seriousness criteria will also be documented on the SAE form in the eCRF. 
Hypoglycemia events will be evaluated based on the following categories of interest 
(Seaquist et al 2013; Agiostratidou et al 2017; American Diabetes Association [ADA] 2021): 
• Overall hypoglycemia. 
• Confirmed hypoglycemia (symptomatic, severe). 
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. A 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 
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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).  
Any hypoglycemic event that leads to unconsciousness, coma, or seizure must be reported as 
an SAE. In addition, any hypoglycemic event, which at the investigator’s discretion, qualifies 
as an SAE must also be reported as an SAE. 
• Asymptomatic hypoglycemia: An event not accompanied by typical symptoms of 
hypoglycemia but with a measured plasma glucose concentration ≤70 mg/dL 
(3.9 mmol/L). 
• Probable symptomatic hypoglycemia: An event during which symptoms typical of 
hypoglycemia are not accompanied by a plasma glucose determination, but was 
presumably caused by a plasma glucose concentration ≤70 mg/dL (3.9 mmol/L); 
symptoms treated with oral carbohydrate without a test of plasma glucose. 


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• Pseudo hypoglycemia: An event during which the person with diabetes reports any of the 
typical symptoms of hypoglycemia with a measured plasma glucose concentration 
>70 mg/dL (>3.9 mmol/L) but approaching that level. 
• Nocturnal hypoglycemia: Any hypoglycemia of the above categories by: 
o Time of the day: Between 00:00 AM and 05:59 AM or 00:00 AM and 7:59 AM 
regardless of whether the patient was awake or work up because of the event. 
o Sleep status: Patient was asleep between bedtime and before getting up in the 
morning (ie, before the morning assessment of fasting prebreakfast SMPG and before 
any insulin injection). The patient wakes up because of the event. 
o Daytime hypoglycemia: Event that occurs between 06:00 and 23:59. 
Hypoglycemia events will be classified and analyzed using the following variables: 
• Percentage of patients with ≥1 episode(s) of confirmed hypoglycemia (cut-off value 
70 mg/dL and 54 mg/dL) and event rate during the 24-week treatment period. 
• Rate of hypoglycemia per patient-year computed as: 365.25/12 × (number of episodes of 
hypoglycemia)/(number of days exposed in time window). 
• Percentage of patients and event rate of hypoglycemia by trial period (for ≤12 weeks, for 
>12 weeks to ≤24 weeks) to evaluate the potentially increased risk of hypoglycemia 
during the initial 12 weeks after initiating basal insulin treatment. 
• The 24-hour (all time), daytime, and nocturnal (00:00 to 05:59, both inclusive) 
distribution of the occurrence of each episode of documented hypoglycemia by category, 
presented by 2-hour timeframe over 24 hours during the 24-week treatment period. 
6.2.3 Local Tolerability at the Injection Site and Hypersensitivity 
Reactions 
If the investigator or the patient recognizes any signs of local intolerability at the study drug 
injection site or hypersensitivity reactions, the event should be recorded in the AE page in the 
eCRF. If a patient reports severe injection site or hypersensitivity reaction between the site 
visits or during a phone call visit, the investigator or designee should ask them to come to the 


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site on the same or the next day, so that the event can be properly assessed, reported, and 
treated. 
6.2.4 Vital Signs 
Vital signs (including body weight, heart rate, SBP, and DBP) will be recorded at the time 
points specified in the SoE (Section 13.2). Height and body weight measurements at 
screening will be used to calculate BMI. 
• Blood pressure (BP) will be assessed in a seated position using the same device 
(automated BP monitor or a manual sphygmomanometer) for each patient. 
• 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 patient is in a seated position. The arm with the 
highest SBP will be determined at this visit, and the BP should be measured using this 
arm throughout the trial. This highest value will be recorded in the eCRF. 
• At subsequent visits, BP should be measured using the patients’ designated arm, to be 
preceded by at least 5 minutes of rest in a quiet setting without distractions 
(eg, television, cell phones). 
• Heart rate (bpm) will be measured concurrently with the measurement of seated BP. 
6.2.4.1 Body Weight 
Body weight will be measured to assess the change from baseline to Week 24. While 
measuring their body weight, the patient 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 trial 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 “0” and the balance bar aligned. The patient should stand in the center 


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of the platform, as standing off-center may affect the measurement. The weights will be 
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; patients must not read the scales themselves. 
6.2.5 Clinical Safety Laboratory Assessments 
All clinical safety laboratory assessments (ie, hematology, clinical chemistry, urinalysis) will 
be performed by the central laboratory. The list of clinical safety laboratory tests to be 
performed is provided in Section 13.4. The timing and frequency of sample collection are 
provided in the SoE (Section 13.2).  
Additional tests may be performed at a local or central laboratory at any time during the trial, 
as deemed necessary by the investigator or required by local regulations. If a test is used to 
evaluate an AE (diagnostic, follow-up, outcome), the results (including, notably, the disease 
progression of CKD) must be entered into the eCRF. 
• The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the trial 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 Patient is symptomatic (and/or laboratory values are clinically significant per the 
investigator’s discretion). 
o Patient requires corrective treatment or consultation. 
o Patient requires study drug treatment to be discontinued or modification of dosing. 
o Event fulfills a seriousness criterion. 
o Event meets the definition of an AESI (Section 6.2.6.2). 


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• All laboratory tests with values that are considered clinically significantly abnormal 
during the trial 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 or baseline within a period of 
time judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified. 
• All protocol-required laboratory assessments, as defined in Section 13.4, must be 
conducted in accordance with the laboratory manual and the SoE (Section 13.2). 
• The recommended decision tree for the management of ALT increase is provided in 
Appendix 13.7. 
6.2.6 Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
trial, regardless of their relationship to the study drug or their clinical significance. The 
investigator remains responsible for following up on all AEs that are serious, considered 
related to the study drug or procedures, or caused the patient to discontinue the study drug 
treatment and/or the trial. 
All AEs (serious or nonserious) will be recorded from the signing of the ICF until the safety 
follow-up visit, patient’s permanent discontinuation from the trial, or loss to follow-up 
(Section 13.2).  
The definitions of AEs and SAEs are provided in Section 13.5. The definition of an AESI is 
provided in Section 6.2.6.2. 
All SAEs and AESIs will be recorded and reported to the sponsor or designee immediately, 
and under no circumstance should this be longer than 24 hours of awareness, as indicated in 
Section 6.2.6.5. The investigator will submit any updated SAE/AESI data to the sponsor or 
designee within 24 hours of receipt of the information. 
After the AEs/SAEs (including AESIs) are initially reported, the investigator is required to 
proactively follow-up with each patient at subsequent visits/contacts. At the prespecified trial 
end date, all SAEs and AESIs will be followed up until resolution, stabilization, the event is 


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otherwise explained, or the patient 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 conclusion 
of the trial. However, if the investigator learns of any SAE, including a death, at any time 
after a patient has been discharged from the trial, and they consider the event to be 
reasonably related to the study drug or trial participation, the investigator must promptly 
notify the sponsor. 
6.2.6.1 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 [IB] for an unapproved study drug). 
A “Dear Investigator” letter must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy, and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing an SAE, SUSAR, or 
any other specific safety information (eg, summary or listing of SAEs) from the sponsor or 
designee will review and then file it along with the package insert and will notify the 
institutional review board (IRB)/independent ethics committee (IEC), if appropriate 
according to local requirements. It is the responsibility of the sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
6.2.6.2 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 trial by protocol amendment. 
The following AEs will be considered as AESIs in this trial:  
• Pregnancy of a female patient enrolled in the trial, as well as pregnancy occurring in a 
female partner of a male patient enrolled in the trial with study drug/NIMP.  


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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 of a female patient, the study drug/NIMP should be discontinued.  
o Follow-up of the pregnancy of a female patient or in a female partner of a male 
patient is mandatory until the outcome has been determined. 
• Symptomatic overdose (serious or nonserious) with the study drug/NIMP.  
o An overdose (accidental or intentional) with the study drug/NIMP is an event 
suspected by the investigator or spontaneously reported by the patient 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. 
o Asymptomatic overdose has to be reported as a standard overdose. The circumstances 
(ie, accidental or intentional) should be clearly specified verbatim on the form and 
symptoms, if any, must be entered on separate AE/SAE forms. 
• Increase in ALT (>3 × ULN; see Section 13.7). 
6.2.6.3 Pregnancy 
A urine pregnancy test (only for WOCBP) will be performed at the time points specified in 
the SoE (Section 13.2).  
To ensure patient safety, each pregnancy must be reported to sponsor or designee 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 patient was 
discontinued from the trial. Pregnancy complications and elective terminations for medical 
reasons must be reported as AEs or SAEs. Spontaneous miscarriages must be reported as 
SAEs. 
Any SAE occurring in association with a pregnancy that is brought to the investigator’s 
attention after the patient has completed the trial and is considered by the investigator as 
possibly related to the study drug must be promptly reported to sponsor. 


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Any female patient who becomes pregnant while participating in the trial will be 
discontinued from study drug treatment. 
6.2.6.4 Eliciting and Documenting AEs 
Adverse events will be assessed from the time the patient signs the ICF until exit from the 
trial. 
Serious AEs will be reported until 30 days after the last dose of study drug. 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 the study drug. 
At every visit, patients will be asked a standard of nonleading questions to elicit any 
medically related changes in their well-being. 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 a patient’s observations, AEs identified from any trial data (eg, laboratory 
values, physical examination findings) or identified from review of other documents  
(eg, the patient’s eDiary) that are relevant to the patient’s safety will be documented on the 
AE page in the eCRF. 
6.2.6.5 Reporting AEs 
All AEs reported or observed during the trial will be recorded on the AE page in the eCRF. 
Information to be collected includes dose, event term, time of onset, investigator-specified 
assessment of severity and relationship to the 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 patient is screened but does not 
deteriorate should not be reported as an AE. However, if it changes during the trial, it should 
be recorded as an AE. 


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Any AE that meets SAE criteria (Section 13.5.2) or an AESI (Section 6.2.6.2) must be 
reported to PPD Pharmacovigilance immediately (ie, within 24 hours) after the site 
personnel first learn about the event (Section 13.5.4). 
6.2.6.6 Assessment of Severity 
The severity, or intensity, of an AE refers to the extent to which an AE affects the patient’s 
daily activities. The intensity of the AE 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. 
6.2.6.7 Assessment of Causality 
The investigator’s assessment of an AE’s relationship to the study drug is part of the 
documentation process (Section 13.5.3), but is not a factor in determining what is or is not 
reported in the trial. 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 the study drug/NIMP and cannot be 
reasonably explained by other factors, such as the patient’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 study 
drug/NIMP. 
6.2.6.8 Follow-Up of Patients 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 patient is considered to be stable (Section 13.5.3). 


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6.2.7 Safety Monitoring Committee 
An independent safety monitoring committee will not be formed for this trial. The medical 
monitor and sponsor will hold meetings at regular intervals to reviews all AEs. 
6.2.8 Guidelines for Reporting Product Complaints  
Recording of product complaints will be done at the time points specified in the SoE 
(Section 13.2). 
Any defect in the study drug must be reported as soon as possible by the investigator to the 
monitoring team, which will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels, or documents [like pictures or photocopies]) 
related to product identification and to the potential deficiencies may need to be gathered. 
The investigator will assess whether the quality issue has to be reported together with an AE 
or SAE. 
6.3 Sample Collections 
Appropriately delegated site personnel will collect blood samples at the time points specified 
in the SoE (Section 13.2). These samples will be processed at the site and shipped the same 
day to the central laboratory, as specified in the laboratory manual. The central laboratory 
will analyze the blood samples for HbA1c and FPG measurements, clinical chemistry, and 
hematology. Results will be returned to the site within 48 to 72 hours. 
6.4 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 patient response to treatment. Therefore, data will be stored and used 
for future research when consented to by patients (Section 9.3) unless prohibited by local 
laws or IRBs (in such case, consent for future use of data will not be included in the local 
ICF). 
For patients who consent to the storage and use of their data, data may be used after the trial 
ends for future research related to the study drug, the mechanism of action, the disease, or its 
associated conditions.  


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In the event future research is conducted for other purposes, trial patients will be informed of 
those purposes and will be given the means to object to those research projects. 
Data will be used in compliance with the information provided to patients in the ICF Part 2 
(future research). 
All trial patient data will be coded such that no patient’s directed identifiers will be linked to 
them. Coded data may be transferred to a sponsor site (or a subcontractor site) that may be 
located outside of the country where the trial is conducted. The sponsor adopts safeguards for 
protecting patient confidentiality and personal data (Section 10.2). 
Trial patients’ coded data will be stored for future research for up to 25 years after the end of 
the trial. 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 trial patient who has requested the destruction of their 
samples). 
Patients’ coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project 
(end of project is defined by publication of the results or finalization of the future research 
project report). 


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7 Trial-Specific Committees 
7.1 Steering Committee 
The steering committee will be composed of key opinion leaders with clinical and 
methodological expertise in diabetes, renal disease, and the conduct of clinical trials.  
This committee, led by a chairman, will have the following roles and responsibilities: 
• Providing input into the development of the protocol and in some cases, of any 
subsequent amendments. 
• Assisting in decisions for protocol amendments (or making recommendations). 
• Assisting with the overall supervision of the trial, including (but not limited to) the 
following tasks:  
o Participating in virtual investigators’ meeting. 
o Assessing global trial progress in conjunction with the sponsor team. 
o Analyzing and interpreting study data. 
o Assisting with resolution of site issues that arise over the course of the trial (as 
necessary) to assure quality trial conduct. 
o Supporting/endorsing sponsor responses to regulatory authority inquiries (as 
necessary). 
o Validating the main features of the SAP. 
o Communicating with the investigator sites, including (but not limited to) major trial 
milestones or decisions. 
o Providing other input, such as editorials in newsletters to be sent to site investigators 
(if needed). 


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• Supporting trial publications with the following tasks: 
o Defining the overall publication plan, including the primary publications reporting 
new scientific findings/data from the trial. 
o Reviewing and approving (or abstain from) all other proposed publications and draft 
manuscripts regarding subsequent publications, including local publications. 


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8 Statistical Considerations 
The statistical considerations summarized in this section outline the plan for data analysis in 
this trial. Details of the analyses to be conducted will be specified in an SAP, which will be 
finalized and approved before database lock. Changes from the analyses planned in this 
protocol will be documented in the SAP. 
8.1 Estimands and Intercurrent Events 
8.1.1 Intercurrent Events 
The relevant intercurrent event (ICE) types in this trial are presented in Table 8-1. 
Table 8-1 
Intercurrent Events 
Label 
Intercurrent Event Types 
ICE1 (Discontinuation due to any 
reasons) 
Discontinuation of study drug treatment due to any reasons  
ICE2 (Rescue therapy) 
Use of rescue therapies  
Abbreviation: ICE, intercurrent event. 
8.1.2 Estimands 
Attributes for the primary and supplementary estimands with the strategies used for handling 
ICEs are presented in Table 8-2. 
Table 8-2 
Primary and Supplementary Estimands 
 
Estimand 1a (Primary)  
Estimand 
Description 
Difference in the mean change from baseline to Week 24 in HbA1c level (Gla-300 vs 
IDeg-100) in insulin-naïve patients with T2DM and renal impairment who have glycemic 
levels above target with OADs with or without GLP-1 RA (oral or injectable), regardless 
of discontinuation of study drug treatment due to any reasons and use of rescue therapies 
Target 
Population  
Insulin-naïve patients with T2DM and renal impairment who have glycemic levels above 
target with OADs with or without GLP-1 RA (oral or injectable) as defined by the 
inclusion/exclusion criteria (Section 4)  
Treatment 
Conditions  
Once daily, SC self-injection of Gla-300 versus IDeg-100 with the planned dose 
modifications outlined in Section 5.5.1 
• Gla-300: Insulin glargine 300 U/mL 
• IDeg-100: Insulin degludec 100 U/mL  
Endpoint 
Change in HbA1c level from baseline to Week 24 
Population 
Level Summary 
Difference in the mean change in HbA1c level from baseline to Week 24 between 
Gla-300 and IDeg-100 


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Estimand 1a (Primary)  
ICEs and 
Strategies  
Treatment policy strategy for handling the ICEs in Table 8-1 
Rationale 
Using the treatment policy strategy for handling ICEs is considered appropriate for 
showing superiority (ICH E9 R1), which allows switching the objective of a trial from 
non-inferiority to superiority (CPMP guideline) 
 
Estimand 1b (Supplementary)  
Estimand 
Description 
Difference in the mean change from baseline to Week 24 in HbA1c level (Gla-300 vs 
IDeg-100) in insulin-naïve patients with T2DM and renal impairment who have glycemic 
levels above target with OADs with or without GLP-1 RA (oral or injectable), assuming 
no discontinuation of study drug treatment due to any reasons and use of rescue therapies 
Target 
Population  
Insulin-naïve patients with T2DM and renal impairment who have glycemic levels above 
target with OADs with or without GLP-1 RA (oral or injectable) as defined by the 
inclusion/exclusion criteria (Section 4) 
Treatment 
Conditions  
Once daily, SC self-injection of Gla-300 versus IDeg-100 with the planned dose 
modifications outlined in Section 5.5.1 
• 
Gla-300 arm: Insulin glargine 300 U/mL 
• 
IDeg-100 arm: Insulin degludec 100 U/mL 
Endpoint 
Change in HbA1c level from baseline to Week 24 
Population 
Level Summary 
Difference in the mean change in HbA1c level from baseline to Week 24 between 
Gla-300 and IDeg-100 
ICEs and 
Strategies  
Hypothetical strategy for handling the ICEs in Table 8-1 
Rationale 
Using the hypothetical strategy for handling ICEs is considered conservative and relevant 
for demonstrating non-inferiority. This supplementary estimand will only be estimated 
for supporting the non-inferiority analysis 
Abbreviations: CPMP, committee for proprietary medicinal products; Gla-300, insulin glargine 300 U/mL; 
GLP-1 RA, glucagon-like peptide 1 receptor agonist; HbA1c, glycated hemoglobin; ICE, intercurrent 
event; ICH, International Council for Harmonisation; IDeg-100, insulin degludec 100 U/mL; OAD, oral 
antidiabetic drug; SC, subcutaneous; T2DM, type 2 diabetes mellitus. 
8.2 Statistical Hypothesis 
The statistical hypothesis associated with the primary non-inferiority analysis of change from 
baseline in HbA1c level to Week 24 is:  
H0: µGla-300 - µIDeg-100 ≥0.3%  
H1: µGla-300 - µIDeg-100 <0.3%  
where µGla-300 and µIDeg-100 denote the true mean change from baseline to Week 24 in HbA1c 
level for Gla-300 and IDeg-100, respectively. 


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If the non-inferiority is demonstrated, the hypothesis for testing superiority will be:  
H0: µGla-300 - µIDeg-100 = 0%  
H1: µGla-300 - µIDeg-100 ≠ 0%  
8.3 Sample Size Determination 
This trial is designed with a primary objective of demonstrating that Gla-300 is non-inferior 
to IDeg-100 regarding change from baseline to Week 24 in HbA1c level, with a 
non-inferiority margin of 0.3%, a 2.5% alpha risk (1-sided), and 90% power, assuming an SD 
of 1.1 and 10% dropouts. The non-inferiority margin was chosen based on the European 
Medicines Agency (EMA) guideline on clinical investigation of medicinal products in the 
treatment or prevention of diabetes mellitus (EMA 2018). 
A sample size of 566 randomized patients (283 per treatment arm with a 1:1 allocation ratio) 
is expected to ensure that the upper bound of the 2-sided 95% CI for the difference in the 
mean change from baseline to Week 24 in HbA1c level between Gla-300 and IDeg-100 
would not exceed the non-inferiority margin of 0.3% with approximately 90% power. This 
calculation assumes a common SD of 1.1% with a 1-sided test at the 2.5% significance level 
and that the true difference in the mean change between Gla-300 and IDeg-100 is 0. 
Assuming a 10% dropout rate, a total of 630 patients will be randomized (315 per treatment 
arm). 
For showing the superiority of Gla-300 to IDeg-100, the power will be at least 90%, 
assuming the true difference in the mean change between Gla-300 and IDeg-100 is ≤ –0.3%.  
Calculations were made using the nQuery Software Version 7.0. 
8.4 Analysis Sets 
The following analysis sets will be used in the statistical analyses: 
• Safety set: The safety set will consist of all patients who receive at least 1 dose of study 
drug treatment. All analyses using the safety set will be done according to the treatment 
actually received. 


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• Intention-to-treat (ITT) set: The ITT set will consist of all patients who sign the ICF and 
are randomized into the trial. All analyses using the ITT set will group patients according 
to their randomized treatment.  
• Per protocol set (PPS): The PPS will consist of all randomized patients who complete the 
trial without major protocol deviations.  
The ITT set will be used for the primary efficacy analyses, the PPS will be used for a 
supportive analysis for non-inferiority, and the safety analyses will be based on the safety set. 
Patients’ disposition will be presented for the ITT set. 
8.5 Description of Subgroups to be Analyzed 
Subgroup analyses will be performed by:  
• Age (<65 years; ≥65 years) 
• Baseline HbA1c (<8.5%; ≥8.5%)  
• SGLT-2i use (yes; no) 
• GLP-1 RA use (yes; no) 
• SU use (yes; no) 
• eGFR (<45 mL/min/1.73m2; ≥45 mL/min/1.73m2)  
Details of these and other possible subgroup analyses will be specified in the SAP.  
8.6 Disposition, Demographics, and Baseline Characteristics 
Summary statistical analyses will be provided for demographics, baseline disease 
characteristics, medical history, and other characteristics.  
Patient disposition will be summarized by study drug treatment and include the number of 
patients in the safety set who completed or withdrew from the study drug treatment, as well 
as the number of patients in each analysis set. 


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The number of patients who withdrew from study drug treatment and withdrew from the trial 
will be summarized by study drug treatment and the reason for withdrawal.  
8.7 Statistical Analysis Methodology 
8.7.1 General Considerations 
Statistical analyses will be performed using SAS software Version 9.4 or higher. Continuous 
variables will be summarized using the mean, SD, median, minimum, and maximum. 
Categorical variables will be summarized using frequency counts and percentages. Data will 
be listed in data listings.  
All CIs presented will be 2-sided 95% CIs, unless otherwise specified. For the primary 
efficacy endpoint, non-inferiority will be established if the 2-sided 95% CI of the difference 
in the mean change from baseline to Week 24 in HbA1c level between Gla-300 and IDeg-100 
lies entirely below 0.3% (equivalent to a 1-sided test at the 2.5% significance level). If 
non-inferiority is demonstrated, superiority of Gla-300 to IDeg-100 will also be considered 
and established if the 95% CI lies entirely below 0%. If non-inferiority has been established 
but the superiority is not met, the declaration of non-inferiority will be further supported by a 
supplementary estimand as described in Section 8.1.2. There is no multiplicity argument that 
affects switching between non-inferiority and superiority, since it corresponds to a simple 
closed testing procedure. 
No multiplicity adjustment will be made on the secondary and exploratory endpoints. When 
presented, 95% CIs and nominal P values, will be provided for descriptive purpose only.  
Details of the statistical analyses, methods, and data conventions will be described in the 
SAP. 


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8.7.2 Overview of Statistical Methods: Estimation of Primary Estimands and Sensitivity Analyses 
Table 8-3 presents a summary of the statistical methods, including the sensitivity/supportive analyses.  
Table 8-3 
Summary of Statistical Methods for Primary Estimands 
 
 
 
Main Estimation 
 
 
Estimand Label 
Estimand Description 
Analysis Set 
Imputation/Data 
Censoring Rules 
Analysis Model/Method Sensitivity/Supportive 
Analysis 
Estimand 1a (Primary) 
Difference in the mean 
change from baseline to 
Week 24 in HbA1c level 
(Gla-300 vs IDeg-100) in 
insulin-naïve patients 
with T2DM and renal 
impairment who have 
glycemic levels above 
target with OADs with or 
without GLP-1 RA (oral 
or injectable), regardless 
of discontinuation of 
study drug treatment due 
to any reason and use of 
rescue therapies 
ITT 
Data collected after ICEs 
will be included. 
An MI strategy and an 
ANCOVA model 
including baseline  
HbA1c value as a 
covariate, and study drug 
treatment and 
stratification factors at 
randomization (other than 
categorized HbA1c) as 
fixed factors. 
Details are provided in 
Section 8.7.3.1. 
An MMRM will be used 
as a sensitivity analysis 
including study drug 
treatment, visit, and 
stratification factors at 
randomization as fixed 
factors, baseline HbA1c 
value as a covariate, and 
treatment-by-visit and 
baseline HbA1c 
value-by-visit 
interactions. 
Least-squares means and 
differences with 95% CIs 
and P values at each time 
point will be presented. 
Reference-based MI 
(sensitivity analysis for 
superiority only): MI will 
be performed assuming 
that the trajectory of 
withdrawals from the 
Gla-300 arm is the same 


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Main Estimation 
 
 
Estimand Label 
Estimand Description 
Analysis Set 
Imputation/Data 
Censoring Rules 
Analysis Model/Method Sensitivity/Supportive 
Analysis 
as that in the  
IDeg-100 arm. 
Penalized MI (sensitivity 
analysis for 
non-inferiority only): 
Imputed missing data at 
Week 24 in the primary 
analysis will be penalized 
by adding 0.3% in the 
Gla-300 arm, and 
imputed values in the 
IDeg-100 arm will not be 
penalized. 
Estimand 1b 
(Supplementary) 
Difference in the mean 
change from baseline to 
Week 24 in HbA1c level 
(Gla-300 vs IDeg-100) in 
insulin-naïve patients 
with T2DM and renal 
impairment who have 
glycemic levels above 
target with OADs with or 
without GLP-1 RA (oral 
or injectable), assuming 
no discontinuation of 
study drug treatment due 
to any reasons and use of 
rescue therapies 
ITT 
Data collected after the 
ICEs will be excluded 
from the analysis.  
An MMRM will be 
performed including 
study drug treatment, 
visit, and stratification 
factors at randomization 
as fixed factors, baseline 
HbA1c value as a 
covariate, and treatment-
by-visit and baseline 
HbA1c value-by-visit 
interactions. 
Least-squares means and 
differences with 95% CIs 
and P values at each time 
point will be presented; 
this estimand will only be 
estimated to support  
non-inferiority.  
Per-protocol analysis 
based on the PPS will be 
performed as a supportive 
analysis for 
non-inferiority. 


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Abbreviations: ANCOVA, analysis of covariance; Gla-300; insulin glargine 300 U/mL; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HbA1c, glycated 
hemoglobin; ICE, intercurrent event; IDeg-100, insulin degludec 100 U/mL; ITT, intention-to-treat; MI, multiple imputation; MMRM, mixed-effect model 
with repeated measurements; MAR, missing at random; OAD, oral antidiabetic drug; PPS, per protocol set; T2DM, type 2 diabetes mellitus.  


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8.7.3 Analysis of Primary Endpoints 
8.7.3.1 Main Estimation of Primary Estimand 
For the primary efficacy endpoint (ie, change from baseline to Week 24 in HbA1c level), data 
collected after the ICEs will be included in the analysis based on the ITT set. Missing data 
will be handled using a multiple imputation (MI) strategy depending on 
treatment-completion status: 
• Missing data from patients discontinuing the study drug treatment will be imputed using 
data from patients also discontinuing the study drug treatment but who have their 
endpoint assessed within each treatment arm.  
• Missing data from patients completing the 24-week treatment period will be imputed 
using a model estimated from data observed in other patients completing the study drug 
treatment within each treatment arm.  
The following two-step approach will be used for the MI: 
• Step 1: The Markov chain Monte Carlo (MCMC) method will be used to impute 
intermediate missing data to create a monotone missing data pattern. 
• Step 2: Using the imputed datasets with monotone missing data pattern obtained from 
Step 1, missing data will then be imputed using the sequential regression method. 
The imputation model for Step 1 will include the treatment arm, baseline HbA1c value, and 
HbA1c values at Week 12 and Week 24. The imputation model for Step 2 will include the 
same variables as in Step 1 with the randomization strata (other than the categorized HbA1c). 
For each multiply imputed dataset, an analysis of covariance (ANCOVA) model will be 
performed; this analysis will include baseline HbA1c value as a covariate, and study drug 
treatment and stratification factors at randomization (other than the categorized HbA1c) as 
fixed factors. The mean difference between treatment arms (Gla-300 vs IDeg-100) will be 
estimated based on the least-squares (LS) means in the ANCOVA model. The estimated 
differences and their SDs obtained across the imputed datasets will be combined to produce a 
single point estimate and CI using Rubin’s rule and presented with a 2-sided 95% CI and a  
P value.  


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The tests for non-inferiority will be performed at a 1-sided 2.5% significance level, and the 
non-inferiority will be demonstrated if the upper bound of the 2-sided 95% CI of the 
difference between Gla-300 and IDeg-100 treatment arms is <0.3%. Superiority will be 
established if the upper bound of the 2-sided 95% CI is <0%.  
8.7.3.2 Sensitivity Analysis of Primary Estimand 
Sensitivity analyses will be conducted for the ITT to assess the robustness of the results 
obtained from the primary analysis. 
Mixed-Effect Model with Repeated Measurements Analysis 
A mixed-effect model with repeated measurements (MMRM) analysis will be used as a 
sensitivity analysis; this analysis will include study drug treatment, visit, and stratification 
factors at randomization (other than the categorized HbA1c) as fixed factors, baseline HbA1c 
value as a covariate, and treatment-by-visit and baseline HbA1c value-by-visit interactions. 
An unstructured covariance matrix will be used to model the within-patient errors. 
Parameters will be estimated using the restricted maximum likelihood method. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  
In this analysis, no imputation of missing data will be performed. 
The mean difference between treatment arms (Gla-300 vs IDeg-100) will be estimated based 
on the LS means for the treatment-by-visit interaction in the MMRM model. The estimates 
will be presented together with P values and 95% CIs at Week 24. 
Penalized Multiple Imputation (For Non-Inferiority Only) 
The imputed missing HbA1c values at Week 24 in the primary analysis will be penalized by 
adding 0.3% (corresponding to the non-inferiority margin) to the imputed HbA1c value in the 
Gla-300 arm, whereas the imputed HbA1c in the IDeg-100 arm will not be penalized.  
Each imputed complete dataset will then be analyzed using the same ANCOVA as described 
for the primary analysis. The treatment differences and their SDs estimated from each 
imputed dataset will be combined using Rubin’s rule for a single estimate and its associated 
95% CI. 


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Reference-Based Multiple Imputation (For Superiority Only) 
The reference-based MI assumes that the trajectory of withdrawals from the Gla-300 arm due 
to any reason is the same as that in the IDeg-100 arm, and imputes the missing HbA1c values 
in the Gla-300 arm using the imputation model established based on the data in the IDeg-100 
arm. 
The details of the imputation procedures will be specified in the SAP. 
8.7.3.3 Main Estimation of Supplementary Estimand 
The supplementary estimand will be estimated to support non-inferiority only. For this 
estimand, data collected after the ICEs will be excluded from the analysis based on the ITT 
set. An MMRM will be performed for the Hb1Ac values at Week 12 and Week 24; this will 
include study drug treatment, visit, and stratification factors at randomization (other than the 
categorized Hb1Ac) as fixed factors, baseline HbA1c value as a covariate, and 
treatment-by-visit and baseline HbA1c value-by-visit interactions. An unstructured 
covariance matrix will be used to model the within-patient errors. Parameters will be 
estimated using restricted maximum likelihood method. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom. Least-squares means and 
differences with 95% CIs and P values at each time point will be presented. 
8.7.3.4 Supportive Analysis of Supplementary Estimand 
A per-protocol analysis based on the PPS will be performed as a supportive analysis for 
non-inferiority. An ANCOVA will be performed as described for the primary analysis.  
No imputation of missing data will be needed, as patients with missing Week 24 
measurements will be excluded from the PPS. 
8.7.4 Analysis of Secondary Endpoints  
All secondary endpoints will be analyzed for the ITT set, in a similar manner as for the 
primary estimand. The continuous secondary endpoints will be analyzed using the same 
approach as described for the primary endpoint above, including the baseline values for the 
corresponding endpoint as covariates. All stratification factors at randomization will be 
included as fixed factors.  


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For the categorical secondary efficacy endpoint (patients reaching HbA1c target of <7.0% at 
Week 24), if a patient has a missing HbA1c value at Week 24, it will be assumed that they 
did not reach an HbA1c target of <7.0%. A logistic regression model adjusting for treatment 
arm and stratification at randomization (other than the categorized HbA1c) and HbA1c at 
baseline will be performed. The odds ratio (OR) estimated from the model will be presented 
together with its 95% CI.  
8.7.5 Analyses of Exploratory Endpoints 
 
 
 
 
 
 
  
Analysis of the CGM Substudy Exploratory Endpoints 
 
 
 
8.7.6 Analysis of Safety Evaluation 
All safety analyses will be performed on the safety set. The summary of safety results will be 
presented by treatment arms. 
CCI
CCI


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8.7.6.1 Analysis of AEs 
The observation period of safety data will be divided as follows: 
• The pre-treatment period is defined as the time between the date of signed informed 
consent and the first injection of the open-label study drug. 
• The on-treatment period (24-week on-treatment period) is defined as the time from the 
first injection of the open-label study drug up to 7 days after the last injection of the 
open-label study drug, regardless of the introduction of rescue therapy. The 7-day interval 
is chosen based on the half-life of the study drug (approximately 5 times the half-life of 
IDeg-100). 
• The post-treatment period is defined as the time starting 8 days after the last injection of 
the open-label study drug (after on-treatment period). 
The AE observations will be classified per the observation periods of safety data (as defined 
above) into: 
• Pre-treatment AEs: AEs that developed or worsened, or became serious during the 
pre-treatment period. 
• Treatment-emergent AEs (TEAEs): AEs that developed or worsened, or became serious 
during the on-treatment period. 
• Post-treatment AEs: AEs that developed or worsened, or became serious during the 
post-treatment period. 
All AEs will be coded to a “preferred term” (PT) and “high-level group term” (HLGT), 
“high-level term” (HLT) and primary “system organ class” (SOC) using the version of 
MedDRA currently in use by the sponsor at the time of database lock. 
Adverse event incidence tables will present data by SOC (sorted by internationally agreed 
order), HLGT, HLT, and PT sorted in alphabetical order for each treatment arm, as well as 
the number (n) and percentage (%) of patients experiencing an AE. Multiple occurrences of 
the same event in the same patient will be counted only once in the tables within a treatment 


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phase. The denominator for computation of percentages is the safety set within each 
treatment arm. 
The AE incidence tables will be provided by treatment arm for all types of TEAEs: All 
TEAEs, all treatment-emergent SAEs, all TEAEs leading to permanent treatment 
discontinuation, and all TEAEs related to local tolerability at injection site, and 
hypersensitivity. 
The following death summaries will be generated for the safety set: 
• Number (%) of patients who died by trial period (TEAE periods, on-trial, post-trial) and 
reasons for death, summarized by treatment received. 
• Death in nonrandomized patients or randomized patients who were not treated. 
Treatment-emergent AEs leading to death (as an outcome on the AE eCRF page as reported 
by the investigator) will be summarized by primary SOC, HLGT, HLT, and PT showing the 
number (%) of patients. The summary table will be sorted by internationally agreed order of 
SOC and alphabetic order of HLGT, HLT, and PT. 
8.7.6.2 Hypoglycemia 
The number and incidence of patients experiencing at least 1 hypoglycemic event will be 
presented by treatment arm and type of hypoglycemic event (ADA category) according to the 
diurnal distribution.  
The ORs and corresponding 95% CIs of the Gla-300 arm compared with the IDeg-100 arm 
will be estimated for each hypoglycemic event using a logistic regression model that includes 
treatment arm and stratification factors at randomization as fixed factors based on observed 
cases. 
The number and rate of hypoglycemic events (in patient-month of exposure) will be 
determined by treatment arm and type of hypoglycemic event (ADA category), according to 
the diurnal distribution. For each hypoglycemic event, the rate ratios and corresponding 
95% CIs of the Gla-300 arm over the IDeg-100 arm will be estimated using a 
negative-binomial regression adjusted for stratification factors at randomization with time on 
treatment as an offset. 


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The number and incidence of patients experiencing at least 1 nocturnal hypoglycemic event 
defined by sleep status and the number and rate of these nocturnal events (in patient-month 
of exposure) will also be presented by treatment arm. 
The aforementioned hypoglycemia analyses will be performed and presented separately for 
the overall 24-week study treatment period, the titration period (ie, Week 1 through 
Week 12), and the maintenance period (ie, Week 13 through Week 24). 
8.7.6.3 Other Safety Analyses  
The clinical safety laboratory test values, vital signs, and physical examination findings will 
be summarized by treatment arm. Potential clinically significant values will be flagged and 
summarized. 
8.7.7 Other Analyses 
Descriptive summary analyses will be provided for medical history and risk factor variables 
at baseline. 
The extent of study drug treatment exposure and compliance will be descriptively 
summarized by treatment for the safety set. 
8.8 Handling of Missing Data 
Details on how missing dates for AEs or concomitant medications will be handled will be 
specified in the SAP. 
For the primary analysis, an MI strategy (as specified in Section 8.7.3.1) will be used for 
handling missing data. An MMRM assuming missing at random (MAR) will be used as a 
sensitivity analyses. A reference-based MI strategy assuming missing not at random (MNAR) 
will be performed as a sensitivity analysis for superiority. The details of missing data 
handling will be specified in the SAP. 
8.9 Interim Analyses 
No interim analyses are planned for this trial. 


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8.10 Data Quality Assurance 
• All patient data relating to the trial 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 trial-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality, 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate trial documents. 
• The sponsor or designee is responsible for the data management of this trial, 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 trial 
must be retained by the investigator for 25 years after the signature of the final trial 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. 
8.10.1 Data Management 
As part of the responsibilities assumed by participating in the trial, the investigator agrees to 
maintain adequate case histories for the patients treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 


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part of the case histories. These source documents may include medical charts, the patient’s 
eDiary, and laboratory reports (Section 13.8). 
PPD will supply the eCRF, whose access will be limited to personnel directly participating in 
the trial, and all eCRFs should be completed in English. 
All eCRF information is to be filled in. 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. 
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 site will receive their 
site-specific eCRF data as entered into Medidata Rave for the trial, including full discrepancy 
and audit history. Additionally, a copy of all data from the trial will be created and sent to the 
sponsor for storage. In all cases, patient initials and their date of birth will not be collected. 


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9 Ethics 
9.1 Independent Ethics Committee or Institutional Review Board 
Federal regulations and the International Council for Harmonisation (ICH) guidelines require 
that approval be obtained from an IRB/IEC before participation of human patients in research 
studies. Before trial onset, any information related to this trial or provided to the patient 
(eg, the protocol, informed consent, advertisements for recruitment of trial participants, any 
other written information) must be approved by the IRB/IEC. Documentation of all IRB/IEC 
approvals and of the IRB/IEC 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/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title or protocol number or 
both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the trial at intervals not exceeding 1 year or otherwise specified by the IRB/IEC.  
The investigator must promptly supply the sponsor or its designee, the IRB/IEC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the trial or increasing the risk to patients. 
9.2 Ethical Conduct of the Trial 
The trial 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 Patient Information and Consent 
A written informed consent in compliance with regulatory authority regulations and/or US 
Title 21 Code of Federal Regulations (CFR) Part 50 shall be obtained from each patient 
before entering the trial or performing any unusual or nonroutine procedure. An informed 
consent template will be provided by the sponsor to investigative sites. If any 
institution-specific modifications to trial-related procedures are proposed or made by the site, 
the consent should be reviewed by the sponsor or its designee or both before submitting the 


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revised ICF to the IRB/IEC. If the ICF is revised during the course of the trial, all active 
patients must sign the revised form. 
Before recruitment and enrollment, each potential patient will be given a full explanation of 
the trial and be allowed to read the approved ICF. Once the investigator is assured that the 
patient understands the implications of participating in the trial, the patient will be asked to 
give consent to participate in the trial by signing the ICF. 
The investigator shall retain the signed original ICF(s) and give a copy of the signed original 
form to the patient. 
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10 Investigator’s Obligations  
The following administrative items are meant to guide the investigator in the conduct of the 
trial 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/IEC 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 patient 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 patient, except as necessary for monitoring and auditing by the sponsor, its 
designee, regulatory authorities (eg, the US FDA), or the IRB/IEC. 
The investigator and all employees and coworkers involved with this trial may not disclose or 
use for any purpose other than performance of the trial, any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
trial. 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 trial will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
General Data Protection Regulation (GDPR). The trial 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 
patients, the sponsor will take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 


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Protection of Patient Data 
The 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 trial objective. 
This trial will attempt to represent a diverse set of patients with T2DM and renal impairment, 
as they represent a growing proportion of the patient population, are historically 
under-represented in clinical trials, and are disproportionately affected by T2DM and renal 
impairment. For example, ethnic minority groups are known to have a higher prevalence of 
T2DM and end-stage renal failure compared with the white majority population  
(Mathur et al 2018).  
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Protection of Data Related to Professionals Involved in the Trial  
• Personal data (eg, contact details, affiliation details, job title and related professional 
information, role in the trial, professional resume, training records) are necessary to allow 
Sanofi to manage involvement in the trial and/or the related contractual or pre-contractual 
relationship. They may be communicated to any company of the Sanofi group (“Sanofi”) 
or to Sanofi service providers, where needed. 
• Personal data can be processed for other trials and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available 
at Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi trial. In case the professionals have 
already been involved in a Sanofi trial, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies’ 
disqualification list. 
• Personal data can be communicated to the following recipients:  
o Personnel within Sanofi or partners or service providers involved in the trial.  
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. 
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• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law, including the following:  
o The standard contractual clauses of the European Commission for transfers towards 
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 with 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. 
• 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 
per requirements of local or national regulatory authorities and/or under 21 CFR 54.  


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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 the completion of the trial. 
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 patient’s disease. 
10.4 Investigator Documentation  
Before beginning the trial, the investigator will be asked to comply with ICH E6(R2) 
Section 8.2 and Title 21 of the CFR and/or with local or national regulatory requirements by 
providing all essential documents, including but not limited to the following: 
• IRB/IEC 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 or designee to submit complete and 
accurate certification. In addition, investigators must provide to the sponsor or designee 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 trial. 
• IRB-/IEC-approved informed consent, samples of site advertisements for recruitment for 
this trial, and any other written information regarding this trial that is to be provided to 
the patient. 
• Signed Clinical Trial Agreement. 
10.5 Trial Conduct  
The investigator agrees that the trial will be conducted according to the principles of ICH 
E6(R2). The investigator will conduct all aspects of this trial in accordance with all national, 
state, and local laws or regulations. Trial information from this protocol will be posted on 
publicly available clinical trial registers before enrollment of patients begins. 


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10.6 Adverse Events and Trial Report Requirements  
The investigator agrees to submit reports of SAEs to the sponsor or designee and/or IRB/IEC 
according to the timeline and method outlined in the protocol (Section 13.5.4). In addition, 
the investigator agrees to submit annual reports to the site IRB/IEC as appropriate. 
10.7 Investigator’s Final Report  
Upon completion of the trial, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC with a summary of the 
trial’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
 


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11 Trial Management 
11.1 Monitoring 
11.1.1 External Data Monitoring Committee 
No data monitoring committee is planned for this trial. 
11.1.2 Monitoring of the Trial 
The clinical monitor, as a representative of the sponsor, has the obligation to follow the trial 
closely. In doing so, the monitor will visit the investigator and site at periodic intervals, in 
addition to maintaining necessary phone and letter contact. The monitor will maintain current 
personal knowledge of the trial through observation, review of trial records and source 
documentation, and discussion of the conduct of the trial with the investigator and personnel. 
In the event a clinical monitor cannot visit the site in a timely manner due to the coronavirus 
disease 2019 (COVID-19) pandemic, alternative monitoring approaches, such as remote 
source data verification may be used to ensure data quality and integrity and maintain patient 
safety. Alternative monitoring approaches should be used only where allowed by the local 
health authority, privacy laws, and permitted by the IRB/IEC. 
The medical monitor and sponsor will hold meetings at regular intervals to review AEs, 
unless an SAE is noted and reported as described in Section 6.2.6.5. 
All aspects of the trial 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 trial will permit trial-related monitoring, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to all trial records.  
In the event of an audit, the investigator agrees to allow the sponsor, representatives of the 
sponsor, or a regulatory agency (eg, US FDA) access to all trial records. 


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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. 
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 patients, 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/IEC for approval before patients can be enrolled into an amended protocol. 
11.2.2 Protocol Deviations 
The investigator or designee must document and explain in the patient’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 trial patients 
without prior IRB/IEC 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/IEC 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/IEC and agreed to by the 
investigator. A significant deviation occurs when there is nonadherence to the protocol by the 
patient or investigator that results in a significant, additional risk to the patient. Significant 
deviations can include nonadherence to inclusion or exclusion criteria or nonadherence to 
local regulations or ICH GCP guidelines, and will lead to the patient being withdrawn from 
the trial (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/IEC should be notified of protocol deviations as applicable. 


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11.3 Trial Termination 
Although sponsor has every intention of completing the trial, they reserve the right to 
discontinue the trial at any time for clinical or administrative reasons. 
The end of the trial is defined as the date of the last visit of the last patient in the trial 
globally. 
11.4 Final Report 
Whether the trial 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 applicable by regulatory requirements, an investigator signatory will be identified for 
the approval of the CSR. The investigator will be provided access to statistical tables, figures, 
and relevant reports and will have the opportunity to review the complete trial results. 
Upon completion of the CSR, the sponsor will provide the investigators with the full 
summary of the trial results. The investigators are encouraged to share the summary results 
with the trial patients, as appropriate. The trial results will be posted on publicly available 
clinical trial registers. 
11.5 Records Retention 
Essential documents should be retained until at least 2 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 2 years have elapsed since the formal 
discontinuation of clinical development of the study drug. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor. It is the responsibility of the sponsor to inform 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 Trial Registration 
11.6.1 Publication Policy and Disclosure 
• The results of this trial 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 trial 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 Trial Registration 
In order to ensure that information regarding clinical trials reaches the public in a timely 
manner and to comply with applicable laws, regulations, and guidance, sponsor (or its 
designee) will register interventional clinical trials it sponsors globally on ClinicalTrials.gov 
or other publicly accessible registers (eg, EudraCT) before the start of the trial. 
11.6.3 Clinical Trial Results Disclosure 
Trial Patients 
Sanofi shares information about clinical trials and results on publicly accessible websites, 
based on company commitments, international and local legal and regulatory requirements, 
and other clinical trial disclosure commitments established by pharmaceutical industry 
associations. These websites include ClinicalTrials.gov, the European Union Clinical Trials 
Register (https://www.clinicaltrialsregister.eu/), and sanofi.com, as well as national registries, 
as applicable. 


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In addition, results from clinical trials in patients are required to be submitted to peer 
reviewed journals following internal company review for accuracy, fair balance, and 
intellectual property. For those journals that request sharing of the analyzable data sets that 
are reported in the publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual patient data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of patients in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com.  
Professionals Involved in the Trial 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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12 Reference List 
ADA. 6. Glycemic targets: standards of medical care in diabetes–2021. Diabetes Care. 
2021;44(Suppl 1):S73-S84. 
Agiostratidou A, Anhalt H, Ball D, et al. Standardizing clinically meaningful outcome 
measures beyond HbA1c for type 1 diabetes: a consensus report of the American Association 
of Clinical Endocrinologists, the American Association of Diabetes Educators, the American 
Diabetes Association, the Endocrine Society, JDRF International, The Leona M. and Harry B. 
Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange.  
Diabetes Care. 2017;40(12):1622-30. 
Alsahli M, Gerich JE. Hypoglycemia, chronic kidney disease, and diabetes mellitus. Mayo 
Clin Proc. 2014;89(11):1564-71. 
Anderson JE, Gavin JR, Kruger DF. Current eligibility requirements for CGM coverage are 
harmful, costly, and unjustified. Diabetes Technol Ther. 2020;22(3):169-73. 
Association of British Clinical Diabetologists and The Renal Association. Managing 
hyperglycaemia in people with diabetes and chronic kidney disease. London: ABCD, 2021. 
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):1593-1603. 
Battelino T, Bosnyak Z, Danne T, et al. InRange: Comparison of the second-generation basal 
insulin analogues glargine 300 U/mL and degludec 100 U/mL in persons with type 1 diabetes 
using continuous glucose monitoring-study design. Diabetes Ther. 2020;11(4):1017-27. 
Bolli GB, Riddle MC, Bergenstal RM, et al. New insulin glargine 300 U/ml compared with 
glargine 100 U/ml in insulin-naïve people with type 2 diabetes on oral glucose-lowering 
drugs: a randomized controlled trial (EDITION 3). Diabetes Obes Metab. 2015;17(4):386-94. 
Cherney DZI, Ferrannini E, Umpierrez GE, et al. Efficacy and safety of sotagliflozin in 
patients with type 2 diabetes and severe renal impairment. Diabetes Obes Metab. 
2021;23(12):2632-42. 


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Danne T, Nimri R, Battelino T, et al. International consensus on use of continuous glucose 
monitoring. Diabetes Care. 2017;40(12):1631-40. 
European Medicines Agency (EMA). Draft guidance. Guideline on clinical investigation of 
medicinal products in the treatment or prevention of diabetes mellitus. January 2018 [cited 
2022 Feb 15]. Available from: Guideline on clinical investigation of medicinal products in 
the treatment or prevention of diabetes mellitus (europa.eu).  
Galindo RJ, Beck RW, Scioscia MF, et al. Glycemic monitoring and management in 
advanced chronic kidney disease. Endocr Rev. 2020;41(5):756-74. 
Goldenberg RM, Aroda VR, Billings LK, et al. Effect of insulin degludec versus insulin 
glargine U100 on time in range: SWITCH PRO, a crossover study of basal insulin-treated 
adults with type 2 diabetes and risk factors for hypoglycaemia. Diabetes Obes Metab. 
2021;23(11):2572-81. 
Haluzík M, Cheng A, Müller-Wieland D, et al. Differential glycaemic control with basal 
insulin glargine 300 U/mL versus degludec 100 U/mL according to kidney function in type 2 
diabetes: a subanalysis from the BRIGHT trial. Diabetes Obes Metab. 2020;22(8):1369-77. 
Mathur R, Dreyer G, Yaqoob MM, et al. Ethnic differences in the progression of chronic 
kidney disease and risk of death in a UK diabetic population: an observational cohort study. 
BMJ Open. 2018;8(3):e020145. 
National Kidney Foundation. CKD-EPI Creatinine Equation (2021) [Internet]. 2022 [cited 
2022 Mar 30]. Available from: https://www.kidney.org/content/ckd-epi-creatinine-equation-
2021. 
Navaneethan SD, Zoungas S, Caramori ML, et al. Diabetes management in chronic kidney 
disease: synopsis of the 2020 KDIGO clinical practice guideline. Ann Intern Med. 
2021;174(3):385-94. 
Papademetriou V, Lovato L, Doumas M, et al. Chronic kidney disease and intensive glycemic 
control increase cardiovascular risk in patients with type 2 diabetes. Kidney Int. 
2015;87(3):649-59. 
Rabkin R. Diabetic nephropathy. Clin Cornerstone. 2003;5(2):1-11. 


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Riddle MC, Bolli GB, Ziemen M, et al. New insulin glargine 300 units/mL versus glargine 
100 units/mL in people with type 2 diabetes using basal and mealtime insulin: glucose 
control and hypoglycemia in a 6-month randomized controlled trial (EDITION 1).  
Diabetes Care. 2014;37(10):2755-62. 
Rosenstock J, Cheng A, Ritzel R, et al. more similarities than differences testing insulin 
glargine 300 units/ml versus insulin degludec 100 units/ml in insulin-naive type 2 diabetes: 
the randomized head-to-head BRIGHT trial. Diabetes Care. 2018;41(10):2147-54. 
Roussel R, Ritzel R, Boëlle-Le Corfec E, et al. Clinical perspectives from the BEGIN and 
EDITION programmes: Trial-level meta-analyses outcomes with either degludec or glargine 
300U/mL vs glargine 100U/mL in T2DM. Diabetes Metab. 2018;44(5):402-9. 
Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a 
Workgroup of the American Diabetes Association and The Endocrine Society. Diabetes Care. 
2013; 36(5):1384-95. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th ed Little, Brown & Co; Boston, 
Mass: 1994. pp. 253-256. 
TRESIBA® (insulin degludec injection) [package insert]. Novo Nordisk Inc. Plainsboro (NJ); 
2019 [cited 2022 Feb16] [58 screens]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/203314s015s016lbl.pdf. 
Tresiba 100 (insulin degludec) [summary of product characteristics]. Novo Nordisk A/S. 
Bagsværd (Denmark); 2021 [cited 2022 Feb 16] [16 screens]. Available from: 
https://www.medicines.org.uk/emc/product/7936/smpc. 
TOUJEO® (insulin glargine injection) U-300 [package insert]. Sanofi-Aventis U.S. LLC.  
A SANOFI COMPANY. Bridgewater (NJ); 2020 [cited 2022 Feb 16] [15 screens]. Available 
from: https://products.sanofi.us/toujeo/toujeo.pdf. 
Toujeo 300 (insulin glargine) [summary of product characteristics]. Sanofi-Aventis 
Deutschland GmbH. Frankfurt am Main (Germany); 2020 [cited 2022 Feb 16] [15 screens]. 
Available from: https://www.medicines.org.uk/emc/product/6938/smpc. 


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Yki-Järvinen H, Bergenstal RM, Bolli GB, et al. Glycaemic control and hypoglycaemia with 
new insulin glargine 300 U/ml versus insulin glargine 100 U/ml in people with type 2 
diabetes using basal insulin and oral antihyperglycaemic drugs: the EDITION 2 randomized 
12-month trial including 6-month extension. Diabetes Obes Metab. 2015;17(12):1142-9. 
 
 


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13 Appendices 
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13.2 Appendix: Schedule of Events for the Main Trial 
Table 13-3 
Schedule of Events for the Main Trial 
Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 
21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography (including 
height) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Current medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Study drug dispensing 
 
X 
 
X 
 
Xg 
 
X 
 
 
 
X 
 
SoloStar or FlexTouch 
pen instructionh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient eDiary setup 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient eDiary completion 
<------------------------------------------------------------------------------------------------------------X---------------------------------------------------------------------> 
 
Collection of eDiary 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
Glucose meter (dispensing 
and instruction) 
X 
 
 
 
 
 
 
 
 
 
 
 
 


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Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 
21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Collection of glucose 
meter (if mandatory by 
local regulation) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Daily dosing of Gla-300 
or IDeg-100i 
 
<-------------------------------------------------------------------------------------------X--------------------------------------------------------------------> 
 
Study drug dose 
adjustments 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study drug adherence and 
accountability 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
HbA1c 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
FPGj 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Fasting SMPGk 
 
<--------------------------------------------------------------------------X----------------------------------------------------------> 
 
 
7-point SMPGl 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Hypoglycemia eventsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Recording of AEs and 
SAEs (including AESIs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Product complaints 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (including 
body weight)n 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Clinical chemistryo 
Xp 
 
 
 
 
 
 
 
 
 
Xp 
 
 
Hematologyo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysiso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine albumin: 
creatinine ratio 
Xp 
 
 
 
 
 
 
 
 
 
Xp 
 
 


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Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 
21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Pregnancy testq 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
Abbreviations: AE, adverse event; AESI, adverse event of special interest; BMI, body mass index; CGM, continuous glucose monitoring; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney 
Disease Epidemiology Collaboration; cr, creatinine; DBP, diastolic blood pressure; DTP, direct-to-patient; eDiary, electronic diary; eGFR, estimated glomerular filtration rate; FPG, fasting plasma 
glucose; Gla-300, insulin glargine 300 U/mL; HbA1c, glycosylated hemoglobin; HCP, healthcare provider; IDeg-100, insulin degludec 100 U/mL; IMP, investigational medicinal product; 
SAE, serious adverse event; SBP, systolic blood pressure; Scr, serum creatinine; SMPG, self-measured plasma glucose; WOCBP, women of childbearing potential. 
a 
During the titration period, the doses of Gla-300 and IDeg-100 will be adjusted using a recommended dose-adjustment algorithm (Table 5-2). After randomization, the dose will be titrated at least 
weekly (but no more than every 3 days) until the patient reaches a target fasting SMPG value of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes. Thereafter, until the 
end of the trial, the doses of Gla-300 and IDeg-100 will be adjusted to maintain this glycemic target, if deemed appropriate by the investigator. Dose adjustments will be based on a median of 
fasting SMPG values from the last 3 measurements, including the value on the day of titration, measured by the patient using glucose meters and accessories supplied by the sponsor through a 
vendor. Best efforts should be made to reach the glycemic target by 8–12 weeks after randomization. 
c 
At the end of the trial, patients should discuss with the investigator, in collaboration with their HCP, whether to continue on the Gla-300 or IDeg-100 treatment regimen or transition to an alternate 
antihyperglycemic therapy. All patients who withdraw from the trial prematurely will, as soon as possible, undergo all end-of-trial and follow-up assessments/procedures at a visit that should be 
identified as “the early trial discontinuation visit.” 
d 
An unscheduled visit can be planned anytime during the treatment period if study drug resupply is required. This will be a site visit or via phone contact with DTP-IMP delivery.  
The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial site. 
e 
This will be a phone contact, but could be a site visit if ongoing or new AEs emerge during the post-treatment period, if necessary. 
f 
A physical examination will be performed per standard of care to assess the health status of patients. A list of assessments is provided in Section 6.2.1. 
g 
Study drug resupply at Visit 10 will be via phone contact with DTP-IMP delivery. The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial 
site. 
h 
All patients will be trained by trial staff on how to use the pen correctly, how to store it, and how to change the needle to ensure that each patient is able to perform self-injection. An instruction 
leaflet will be provided to patients that explains how to use the disposable pen and needles. Training will be repeated during the treatment period as often as deemed necessary by site staff. 
i 
Gla-300 or IDeg-100 should be self-administered once daily between 6:00 PM and 8:00 PM throughout the treatment period. The investigator and patient will discuss and agree upon the injection 
time. Gla-300 or IDeg-100 will be administered after the fasting blood sample draw during site visits. The need for dose adjustment will be assessed at each visit. 
j 
For scheduled site visits, patients will be required to arrive having fasted without administering the study drug. Fasting is defined as no intake of food or drink, except water, in the 8 hours before 
blood sampling. 
k 
Fasting SMPG values will be used to titrate and adjust study drug doses and monitor glycemic levels. Patients will be required to measure fasting SMPG values (using the glucose meter supplied 
during the screening period) before breakfast and before administration of study drug once daily throughout the treatment period and to record the results in the eDiary.  
l 
The 7-point SMPG profile will be measured (and recorded in the patient’s eDiary) at the following 7 points: preprandial and 2 hours after starting breakfast, lunch, and dinner, and at bedtime.  
The 7-point SMPG profile will be performed over a single, 24-hour period, on at least 2 days within the week before selected site visits. 
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m 
Hypoglycemia events will be evaluated based on the categories of interest described in Section 6.2.2. 
n 
This includes body weight, heart rate, SBP, and DBP. Height and body weight measurements at screening will be used to calculate BMI. 
o 
The list of clinical safety laboratory tests to be performed is provided in Section 13.4). Additional tests may be performed at a local or central laboratory at any time during the trial as deemed 
necessary by the investigator or required by local regulations. The central laboratory should calculate eGFR using the CKD-EPI equation: eGFRcr = 142 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.200 × 
0.9938Age × 1.012 [if female] (National Kidney Foundation 2022). 
p 
Creatinine and eGFR (clinical chemistry) and spot urine albumin: creatinine ratio will be measured for CKD monitoring. 
q 
This is only for WOCBP and is a urine pregnancy test. 
 
 
 


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13.3 Appendix: Patient eDiary Information 
Patients will be provided with an eDiary to use during the trial, and site staff will instruct 
them on how to complete the eDiary. Training on eDiary use will be documented in the 
patient’s source documents.  
Patients are required to make eDiary entries at least once daily from the screening period 
(Visit 1) through the end of the treatment period (Visit 17) and bring completed eDiaries at 
each site visit. Site staff will verify the eDiary (at the time points specified in the SoE 
[Section 13.2]) by viewing the data transmitted from the eDiaries into the database. 
The information to be recorded in the eDiary may include, but not be limited to, the 
following: 
• Each dose of study drug taken (date/time and actual dose) and type and dose of daily 
background noninsulin antidiabetic drug(s). The patient will document any temporary 
treatment discontinuations. 
• Fasting SMPG values (using the glucose meter supplied during the screening period) 
before breakfast and before administration of study drug once daily throughout the 
treatment period. 
• 7-point SMPG profile: 7-point SMPG profiles measured at the following 7 points: 
preprandial and 2 hours after starting breakfast, lunch, and dinner, and at bedtime.  
The time points are specified in the SoE (Section 13.2). 
• Symptoms of hypoglycemia: Patients 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 Safety Laboratory Tests 
• The tests detailed in Table 13-4 will be performed at the central laboratory, except urine 
pregnancy tests, which will be performed at sites using urine pregnancy test kits that are 
provided by PPD. 
• Protocol-specific requirements for inclusion or exclusion of patients are detailed in 
Section 4 of the protocol. 
• Additional tests may be performed at a local or central laboratory at any time during the 
trial as deemed necessary by the investigator or required by local regulations. If a test is 
used to evaluate an AE (diagnostic, follow-up, outcome), the results (including notably, 
the disease progression of CKD) must be entered into the eCRF. 


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Table 13-4 
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) 
Albumin (serum) 
Creatinine (serum)b 
Spot urine albumin: creatinine ratiob  
eGFRb,c 
Sodium 
Potassium 
Urinalysis 
pH 
Glucose 
Ketones 
Leukocytes 
Blood/Hb 
Protein 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CKD, chronic kidney disease; 
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; cr, creatinine; eCRF, electronic case 
report form; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; MDRD, Modification of Diet in 
Renal Disease; Scr, serum creatinine; ULN, upper limit of normal. 
a 
All protocol-required safety laboratory assessments will be performed at the central laboratory, except urine 
pregnancy tests, which will be performed locally; the results of each test must be entered into the eCRF. 
b 
Creatinine and eGFR (clinical chemistry) and spot urine albumin: creatinine ratio will be measured for 
CKD monitoring. 
c 
The central laboratory should calculate eGFR using the CKD-EPI equation: eGFRcr = 142 × min(Scr/κ, 1)α 
× max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if female] (National Kidney Foundation 2022). 


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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 trial patient, 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, vital sign measurements), including those that worsen 
from baseline, that are 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 corrective treatment or consultation.  
o Lead to study drug discontinuation. 
o Fulfill a seriousness criterion.  
o Meet the definition of an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition, including 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 trial. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 


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• Signs, symptoms, or the clinical sequelae of a suspected overdose of study drug or a 
concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as 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 patient’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 patient’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 trial 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 patient 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 patient 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), which 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 patient or may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 


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• Chronic neurodegenerative diseases diagnosed during the trial. 
• Cancers diagnosed during the trial. 
• Bullous cutaneous eruptions. 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling). 
• Suicide attempt or any event suggestive of suicidality. 
• ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × ULN. 
• Allergic bronchospasm, convulsions. (seizures, epilepsy, epileptic fit, absence, etc.). 
• Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc.). 
13.5.3 Recording and Follow-Up of AEs and/or SAEs 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to the sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the sponsor’s representative. In this case, all patient identifiers, with the exception of the 
patient number, will be redacted on the copies of the medical records before submission 
to the sponsor’s representative. 


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• 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 trial and assign it to one of the following categories: 
• Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering 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, and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between the study drug/NIMP and 
each occurrence of an AE/SAE (including 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. 


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• The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment. 
• For each AE/SAE (including AESI), the investigator must document in the medical notes 
that they have reviewed the AEs/SAEs (including 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 always make an assessment of causality for every event before the 
initial transmission of the SAE/AESI data to the sponsor or designee. 
• The investigator may change their opinion of causality in light of follow-up information 
and send an SAE/AESI follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-Up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor’s 
representative to elucidate the nature and/or causality of the AEs or SAEs (including 
AESIs) as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• If a patient dies during participation in the trial or during a recognized follow-up period, 
the investigator will provide the sponsor’s representative 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/AESI data to the sponsor or designee 
within 24 hours of receipt of the information. 


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13.5.4 Reporting of SAEs, Including AESIs 
SAE/AESI Reporting to the Sponsor via an EDC Tool 
• The primary mechanism for reporting an SAE/AESI 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 backup paper SAE/AESI 
data collection tool (see the following section) to report the event within 24 hours. 
• The site will enter the SAE/AESI data into the electronic system as soon as it becomes 
available. 
• After the trial is completed at a given site, access to the EDC tool will be reduced to 
read-only or revoked to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE/AESI from a trial patient or receives updated data 
on a previously reported SAE/AESI after access to the EDC tool has been reduced 
(read-only or revoked), then the site can report this information on a paper SAE/AESI 
form (see the following section) or to the sponsor’s representative by fax. 
• Contacts for SAE reporting can be found in the Investigator’s Trial File. 
SAE/AESI Reporting to the Sponsor via Paper Data Collection Tool 
• Facsimile transmission of the SAE/AESI 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 
• Initial notification via fax does not replace the need for the investigator to complete and 
sign the SAE/AESI data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator’s Trial File. 
CCI


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13.6 Appendix: Contraceptive and Barrier Guidance 
Definitions: 
Woman of Childbearing Potential 
• A woman is considered a 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 trial. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before trial enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be applied to determine trial eligibility. 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 


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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. 
Woman of Nonchildbearing 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 an alternate medical cause other than 
the above (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining trial 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 trial enrollment. 
Note: Documentation can come from the site personnel’s review of the patient’s medical 
records, medical examination, or medical history interview. 


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Contraception Guidance 
CONTRACEPTIVESa ALLOWED DURING THE TRIAL 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 
ovulation.c 
• Intrauterine device (IUD). 
• 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 patient can come from the site 
personnel’s review of the patient’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 ovulation.c 
• Oral 
• Intravaginal 
• Transdermal 
• Injectable 
Progestogen-only hormone contraception associated with inhibition of ovulation.c 
• Oral 
• Injectable 


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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 trial and the preferred and usual lifestyle of the patient. 
a Contraceptive use by men or women should be consistent with local regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
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 lactational amenorrhea method (LAM) are not 
acceptable methods of contraception for this trial. Male condom and female condom 
should not be used together (due to risk of failure from friction). 
Collection of Pregnancy Information 
Male Patients With Partners Who Become Pregnant 
• The investigator will attempt to collect pregnancy information on any male patient’s 
female partner who becomes pregnant while the male patient is in this trial. This applies 
only to male patients who receive the study drug. 
• After obtaining the necessary signed ICF 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.  


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Female Patients Who Become Pregnant 
• The investigator will collect pregnancy information on any female patient who becomes 
pregnant while participating in this trial. The initial information will be recorded on the 
appropriate form and submitted to the sponsor or designee within 24 hours of learning of 
a patient’s pregnancy.  
• The patient will be followed up to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the patient 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. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or medical reasons resulting in an elective termination will be reported as 
an AE or SAE.  
• A spontaneous abortion (occurring at <22 weeks gestational age) or still birth (occurring 
at >22 weeks gestational age) is always considered to be an SAE and will be reported as 
such.  
• Any post-trial pregnancy-related SAE considered reasonably related to the study drug by 
the investigator will be reported to the sponsor as described in Section 13.5.4. While the 
investigator is not obligated to actively seek this information in former trial patients, they 
may learn of an SAE through spontaneous reporting. 
• Any female patient who becomes pregnant while participating in the trial will be 
discontinued from study drug treatment. 
 


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13.7 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 
INCREASE IN ALT
ALT > 3 ULN
Confirm ALT > 3 ULN
Retest within 72 hours of initial 
sample*
No
Yes
COMPLETE the specific CRF forms for 
„ALT Increase” and inform the 
Monitoring Team within 24 hours
Total Bilirubin > 2 ULN 
No
Yes
ALT > 5 ULN (if baseline ALT ≤ 2 ULN), or 
ALT >8 ULN (if baseline ALT > 2 ULN)
Continue IMP administration
No
Monitor LFTs every 72 hours
IMP administration can be continued as 
long as – under close monitoring –
conditions for permanent 
discontinuation or temporary 
interruption per protocol are not met
Yes
Permanent Discontinuation of IMP
In ANY CASE, FOLLOW the instructions listed in the box below: 
1.
INFORM the Site Monitor who will forward the information to the Study Manager
2.
INVESTIGATE specifically for malaise with or without loss of consciousness, dizziness, and/or hypotension and/or episode of 
arrhythmia in the previous 72 hours; rule out muscular injury
3.
PERFORM the following tests:
- LFTs: AST, ALT, alkaline phosphatase, total and conjugated bilirubin and prothrombin time / INR
- CPK, serum creatinine, complete blood count
- Anti-HAV IgM, anti-HBc IgM (HBV-DNA if clinically indicated), anti-HCV and HCV RNA, anti-
CMV  IgM and anti-HEV IgM antibodies
- Depending on the clinical context, check for recent infection with EBV, herpes viruses, and toxoplasma
- Hepatobiliary ultrasonography (or other imaging investigations if needed)
4.
CONSIDER Auto-antibodies: antinuclear, anti-DNA, anti-smooth muscle, anti-LKM
5.
CONSIDER consulting with hepatologist
6.
CONSIDER patient hospitalisation if INR>2 (or PT<50%) and/or central nervous system disburbances suggesting hepatic 
encephalopathy
7.
MONITOR LFTs after discontinuation of IMP:
- As closely as possible (or every 48 hours) until stabilization, then every 2 weeks until return to normal/baseline or clinical 
resolution.
8.
FREEZE serum sample (5ml x 2)
9.   In case of SUSPICION of GILBERT Syndrome, a DNA diagnostic test should be done


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virus; HAV, hepatitis A virus; HBc, hepatitis B core; HBV, hepatitis B virus; HCV, hepatitis C virus; 
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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13.8 Appendix: Source Documents 
Source documents provide evidence for the existence of the patient 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 trial. Also, current 
medical records must be available. 
Definition of Source Data 
Source Data to Be Found in the Patient’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 trial identification and any 
privacy forms. 
• Trial identification (name). 
• Treatment kit number, dates of administration, and doses of study drug administered. 
• Medical, surgical, and disease 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 trial. 
o Contraception method for WOCBP. 
o Previous and concomitant medications, including treatment for diabetes. 
o Dates and times of visits and assessments, including examination report. 


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o Vital signs, height, body weight, clinical safety laboratory reports. 
o AEs and follow-up. 
• If there is an SAE, the site should file in the source documents, at least, copies of the 
hospitalization reports and any relevant examination reports documenting the follow-up 
of the SAE. 
• Date of premature trial discontinuation (if any) and reason. 
Source documentation may be found in the following: 
• Patient’s identity (identification card or other verification document). 
• Medical history. 
• Nursing notes. 
• Physician’s notes. 
• Patient’s eDiary. 
• Dated and signed print outs with SMPG downloaded from glucose meter. 
Source Data Verification Requirements for Screen Failures 
For screen failure patients, the following source data must be verified: patient’s identification 
details, the informed consent signed by the patient, the trial identification (name), dates of 
trial visits, and the main reasons for screen failure. 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
Trial 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 patients are being protected; and that the trial is being 
conducted in accordance with the currently approved protocol and any other trial agreements, 
ICH GCP, and all applicable regulatory requirements. 

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 
 .m 
STATISTICAL ANALYSIS PLAN          
Protocol title: 
A 24-Week, Multicenter, Randomized, Open-Label, 
Parallel-Group Trial Comparing the Efficacy and 
Safety of Insulin Glargine 300 U/mL (Gla-300) and 
Insulin Degludec 100 U/mL (IDeg-100) in Insulin-Naïve 
People with Type 2 Diabetes Mellitus and Renal 
Impairment: TRENT Trial  
Protocol number: 
LPS17007  
Compound number 
(INN/Trademark): 
HOE901-U300  
(Insulin Glargine 300 U/mL) 
Study phase: 
Phase 4 
Short title: 
Gla-300 and IDeg-100 in Insulin-Naïve People with 
Type 2 Diabetes Mellitus and Renal Impairment  
Statistician: 
 
 
Statistical project leader: 
 
Date of issue: 
17-Oct-2023 
Regulatory agency identifier number(s): 
 
Registry: 
NCT05552859 
Enter Registry Name: 
LPS17007 
Eudra CT Number: 
2022-011485-35 
 
 
 
Total number of pages: 
58 
VV-CLIN-0656049 2.0
PPD
PPD
PPD


Statistical Analysis Plan  
17-Oct-2023 
HOE901-U300-LPS17007 - insulin glargine 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
VERSION HISTORY ....................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 8 
1.2.1 
Estimands ...................................................................................................................................... 10 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 12 
3 
ANALYSIS POPULATIONS .......................................................................................................... 13 
4 
STATISTICAL ANALYSES ........................................................................................................... 14 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 14 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 16 
4.3 
PRIMARY ENDPOINT ANALYSIS ................................................................................................ 18 
4.3.1 
Definition of endpoint ..................................................................................................................... 18 
4.3.2 
Main analytical approach ............................................................................................................... 18 
4.3.3 
Sensitivity analysis ......................................................................................................................... 20 
4.3.4 
Analysis of supplementary estimand (For non-inferiority only) ...................................................... 21 
4.3.5 
Supportive analysis of supplementary estimand (For non-inferiority only) .................................... 21 
4.3.6 
Subgroup analyses ........................................................................................................................ 21 
4.4 
SECONDARY ENDPOINTS ANALYSIS........................................................................................ 22 
4.4.1 
Secondary endpoints ..................................................................................................................... 22 
4.4.1.1 
Definition of endpoints ................................................................................................................... 22 
4.4.1.2 
Main analytical approach ............................................................................................................... 23 
4.5 
TERTIARY/EXPLORATORY ENDPOINTS ANALYSIS ................................................................ 24 
4.5.1 
Definition of endpoints ................................................................................................................... 24 
4.5.2 
Main analytical approach ............................................................................................................... 28 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 30 
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Statistical Analysis Plan  
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Page 3 
4.7 
SAFETY ANALYSES ..................................................................................................................... 31 
4.7.1 
Extent of exposure ......................................................................................................................... 31 
4.7.2 
Hypoglycemic events ..................................................................................................................... 33 
4.7.3 
Adverse events .............................................................................................................................. 37 
4.7.4 
Additional safety assessments ....................................................................................................... 40 
4.7.4.1 
Laboratory variables and vital signs............................................................................................... 40 
4.7.4.2 
Product complaints......................................................................................................................... 42 
4.8 
OTHER ANALYSES....................................................................................................................... 42 
4.9 
INTERIM ANALYSES .................................................................................................................... 42 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 43 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 43 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 44 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, MEDICAL (OR 
SURGICAL HISTORY), DISEASE CHARACTERISTICS AT BASELINE, PRIOR AND 
CONCOMITANT MEDICATIONS .................................................................................................. 45 
5.3.1 
Demographics and baseline characteristics .................................................................................. 45 
5.3.2 
Medical (or surgical) history ........................................................................................................... 45 
5.3.3 
Disease characteristics at baseline ................................................................................................ 45 
5.3.4 
Prior and concomitant medications ................................................................................................ 46 
5.3.4.1 
Non-antidiabetic medications ......................................................................................................... 47 
5.3.4.2 
Antidiabetic medications ................................................................................................................ 47 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 49 
5.4.1 
Demographic formulas ................................................................................................................... 49 
5.4.2 
Disease characteristics formulas ................................................................................................... 49 
5.4.3 
Reference date, study day, and baseline ...................................................................................... 49 
5.4.4 
Missing data ................................................................................................................................... 49 
5.4.5 
Analysis windows for time points ................................................................................................... 50 
5.4.5.1 
Main Study ..................................................................................................................................... 50 
5.4.5.2 
CGM Substudy ............................................................................................................................... 51 
5.5 
APPENDIX 5 CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITIES .......................................................................................................................... 51 
5.6 
APPENDIX 6 TABLE OF CONTENTS FOR ABBREVIATED CSR ............................................... 52 
5.7 
SCHEDULE OF EVENTS .............................................................................................................. 54 
5.7.1 
Schedule of events for the main trial .............................................................................................. 54 
5.7.2 
Schedule of events for the CGM substudy .................................................................................... 57 
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Statistical Analysis Plan  
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Page 4 
6 
REFERENCES ............................................................................................................................... 58 
 
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Statistical Analysis Plan  
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Page 5 
LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 6 
Table 2 - Objectives and endpoints ................................................................................................................. 8 
Table 3 - Summary of primary and supplementary estimands for main endpoint......................................... 11 
Table 4 - Populations for analyses ................................................................................................................ 13 
Table 5 - Sorting of AE tables ....................................................................................................................... 38 
Table 6 - Analyses of adverse events ........................................................................................................... 39 
Table 7 - Selections for AESIs ...................................................................................................................... 40 
Table 8 - Prohibited Medications ................................................................................................................... 48 
Table 9 - Antidiabetic Medications ................................................................................................................ 48 
Table 10 - Analysis window definition ........................................................................................................... 50 
Table 11 - CGM Substudy analysis window definition .................................................................................. 51 
Table 12 - Criteria for Potentially Clinically Significant Abnormalities ........................................................... 51 
Table 13 - Schedule of events for the main trial ............................................................................................ 54 
Table 14 - Schedule of events for the CGM substudy .................................................................................. 57 
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Statistical Analysis Plan  
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Page 6 
VERSION HISTORY  
This statistical analysis plan (SAP) for study LPS17007 is based on the protocol dated 
28 April 2022. There are no major changes to the statistical analysis features in this SAP. 
The first participant was randomized on 20 December 2022.  
Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
1 
17-Oct-2023 
Not Applicable 
Original version 
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Statistical Analysis Plan  
17-Oct-2023 
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Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 7 
1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a multicenter, multinational, randomized, open-label, parallel-group clinical trial 
comparing the efficacy and safety of second-generation basal insulin analogs, insulin glargine 
300 U/mL (Gla-300) and insulin degludec 100 U/mL (IDeg-100), in insulin-naïve participants 
with type 2 diabetes mellitus (T2DM) and renal impairment who have glycemic levels above 
target with oral antidiabetic drugs (OADs) with or without glucagon-like peptide 1 receptor 
agonist (GLP-1 RA [oral or injectable]), defined as a glycated hemoglobin (HbA1c) level of 
≥7.5% and ≤10.5% and an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 
and ≥15 mL/min/1.73 m2 at screening. As Gla-300 and IDeg-100, the control drug, are 
distinguishable, this trial is an open-label design, and no attempt will be made to blind 
administration from the patients and the physicians. However, the team in charge of statistical 
analysis plan and programming of analyses, and of data review that occur before database lock, 
will be blinded from treatment allocation. Study drug titration review will also be performed by 
dedicated and qualified unblinded persons. 
The trial will be conducted in approximately 630 participants. At baseline (Day 0, Visit 2), 
participants will be randomly assigned in a 1:1 ratio to 1 of the 2 treatment arms: Gla-300 arm or 
IDeg-100 arm and will initiate their study drug treatment. Randomization will be stratified by 
HbA1c value at screening (<8.5%, ≥8.5%), SU (sulfonylureas) use (Yes, No), and eGFR 
(<45 mL/min/1.73 m2, ≥45 mL/min/1.73 m2). Participants will be allowed to continue their 
current treatment with OADs with or without glucagon-like peptide-1 receptor antagonist (GLP-
1RA) (oral or injectable; with stable doses for ≥3 months) throughout the trial period unless such 
treatments must be stopped or modified for safety reasons. 
 During the titration period (ie, from Week 1 through Week 12), the doses of Gla-300 and 
IDeg-100 will be adjusted using a recommended dose-adjustment algorithm. After randomization, 
the dose will be titrated at least weekly (but no more than every 3 days), until the participant 
reaches a target fasting self-measured plasma glucose (SMPG) value of 80 to 100 mg/dL (4.4 to 
5.6 mmol/L) while avoiding hypoglycemia episodes. Dose adjustments will be based on a median 
of fasting SMPG values from the last 3 measurements, including the value on the day of titration, 
measured by the participant using glucose meters and accessories supplied by the sponsor through 
a vendor. Best efforts should be made to reach the glycemic target by 8-12 weeks after 
randomization.  
 The maximum trial duration per participant will be 27 weeks. Five site visits and at least 
13 phone contacts are scheduled, as well as an unscheduled phone contact (during the treatment 
period) for study drug resupply, if required. A participant will be considered to have completed 
the trial if they have completed all phases of the trial, including the last visit (Week 25 follow-up 
phone contact). 
 
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The study was early terminated by the Sponsor on 27 June 2023 (hereinafter referred to as “early 
termination”). Early termination by Sponsor was due to severe recruitment delay. There are no 
safety signals detected, and the study team remained blinded to the data collected for the 
randomized subjects at the time of early termination decision. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To demonstrate non-inferiority (with a margin of 
0.3%) and, if achieved, to demonstrate the 
superiority in the efficacy of Gla-300 compared 
with IDeg-100 in terms of change in HbA1c from 
baseline to Week 24 in insulin-naïve participants 
with T2DM and renal impairment who have 
glycemic levels above target with OADs with or 
without GLP-1 RA 
 
• 
HbA1c level: Change from baseline to Week 24 
Secondary 
• 
To evaluate the effects of treatment with Gla-300 
compared with IDeg-100 on the clinical 
parameters 
• 
To assess the safety and tolerability of Gla-300 
and IDeg-100 
 
• 
FPG: Change from baseline to Week 24 
• 
Fasting SMPG: Change from baseline to Week 24 
• 
7-point SMPG profiles: Change from baseline to 
Week 24, per time point within 24-hour period 
• 
Percentage (%) of participants reaching HbA1c target 
of <7.0% at Week 24 
• 
Safety evaluations of the following (during the 24-week 
treatment period, during the titration period, and during 
the maintenance period): 
- 
All hypoglycemia events 
- 
The frequency of and diurnal distribution (all day, 
daytime (occurring between 06:00 and 23:59 
inclusively), and nocturnal (occurring between 
00:00 and 05:59 inclusively) of hypoglycemia by 
category (symptomatic, asymptomatic, severe) 
per the ADA/EASD hypoglycemia classification 
- 
Local tolerability at injection site 
- 
Hypersensitivity reactions 
- 
Adverse events (AEs) and serious adverse events 
(SAEs), including AESIs, and other safety 
evaluations, including vital signs and body weight 
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Objectives 
Endpoints 
Exploratory 
 
 
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Objectives 
Endpoints 
1.2.1 Estimands  
The primary estimands defined for the main endpoint are summarized in below Table 3. More 
details are provided in Section 4. 
For each of these estimands, the comparison of interest will be the comparison of Gla-300 versus 
IDeg-100. 
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Table 3 - Summary of primary and supplementary estimands for main endpoint  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling 
strategy 
Population-level summary  
(Analysis and missing data handling) 
Primary objective: To demonstrate non-inferiority (with a margin of 0.3%) and, if achieved, to demonstrate the superiority in the efficacy of Gla-300 compared with IDeg-100 in 
terms of change in HbA1c from baseline to Week 24 in insulin-naïve participants with T2DM and renal impairment who have glycemic levels above target with OADs with or 
without GLP-1 RA 
Primary endpoint 
(Estimand 1a: treatment 
policy, primary) 
Change in HbA1c level from 
baseline to Week 24 
Intent-to-treat 
Regardless of discontinuation of study drug treatment 
due to any reasonsa / regardless of use of rescue 
therapies (treatment policy) 
Missing data to be handled using a multiple imputation (MI) 
strategy dependent upon treatment-completion statusa. An 
ANCOVA model that includes baseline HbA1c value as a 
covariate and study drug treatment and stratification factors at 
randomization (other than categorized HbA1c) as fixed factors 
to be implemented for each imputed dataset. The mean 
difference between treatment arms (Gla-300 vs IDeg-100) will 
be estimated based on the least-squares (LS) means in the 
ANCOVA model. Estimated differences and their SEs will be 
combined across imputed data sets to produce a single point 
estimate and CI using Rubin’s rules and presented with a 
2-sided 95% CI and p-value. 
Primary endpoint 
(Estimand 1b: 
hypothetical strategy, 
supplementary) 
Change in HbA1c level from 
baseline to Week 24 
 
Intent-to-treat 
Assuming no discontinuation of study drug treatment 
due to any reasons and use of rescue therapies 
(hypothetical strategy)b 
A mixed-effect model with repeated measures (MMRM) to be 
performed for Hb1Ac values at Week 12 and Week 24 that 
includes study drug treatment, visit, and stratification factors at 
randomization (other than categorized HbA1c) as fixed factors, 
baseline HbA1c value as a covariate and treatment-by-visit 
and baseline HbA1c value-by visit-interactions. Least-squares 
(LS) means and differences with 95% CIs and p-values to be 
presented. This estimand is only to be estimated to support 
non-inferiority. 
a Missing data from participants discontinuing the study drug treatment will be imputed using data from participants also discontinuing the study drug treatment but who have their endpoint assessed within each 
treatment arm. Missing data from participants completing the 24-week treatment period will be imputed using a model estimated from data observed in other participants completing the study drug treatment 
within each treatment arm. 
b Data collected after discontinuation of study drug treatment due to any reasons or after use of rescue therapies will be considered as missing in the analysis of change from baseline to Week 12 and Week 24 in 
HbA1c level (Gla-300 vs IDeg-100). 
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2 
SAMPLE SIZE DETERMINATION  
A total sample size of 566 participants (283 per treatment arm with a 1:1 allocation ratio) was 
determined to demonstrate non-inferiority of Gla-300 versus IDeg-100 with 90% power and 2.5% 
1-sided significance level based on the following assumptions on the primary endpoint: 
• True mean difference in change from baseline to Week 24 in HbA1c level of 0 between 
Gla-300 and IDeg-100. 
• Common standard deviation (SD) of 1.1%. 
• Non-inferiority margin on the mean difference of 0.3%. 
The non-inferiority margin was chosen based on the European Medicines Agency (EMA) 
guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes 
mellitus (1). 
Assuming a 10% dropout rate, a total of 630 participants will be randomized (315 per treatment 
arm). 
For showing the superiority of Gla-300 to IDeg-100 the power will be at least 90%, assuming the 
true difference in the mean change between Gla-300 and IDeg-100 is ≤-0.3%. 
Calculations were made using nQuery Software Version 7.0. 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined: 
Table 4 - Populations for analyses  
Population 
Description 
Analyses 
Screened 
All participants who signed the informed consent 
form (ICF). 
Participant disposition analyses. 
Safety 
All randomized participants who receive at least 
1 dose of study drug treatment. All analyses using 
the safety set will be done according to the 
treatment actually received.  
Safety analyses. 
Intent-to-treat (ITT) 
All participants who sign the ICF and are 
randomized into the trial. All analyses using the ITT 
set will group participants according to their 
randomized treatment.  
Primary endpoint analyses (including 
subgroup analyses), secondary endpoints 
analyses, exploratory endpoints analyses 
not related to the CGM substudy, 
demographics analyses, baseline 
characteristic analyses, participant 
disposition analyses.  
Per-protocol (PP) 
All randomized participants who complete the trial 
without significant protocol deviations impacting the 
primary endpoint. 
Supportive analysis of the primary endpoint 
analysis. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization will be used in any analysis population. The safety experience associated with any 
later randomization will be reported separately. 
For participants receiving more than one study intervention during the study, the intervention 
group for as-treated analyses will be the as-randomized intervention group if the participant has 
received at least one administration of the as-randomized intervention. 
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4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
Due to early termination of the study, the analyses described in this SAP were not performed in 
totality due to lack of data and in accordance with the abbreviated CSR (clinical study report). See 
Appendix 2 (Section 5.2): Changes to protocol-planned analyses for additional details.  
In general, continuous data will be summarized using the number of observations available, mean, 
SD, median, Q1, Q3, minimum, and maximum. 
All mean, SD, median, Q1 and Q3 values will be formatted to one more decimal place than the 
measured value. Minimum and maximum will be formatted to the same number of decimal places 
as the measured value. 
Categorical data will be summarized using frequency counts and percentage of participants. When 
count data are presented, the percent will be suppressed when the count is zero 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. 
All CIs presented will be 2-sided 95% CIs, unless otherwise specified, and will be 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 rounded to four decimal places. If a p-value is less than 0.0001 it will be 
reported as ‘<0.0001’. If a p-value is greater than 0.9999 it will be reported as ‘>0.9999’. The 
baseline value is defined as the last available non-missing value before the first injection of study 
drug (Gla-300 or IDeg-100). For participants randomized but not treated, the baseline value is 
defined as the last available non-missing value recorded before randomization occurs at the end of 
the screening period. Where time is collected, it will be included in the determination of baseline 
records. Any measurement or assessment recorded on the day of first dose administration of 
open-label IMP (or day of randomization for participants randomized but not treated) with 
missing assessment time will be considered as Baseline. 
If multiple valid values of a variable (efficacy or safety) occur within the same day considered as 
Baseline (and the recorded times of measurement do not identify which of them is the latest 
assessment), the following rules will be considered:  
• If only one of the multiple valid values was measured during a scheduled visit, it will be 
considered as Baseline in the analysis. 
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• If multiple values are measured during a scheduled visit within the same day, then these 
values will be averaged, and the average will be considered as Baseline for the analysis. If 
there are also values within the same day not collected during a scheduled visit, these will 
be excluded from the average. 
• If no values measured within the same day were assessed during a scheduled baseline, 
then all measurements from that day will be averaged, and this value will be considered as 
Baseline for the analysis. 
A stepwise closed testing approach will be used for the primary efficacy endpoint to assess 
non-inferiority and superiority sequentially. 
• Step 1 will assess non-inferiority of Gla-300 versus IDeg-100. To assess non-inferiority,  
the 2-sided 95% CI of the difference in the mean change from baseline to Week 24 in 
HbA1c level between Gla-300 and IDeg-100 in the ITT population will be compared with 
the predefined non-inferiority margin of  0.3%. Non-inferiority will be demonstrated if the 
2-sided 95% CI of the difference in the mean change from baseline to Week 24 in HbA1c 
level between GLa-300 and IDeg-100 lies entirely below 0.3% (equivalent to a 1-sided test 
at the 2.5% significance level). 
• Step 2 will test superiority of Gla-300 versus IDeg-100 if noninferiority of Gla-300 versus 
IDeg-100 as described above has been demonstrated. The superiority of Gla-300 versus 
IDeg-100 will be established if the 95% CI for the difference in mean change from 
baseline to Week 24 in HbA1c level between Gla-300 and IDeg-100 lies entirely below 
0%. If non-inferiority has been established but the superiority is not met, the declaration of 
non-inferiority will be further supported by a supplementary estimand as described 
in Section 4.3.4. 
There is no multiplicity argument that affects switching between non-inferiority and superiority in 
the analysis of the primary endpoint, since both are based on the same estimand and it therefore 
corresponds to a simple closed testing procedure. If superiority for the primary endpoint (change 
from baseline to Week 24 in HbA1c level) is achieved, secondary endpoints will be assessed for 
superiority and adjusted for Type I error related to multiple testing using the Holm procedure as 
described in Section 4.6.  Control of Type I error will be limited to the primary and key secondary 
efficacy endpoints for the overall population. No statistical claim will be made on the exploratory 
efficacy endpoints (including the CGM substudy endpoints), nor for subgroup analyses. 
All safety analyses will be performed on the safety set. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and absolute 
change from baseline) by analysis visits will be provided on observed cases (OC; ie, inclusion of 
only participants having non-missing assessments for a specific analysis visit). Descriptive 
summaries of continuous efficacy and safety data at baseline will be included when presenting 
descriptive summaries of the corresponding changes from baseline, where appropriate. Unless 
otherwise specified, analyses will be performed by intervention group (and overall for baseline 
and demographics characteristics). 
Despite the open-label administration of the study drugs, all statistical analyses outlined in this 
plan prior to final database lock will be developed and performed blindly. A process will be 
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applied to ensure blinding of Gla-300 and IDeg-100 administrations and any potentially 
unblinding information. 
 All statistical analyses will be performed using SAS software Version 9.4 or higher. 
Observation period  
The observation period will be divided into 3 segments for non-safety analyses: 
• The pre-treatment period (up to 2 weeks) is defined as the time between the date of 
signed informed consent and the first injection of the open-label study drug. 
• The on-treatment period (24-weeks) is defined as the 24-week open-label treatment 
period. The on-treatment period includes a 12-week titration period where study drug 
doses will be adjusted using a recommended dose-adjustment algorithm, as well as a 
12-week maintenance period at the titrated dose. 
• The post-treatment period is defined as the 7-day, post-treatment, safety follow-up 
period after the last dose of the study drug or after premature/permanent discontinuation 
from study drug treatment. 
The on-study period is defined as the time from the date of signed informed consent until the end 
of the study defined as the last scheduled visit for those who completed the study and the 
end-of-study date (“Status Date”) collected on electronic case report form (eCRF) page 
“Completion of End of Study” for those who did not complete the study. If death is the 
end-of-study reason, date of death will be used. 
The observation period used for safety analyses is described in Section 4.7. 
The maximum trial duration per participant will be 27 weeks. 
4.2 
PARTICIPANT DISPOSITIONS  
The number of participants included in each of the analysis populations listed in Table 4 will be 
summarized. Percentages for the PP population and CGM Substudy population will be calculated 
using the ITT set as the denominator. 
Screen failures are defined as participants who consent to participate in the study but are not 
subsequently randomized. The number of participants screened, the number (%) of screen 
failures, and number (%) of reason for screen failures will be summarized for the screened set. 
The number (%) of participants in the following categories will also be provided, using the ITT 
(randomized population) as the denominator: 
• Randomized and not exposed participants. 
• Randomized and exposed participants. 
• Participants who completed the 24-week study treatment period as per protocol. 
• Participants who did not complete the 24-week study treatment period as per protocol and 
main reason for permanent intervention discontinuation. 
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• Participants who completed the study period as per protocol. 
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation. 
The number of exposed and not randomized participants will also be included in the summary 
above. 
In addition, the number (%) of participants screened, screened-failed, randomized, randomized 
and exposed, with study drug discontinuation and with study discontinuation will be provided by 
country and site. For the number (%) of participants screened and screen-failed, the screened set 
will be used as a denominator; for the remaining summaries, the ITT set will be used as the 
denominator for percentages. 
The number (%) of participants with trial impacts (disruptions) due to coronavirus disease 2019 
(COVID-19) will also be summarized for the safety set. 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 (AE) 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 
“Subject Status” 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:”. 
Protocol deviations 
Significant protocol deviations (automatic or manual), including drug dispensing irregularities, 
will be summarized for the ITT population. 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. For the 
purpose of this analysis, significant deviations will be defined and reviewed on a case-by-case 
basis for each participant in a blinded data review meeting, where a significant protocol deviation 
is considered to be a deviation that affects primary efficacy and safety assessments (as 
applicable), the safety or mental integrity of a subject, or the scientific value of the trial. Only 
those protocol deviations impacting the primary endpoint will lead to exclusion from the Per 
Protocol Set.  
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4.3 
PRIMARY ENDPOINT ANALYSIS  
4.3.1 Definition of endpoint  
The primary endpoint is the change from baseline to Week 24 in HbA1c level. For efficacy 
assessments of the trial, HbA1c will be measured with blood samples collected at the central 
laboratory at the time points specified in Section 5.7 (baseline, Week 12, Week 24). If a 
participant needs to receive a rescue antidiabetic therapy, the HbA1c assessment should be 
performed before the antidiabetic therapy is introduced. In addition, in case of study drug 
treatment discontinuation, participants will be followed up per protocol. In case of trial 
discontinuation, HbA1c assessment will be performed at the time of withdrawal. If HbA1c 
measurements fall out of windowed assessments (baseline, Week 12, Week 24), the results for 
those assessments will be excluded (considered as missing for analysis). 
4.3.2 Main analytical approach  
The primary estimand is the difference in the mean change from baseline to Week 24 in HbA1c 
level (Gla-300 vs IDeg-100) in insulin-naïve participants with T2DM and renal impairment who 
have glycemic levels above target with OADs with or without GLP-1 RA (oral or injectable), 
regardless of discontinuation of study drug treatment due to any reason or use of rescue therapies 
(treatment policy strategy). 
The statistical hypothesis associated with the primary non-inferiority analysis of change from 
baseline in HbA1c level to Week 24 is: 
H0: μGla-300 - μIDeg-100  ≥0.3% 
H1: μGla-300 - μIDeg-100  <0.3% 
where μGla-300 and μIDeg-100 denote the true mean change from baseline to Week 24 in HbA1c level 
for Gla-300 and IDeg-100, respectively. 
If the non-inferiority is demonstrated, the hypothesis for testing superiority will be: 
H0: μGla-300 - μIDeg-100 = 0% 
H1: μGla-300 - μIDeg-100 ≠ 0% 
HbA1c data collected after ICEs (discontinuation of study drug treatment due to any reasons, use 
of rescue therapies) will be included in the analysis based on the ITT set. Missing data will be 
handled using a MI strategy dependent on treatment-completion status: 
• Missing data from participants discontinuing the study drug treatment will be imputed 
using data from participants also discontinuing the study drug treatment but who have 
their endpoint assessed within each treatment arm. 
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• Missing data from participants completing the 24-week treatment period will be imputed 
using a model estimated from data observed in other participants completing the study 
drug treatment within each treatment arm. 
The number (%) of participants for each missing pattern will be summarized by treatment group 
for the ITT set: 
• Patients with non-missing baseline HbA1c data but without post-baseline HbA1c data. 
• Patients with non-missing baseline and Week 12 HbA1c data who are missing Week 24 
HbA1c data. 
• Patients with non-missing baseline and Week 24 Hba1c data who are missing Week 12 
HbA1c data. 
The following two-step approach will be used for the MI: 
• Step 1: The Markov chain Monte Carlo (MCMC) method will be used to impute 
intermediate missing data to create a monotone missing data pattern. 
• Step 2: Using the 100 imputed datasets with monotone missing data pattern obtained from 
Step 1, missing data will then be imputed for each imputed data set using the sequential 
regression method. 
The imputation model for Step 1 will be performed by randomized treatment arm and include 
baseline HbA1c value and HbA1c values at Week 12 and Week 24 and use SEED=17007. Step 1 
will impute intermediate missing data to a monotone missingness pattern and create 100 imputed 
datasets (the SAS default of 1000 burn-in iterations for MCMC will be used when creating the 
100 imputed datasets). The number of imputations may be increased if large variability of the 
results produced with increasing number of imputations before reaching 100 imputations is 
observed. 
The imputation model for Step 2 will include the same variables as in Step 1, as well as 
randomization strata: SU use (Yes, No) and eGFR at Screening (<45 mL/min/1.73 m2; 
≥mL/min/1.73 m2). Step 2 will be performed based on the imputed datasets in Step 1 with 
monotone missing pattern, and the model will use SEED=70071. If there is an insufficient number 
of participants with complete data within a randomization stratum for establishing the imputation 
model, some randomization stratification factors may be removed from the imputation model by 
combining groups together where needed. In the case that there is an insufficient number of 
patients who have discontinued treatment but have data available at Week 24 in either treatment 
arm for establishing the model, treatment arm may also be removed from the model, and missing 
data for patients discontinuing the study drug treatment will be randomly sampled from the 
normal distribution, using observed baseline value as the mean of the distribution. 
After completing Step 2, an analysis of covariance (ANCOVA) model will be performed for each 
imputed data set; this analysis will include baseline HbA1c value as a covariate, study drug 
treatment, and randomization strata (SU use (Yes, No) and eGFR (<45 mL/min/1.73 m2; 
≥45 mL/min/1.73 m2)) as fixed factors. Graphical methods will be used to check if there are major 
deviations from normality. The difference in mean change from baseline to Week 24 in HbA1c 
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values between treatment arms (Gla-300 vs IDeg-100) will be estimated based on the difference 
of LS means in the ANCOVA model. The estimated differences and associated standard errors 
(SEs) obtained across the imputed datasets will be combined via SAS PROC MIANALYZE to 
produce a single point estimate difference, corresponding SE, 2-sided 95% CI (Wald), and 
two-sided p-value for superiority, all based on Rubin’s rules. 
The test for non-inferiority will be performed at a 1-sided 2.5% significance level, and the 
non-inferiority will be demonstrated if the upper bound of the 2-sided 95% CI of the pooled 
difference in change from baseline to Week 24 in HbA1c values between Gla-300 and IDeg-100 
treatment arms is <0.3%. Superiority will be established if the upper bound of the 2-sided 95% CI 
is <0%. 
In addition, a box plot based of HbA1c from baseline to Week 24 (OC) will be produced. 
4.3.3 Sensitivity analysis  
Sensitivity analyses will be conducted for the ITT population to assess the robustness of the 
results obtained from the primary analysis described in Section 4.3.2. 
Mixed-Effect Model with Repeated Measurements 
An MMRM analysis based on OC and assuming MAR will be carried out via SAS PROC 
MIXED; this sensitivity analysis will include randomized study drug treatment (Gla-300, 
IDeg-100), visit (Week 12, Week 24), and stratification factors at randomization (SU use (Yes, 
No) and eGFR (<45 mL/min/1.73 m2; ≥45 mL/min/1.73 m2) as fixed factors, continuous baseline 
HbA1c value as a covariate, and treatment-by-visit and baseline HbA1c value-by-visit 
interactions. An unstructured covariance matrix will be used to model the within-participant 
errors. Graphical methods will be used to check if there are major deviations from normality. 
Parameters will be estimated using the restricted maximum likelihood method. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. In this 
analysis, no imputation of missing data will be performed. The difference in mean change from 
baseline to Week 24 in HbA1c between treatment arms (Gla-300 vs IDeg-100) will be estimated 
based on the baseline adjusted MMRM model. The estimates will be presented together with their 
corresponding SE, 95% CI and 2-sided p-value for superiority at Week 24. 
Penalized MI (For Non-Inferiority Only) 
Separately, penalized MI will be performed as an additional sensitivity analysis (for 
non-inferiority only). The multiply imputed missing HbA1c values at Week 24 in the primary 
analysis will be penalized by adding 0.3% (corresponding to the non-inferiority margin) to the 
imputed HbA1c value in the Gla-300 arm, whereas the imputed HbA1c in the IDeg-100 arm will 
not be penalized. Each imputed complete dataset will then be analyzed using the same ANCOVA 
as described for the primary analysis in Section 4.3.2. The treatment differences and their SEs 
estimated from each imputed (penalized or not) dataset will be combined using Rubin’s rules for a 
point estimate and presented with associated 2-sided 95% CI (Wald). 
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Reference-Based MI (For Superiority Only) 
Reference-based MI assuming missing not at random (MNAR) pattern of missingness will also be 
performed (for superiority only). The reference-based MI approach will assume that the trajectory 
of withdrawals from the Gla-300 arm due to any reason is the same as that in the IDeg-100 arm. 
Following the completion of Step 1 (impute to monotone step) as described in the primary 
analysis approach in Section 4.3.2, missing Week 12 HbA1c values and Week 24 HbA1c values 
in the Gla-300 arm will then be imputed using a sequential regression imputation model 
established using data in the IDeg-100 arm. Each imputed complete dataset will be analyzed using 
the same ANCOVA as described for the primary analysis in Section 4.3.2. The treatment 
differences and their SEs estimated from each imputed dataset will then be combined using 
Rubin’s rules for a point estimate and presented with associated two-sided p-value for superiority 
and 2-sided 95% CI (Wald). 
4.3.4 Analysis of supplementary estimand (For non-inferiority only)  
An analysis will also be performed to estimate the supplementary estimand. It will be performed 
for the ITT population to support non-inferiority only. For this analysis, data collected after 
discontinuation of study drug treatment due to any reasons or after use of rescue therapies will be 
excluded in the analysis of change from baseline to Week 12 and Week 24 in HbA1c level 
(Gla-300 vs IDeg-100) (hypothetical strategy).  
An MMRM based on OC and assuming MAR will be performed for the change from baseline in 
HbA1c values at Week 12 and Week 24, and it will include study drug treatment, visit, and 
stratification factors at randomization (other than categorized Hb1Ac) as fixed factors, baseline 
HbA1c value as a covariate and treatment-by-visit and baseline HbA1c value-by-visit interactions. 
Graphical methods will be used to check if there are any major deviations from normality. An 
unstructured covariance matrix will be used to model the within-participant errors. Parameters 
will be estimated using restricted maximum likelihood method. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. Least-squares means, 
differences, and associated SEs will be presented with 2-sided 95% CIs. 
4.3.5 Supportive analysis of supplementary estimand (For non-inferiority only)  
As a supportive analysis of the supplementary estimand, a per-protocol analysis based on the PPS 
will be performed for non-inferiority. An MMRM assuming MAR will be performed as described 
for the primary analysis in Section 4.3.3. Least-squares means, differences, and associated SEs 
will be presented with 2-sided 95% CIs. The analysis will also be repeated for the ITT set. 
4.3.6 Subgroup analyses  
An ANCOVA model similar to that described for the primary analysis in Section 4.3.2 will be 
performed for each of the following subgroups, including a treatment-by-subgroup interaction 
term (if the minimum number of participants in each subgroup is at least 20): 
• Age (<65 years; ≥65 years) 
• Baseline HbA1c (<8.5%; ≥8.5%) 
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• SGLT-2i use (yes; no) 
• GLP-1 RA use (yes; no) 
• SU use (yes; no) 
• eGFR 
- 
<45 mL/min/1.73 m2; ≥45 mL/min/1.73 m2 
- 
15 - <30 mL/min/1.73 m2 ; ≥30 - <45 mL/min/1.73 m2; ≥45 - 60 mL/min/1.73 m2  
The treatment effects (Gla-300 vs IDeg-100) across the subgroups defined for each of these 
factors will be estimated for the change from baseline to Week 24 in HbA1c values for the ITT 
population. The ANCOVA model will include a treatment-by-subgroup interaction term and a 
subgroup term, in addition to the following covariates which are included in the model used for 
primary endpoint analysis: baseline HbA1c value, study drug treatment, SU use (Yes, No), and 
eGFR (<45 mL/min/1.73 m2; ≥45 mL/min/1.73 m2). In the case that the subgroup factor is 
identical or similar to other factor(s) in the model, those factors will be excluded from the model 
and the subgroup factor will be used exclusively. If the ANCOVA model does not converge, 
randomization strata may be removed from the model. 
The mean difference in change from baseline to Week 24 in HbA1c values between treatment 
arms (Gla-300 vs IDeg-100) will be estimated based on the least-squares (LS) means in the model 
for each subgroup level. The estimated treatment means differences and their SEs obtained across 
the imputed datasets will be combined via SAS PROC MIANALYZE to produce a single point 
estimate difference along with a 2-sided 95% CI (Wald) all based on Rubin’s rules. In addition, 
the p-value of the treatment-by-subgroup interaction will be presented. 
In addition to the analyses described above, a forest plot will be presented for each of the 
subgroup analyses listed above and will present the number, the LS means differences (SE) 
between treatments and their associated 2-sided 95% CIs. The p-value of the 
treatment-by-subgroup interaction will also be presented. 
Further subgroup analyses may be performed if deemed necessary for interpretation of results. 
4.4 
SECONDARY ENDPOINTS ANALYSIS  
4.4.1 Secondary endpoints  
4.4.1.1 Definition of endpoints  
• Change from baseline to Week 24 in fasting plasma glucose (FPG): blood samples will 
be collected to measure FPG levels at the central laboratory at the time points specified 
in Section 5.7. For scheduled site visits, participants will be required to arrive having 
fasted (no intake of food or drink, except water, in the 8 hours before blood sampling) 
without administering the study drug. 
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• Change from baseline to Week 24 in fasting SMPG: participants will be required to 
measure fasting SMPG values (using the glucose meter supplied during the screening 
period) before breakfast and before administration of the study drug once daily throughout 
the treatment period; results will be recorded in the participant’s electronic diary (eDiary). 
Additional glucose measurements may be done at the investigator’s discretion. Fasting 
SMPG measurements will be averaged for over the 7-day window preceding the date of 
each participant’s Week 12 and Week 24 site visit and will be considered missing if there 
are less than 4 days of SMPG measurements in the week preceding the visit. Baseline 
values will not be based on a weekly average and will instead be identified as described 
in Section 4.1. 
• Change from baseline to Week 24, per time point within 24-hour period in 7-point 
SMPG profiles: the 7-point SMPG profile will be measured using the participant’s 
glucose meter and recorded in the eDiary at the following 7 points: pre-prandial breakfast, 
2 hours after breakfast, pre-prandial lunch, 2 hours after lunch, pre-prandial dinner, 
2 hours after dinner and at bedtime. Timepoints are specified in the Section 5.7. The 
7-point SMPG profile will be performed over a single 24-hour period, on at least two days 
within the week before selected site visits. The records for each time point will be 
averaged for Week 12 and Week 24 measurements (including measurements taken on the 
7 days preceding the visit). If less than 2 days of measurements (a ‘day’ being a 24-hour 
period including each time point) are completed for a time point, the SMPG value will be 
considered missing for that time point. Baseline values will not be based on a weekly 
average and will instead be identified as described in Section 4.1. 
• Percentage (%) of participants reaching HbA1c target of <7.0% at Week 24: blood 
samples will be collected to measure HbA1c at the different time points specified in the 
Section 5.7. The number and percentage of subjects reaching the HbA1c target of <7.0% 
at Week 24 will be presented. If a participant has a missing HbA1c value at Week 24, it 
will be assumed that they did not reach an HbA1c target of <7.0%. 
4.4.1.2 Main analytical approach  
All secondary endpoints will be analyzed for the ITT set. 
The continuous secondary endpoints described above will be analyzed using the same main 
analytical approach as described for the primary endpoint in Section 4.3.2. Missing data will be 
multiply imputed as described in Section 4.3.2 for the primary endpoint analysis. The imputation 
model for Step 1 will use the corresponding baseline continuous endpoint value as a covariate, 
and continuous endpoint values at Week 12 and 24 as variables; the imputation model for Step 2 
will additionally include all stratification factors at randomization (categorized baseline HbA1c 
value ([8.5%, ≥8.5%], SU use [yes, no], and eGFR [<45 mL/min/1.73 m2; ≥45 mL/min/1.73 m2]). 
Following imputation of missing data, an ANCOVA model will be performed for each imputed 
data set; this analysis will include the continuous baseline secondary endpoint value as a 
covariate, study drug treatment, and randomization strata (categorized baseline HbA1c value 
[<8.5%, ≥8.5%], SU use [yes, no] and eGFR [<45 mL/min/1.73 m2; ≥45 mL/min/1.73 m2]) as 
fixed factors. The difference in mean change from baseline to Week 24 in each continuous 
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secondary endpoint’s values between treatment arms (Gla-300 vs IDeg-100) will be estimated 
based on the difference of LS means in each ANCOVA model. The estimated differences and 
associated SEs obtained across the imputed datasets will be combined via SAS PROC 
MIANALYZE to produce a single point estimate difference along with a 2-sided 95% CI (Wald) 
and nominal 2-sided p-value, all based on Rubin’s rules. 
Box plots based on OC will also be produced for each of the continuous endpoints from baseline 
to Week 24, other than the 7-point SMPG profile data, for which a line plot of mean and standard 
error will be plotted for each time point. 
For the categorical secondary endpoint (participants reaching HbA1c target of <7.0% at 
Week 24), a logistic regression model with terms of treatment arm, stratification at randomization 
(SU) use (Yes, No), and eGFR (<45 mL/min/1.73 m2; ≥45 mL/min/1.73 m2), and HbA1c value at 
baseline will be performed. If a patient has a missing HbA1c value at Week 24, the endpoint will 
be imputed, and it will be assumed that they did not reach an HbA1c target of <7.0%. The 
adjusted odds ratio (OR) estimated from the model will be presented together with a 2-sided 95% 
CI and nominal 2-sided p-value. 
A bar chart based on OC will also be presented that displays the frequency and percent of 
participants reaching the HbA1c target of <7.0% at Week 24 by treatment arm. 
Note that if superiority is achieved for the primary endpoint (change from baseline to Week 24 in 
HbA1c level), the p-values for each secondary endpoint described as ‘nominal’ above will be 
assessed for superiority. To address the issue of Type I error related to multiple testing, the Holm 
procedurce will be used to control the overall family-wise Type I error rate as described 
in Section 4.6. 
4.5 
TERTIARY/EXPLORATORY ENDPOINTS ANALYSIS  
4.5.1 Definition of endpoints  
Exploratory:  
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4.5.2 Main analytical approach  
Exploratory endpoints: 
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4.6 
MULTIPLICITY ISSUES  
There is no multiplicity argument that affects switching between non-inferiority and superiority in 
analysis of the primary endpoint, since it corresponds to a simple closed testing procedure. 
If superiority is achieved for the primary endpoint (change from baseline to Week 24 in HbA1c 
level), superiority will be assessed for the key secondary endpoints defined in Section 4.4.1.1. To 
address the issue of multiple testing, the Holm procedure will be used to control the family-wise 
Type I error rate:  
• Let α be the significance threshold for rejecting the null hypothesis and m be the number 
of hypotheses. 
• Order m hypotheses (𝐻1, 𝐻2, … , 𝐻𝑚) by their respective p-values (𝑝1, 𝑝2, … , 𝑝𝑚) from 
lowest to highest. 
• If p1 <
𝛼
𝑚, reject the null hypothesis; otherwise, all null hypotheses should be accepted and 
testing should be stopped.  
• Repeat this process until 𝑝𝑘<
𝛼
𝑚+1−𝑘, where k represents the first p-value that is not low 
enough to reject the null hypothesis 𝐻𝑘, at which time all remaining null hyotheses 
𝐻1, … , 𝐻𝑘−1 are non-significant and should not be rejected.  
No multiplicity adjustment will be made on the exploratory efficacy endpoints (including the 
CGM substudy endpoints), nor for subgroups. When presented for these analyses, 95% CIs, will 
be provided for descriptive purpose only. 
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4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 3, unless 
otherwise specified, using the common rules:  
• The analysis of the safety variables will be essentially descriptive, and no formal 
hypothesis testing is planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided separately. 
The observation period of safety data will be divided into 3 periods as defined below: 
• Pre-treatment period: the time between the date of signed informed consent and the first 
injection of the open-label study drug.  
• On-treatment period: the time from the first injection of the open-label study drug up to 
7 days after the last injection of the open-label study drug, regardless of the introduction of 
rescue therapy. The 7-day interval is chosen based on the half-life of the study drug 
(approximately 5 times the half-life of IDeg-100).  
• Post-treatment period: the time starting 8 days after the last injection of the open-label 
study drug.  
The denominator for computation of percentages is the safety set within each treatment arm unless 
otherwise specified.  
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure, compliance, and 
dose and summarized within the safety population. 
Duration of IMP exposure 
Duration of IMP exposure (in days) is defined as last IMP administration date - first IMP 
administration date +1 day, regardless of unplanned intermittent discontinuations. If the date of 
the last dose of IMP is missing, the duration of IMP will be left as missing.  
Duration of IMP exposure (in weeks) is defined as (Last day of exposure - first day of 
exposure +1)/7. Duration of IMP exposure (in weeks) will be summarized quantitatively using 
descriptive statistics and categorically as below: 
• ≤12 weeks  
• >12 weeks to ≤24 weeks  
• >24 weeks  
Additionally, cumulative duration of treatment exposure expressed in participant-years will be 
calculated, defined as the sum of days of the duration of treatment exposure for all participants 
divided by 365.25. 
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Treatment compliance 
A given administration will be considered noncompliant if the participant did not receive a once 
daily administration between 6:00 AM and 8:00 PM as required by the protocol. No imputation 
will be made for participants with missing or incomplete data. 
Percentage of treatment compliance for a participant will be defined as the number of injections 
that the participant was compliant divided by the total number of injections that the participant 
was planned to take from the first administration of IMP up to the actual last administration of 
IMP multiplied by 100. 
The number of planned injections is equal to the duration of IMP exposure (in days).  
Treatment compliance will be summarized quantitatively using descriptive statistics and  will also 
be summarized categorically: <60%, ≥60% to <80%, ≥80% to ≤100%, >100%. 
Cases of overdose will constitute AESIs and will be listed as such. 
Dosing 
During the trial, the dose of study drug (Gla-300 or IDeg-100) will be titrated for each participant 
to achieve glycemic targets without hypoglycemia using a dose-adjustment algorithm. After 
randomization, the dose is titrated at least weekly (but no more than every 3 days) until the 
participant reaches a target fasting SMPG value of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while 
avoiding hypoglycemia episodes. Best efforts should be made to reach the glycemic target by 
8-12 weeks after randomization. Thereafter, until the end of the trial, the doses of Gla-300 and 
IDeg-100 will be adjusted to maintain this glycemic target, if deemed appropriate by the 
investigator. Dose adjustments will be based on the median value of fasting SMPG values from 
the last 3 measurements, including the value on the day of titration, measured by the patient using 
glucose meters and accessories supplied by the sponsor through a vendor.  
Mean daily insulin doses received by each participant will be summarized descriptively at the end 
of the titration period (Week 12) and the end of the maintenance period (Week 24). The mean 
daily insulin dose is calculated as the mean of daily insulin doses collected over the 7 days 
preceding the visit. If less than 4 days of daily dosing data are available for a participant in the 
7-day period preceding the timepoint, the mean daily insulin dose for that participant will be 
reported as missing.  
The frequency and percentage of participants requiring dose adjustments after Week 12 will be 
presented.  
A box plot of mean daily insulin dose at the end of the titration period (Week 12) and the end of 
the maintenance period (Week 24), will be produced, as well as a bar chart presenting the 
percentage (%) of participants requiring dose adjustments after Week 12. 
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4.7.2 Hypoglycemic events  
During the trial, participants will be instructed to document any hypoglycemia events (including 
any possible reasons for hypoglycemia (eg, physical exercise, skipped meal)) in their eDiary. 
Hypoglycemia will be reported in the specific hypoglycemia event information form in the eCRF. 
The information recorded will include onset date and time; symptoms and/or signs; the SMPG 
value, if available; and the treatment, with documentation of whether the participant required 
outside assistance to achieve neurologic recovery. A hypoglycemia event that fulfills the 
seriousness criteria will also be documented on the SAE form in the eCRF. 
Hypoglycemic events will be evaluated based on the following categories of interest (3, 4, 5): 
• Any Hypoglycemic Event: 
- 
Any event recorded on the 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. 
• Confirmed hypoglycemia (symptomatic, severe) - each of the events below will be 
captured if the response to the question “Was a glucose measurement obtained at the time 
of the event before countermeasure?” on the Hypoglycemic Event Information Library 
eCRF page is “Yes”. Classification below will be dependent on glucose measurement.  
- 
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. A 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.  
- 
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. 
- 
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 participant such that the participant requires assistance from 
others 
• Documented Hypoglycemia (<70 mg/dL): event with a glucose level of <70 mg/dL (or 
<3.9 mmol/L) (with or without symptoms). 
- 
Documented Symptomatic Hypoglycemia: Any Documented Hypoglycemic event 
with a response of “Yes” to “Were symptoms present?” on the Hypoglycemic Event 
Information Library eCRF page will be considered a Documented Symptomatic 
Hypoglycemia event. 
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- 
Documented Serious Symptomatic Hypoglycemia: Any Documented Symptomatic 
Hypoglycemia where the participant also requires assistance from another person 
for recovery due to the participant’s inability to help themselves (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: Any Documented 
Symptomatic Hypoglycemia event as defined above where the participant does not 
require assistance from another person for recovery (identified in the 
Hypoglycemic Event Information Library eCRF page as “No Assistance” or 
“Received Assistance but Subject was Capable of Helping Self). 
- 
Documented Asymptomatic Hypoglycemia: An event not accompanied by typical 
symptoms of hypoglycemia but with a measured plasma glucose concentration 
<70 mg/dL (3.9 mmol/L). Any event with a glucose level recorded as <70 mg/dL 
(3.9 mmol/L) on the Hypoglycemic Event Information Library eCRF that has “No” as 
a response to “Were symptoms present?” will be considered an Asymptomatic 
Hypoglycemia event.  
• Probable Symptomatic Hypoglycemia: An event during which symptoms typical of 
hypoglycemia are not accompanied by a plasma glucose determination but was 
presumably caused by a plasma glucose concentration <70 mg/dL (3.9 mmol/L); 
symptoms treated with oral carbohydrate without a test of plasma glucose. An event will 
be considered a Probable Symptomatic Hypoglycemia event if the following conditions 
are met: 
- 
Response to the question “Was a glucose measurement obtained at the time of the 
event before countermeasure?” on the Hypoglycemic Event Information Library eCRF 
page is “No”. 
- 
“Were symptoms present” is reported as “Yes” on the Hypoglycemic Event 
Information Library eCRF and at least one symptom is reported. 
- 
“Oral Carbohydrate” is marked “Yes” as a treatment of hypoglycemia on the 
Hypoglycemic Event Information Library eCRF page. 
• Pseudo Hypoglycemia: An event during which the person with diabetes reports any of the 
typical symptoms of hypoglycemia with a measured plasma glucose concentration 
>70 mg/dL (>3.9 mmol/L) but approaching that level. Any event with a glucose level 
recorded as >70mg/dL (>3.9 mmol/L) on the Hypoglycemic Event Information Library 
eCRF that has “Yes” as a response to “Were symptoms present?” and at least one 
symptom reported will be considered a Pseudo Hypoglycemia event.  
• Nocturnal Hypoglycemia: Any hypoglycemia of the above categories defined by 
- 
Time of the day:  
- 
Between 00:00 AM and 05:59 AM regardless of whether the participant was awake 
or woke up because of the event. 
- 
“Time of Event” will be reported on the Hypoglycemic Event Information Library 
eCRF page. An event will be considered a Nocturnal Hypoglycemia Defined by 
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Time of the Day event depending on whether the reported time of the event falls 
into the range above. 
- 
Sleep status:  
- 
A Nocturnal Hypoglycemic Event Defined by Sleep Status is an event in which the 
participant was asleep between bedtime and before getting up in the morning and 
was woken up because of the event (ie, the event occurred before the morning 
assessment of fasting prebreakfast SMPG and before any insulin injection). 
- 
Any event reported as “Between Bedtime and Waking” on the Hypoglycemic 
Information Library eCRF page as a response to the question “When did the 
Hypoglycemic Event occur?”, regardless of reported time of the event, will be 
considered Nocturnal Hypoglycemia Defined by Sleep Status). 
• Daytime Hypoglycemia: Any hypoglycemia of the above categories defined by: 
- 
Time of the day:  
- 
Between 6:00 and 23:59 regardless of sleep status 
- 
“Time of Event” will be reported on the Hypoglycemic Event Information Library 
eCRF page. An event will be considered Daytime Hypoglycemia Defined by Time 
of the Day depending on whether the reported time of the event falls into the range 
above. 
- 
Awake status:  
- 
A Daytime Hypoglycemic Event Defined by Awake Status is any event that occurs 
while the participant was awake and before going to sleep. 
- 
Any event reported as “Between Waking and Bedtime” on the Hypoglycemic 
Information Library eCRF page as a response to the question “When did the 
Hypoglycemic Event occur?”, regardless of reported time of the event, will be 
considered Daytime Hypoglycemia Defined by Awake Status. 
Hypoglycemia analyses will be presented separately for the following observation periods to 
evaluate the potentially increased risk of hypoglycemia during the initial 12 weeks after initiating 
basal insulin treatment: 
• Overall 24-week treatment period 
• Titration period (Week 1 through Week 12) 
• Maintenance period (Week 12 through Week 24)  
The following hypoglycemia events will be summarized. Analysis will include both the number 
and percentage of participants experiencing 1 event and the total number of events, summarized 
using descriptive statistics: 
• Any hypoglycemia events, further summarized by: 
- 
Observation period 
- 
ADA classification level 
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- 
Diurnal distribution: 24 hour (all time), daytime, and nocturnal (0:00 to 5:59 inclusive) 
• Documented Hypoglycemia, further summarized by: 
- 
Documented symptomatic hypoglycemia  
- 
Documented serious symptomatic hypoglycemia  
- 
Documented non-serious symptomatic hypoglycemia  
- 
Asymptomatic hypoglycemia 
• Nocturnal Hypoglycemia Defined by Time of the Day, further summarized by: 
- 
ADA levels 
• Nocturnal Hypoglycemia Defined by Sleep Status, further summarized by 
- 
ADA levels 
• Daytime Hypoglycemia Defined by Time of the Day, further summarized by: 
- 
ADA levels 
• Daytime Hypoglycemia Defined by Awake Status, further summarized by: 
- 
ADA levels 
Bar charts will also be produced for the percentage (%) of participants experiencing at least one 
documented hypoglycemia event, at least one daytime hypoglycemia event (defined by sleep 
status), and at least one nocturnal hypoglycemia event (defined by sleep status). Each bar chart 
will be produced overall, and by ADA level and observation period. 
ORs and corresponding 95% CIs of the Gla-300 arm compared with the IDeg-100 arm will be 
calculated for the overall rate of on-treatment hypoglycemic events over the 24-week period using 
a logistic regression model that includes treatment arm and stratification factors at randomization 
as fixed factors based on OC. This analysis will be repeated for each observation period and by 
each level of diurnal distribution and ADA level. In addition to the summary table, a forest plot 
will be produced for this analysis. 
The overall rate of hypoglycemic events in participant-months of exposure will also be calculated 
and presented by treatment arm for the entire 24-week period, and then repeated for each 
observation period, diurnal distribution, and ADA level. The rate ratios and corresponding 95% 
CIs of the Gla-300 arm over the IDeg-100 arm for hypoglycemic events in patients-months of 
exposure will be estimated using a negative-binomial regression adjusted for stratification factors 
at randomization with time on treatment as an offset. In addition to the summary table, a forest 
plot will be produced for this analysis. 
The formula for the sample hypoglycemic events rate in patients-months of exposure is: 
Hypoglycemic event rates per patient-month of exposure = 
Number of participants with hypoglycemic events
Total participant-months of exposure
  
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Total participant-months of exposure is calculated as shown below:  
Total participant-months of exposure = 12 × (∑
𝑥𝑖
𝑛
𝑖=1
) 
365.25
 
𝑥𝑖 = (last dose date for 𝑖𝑡ℎ participant −first dose date for 𝑖𝑡ℎ participant + 1)  
The number as well as the rate of nocturnal hypoglycemic events (as defined by sleep status) in 
patient-months of exposure will also be summarized. 
In addition, the distribution of the total occurrence of each episode of documented hypoglycemia 
will be presented by 2-hour timeframe over 24 hours during the 24-week treatment. This will be 
repeated for each category of documented hypoglycemia. 
4.7.3 Adverse events  
General common rules for adverse events (AEs) 
All 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) currently in use by the sponsor at the 
time of database lock.  
The AEs will be analyzed in the following 3 categories (as defined by study periods for the safety 
analyses): 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the 
pre-treatment period. 
• Treatment-emergent adverse events (TEAEs): AEs that developed, worsened or became 
serious during the on-treatment period 
• Post-treatment AEs: AEs that developed or worsened, or became serious during the post-
treatment period  
Similarly, deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods. 
The primary focus of AE reporting will be on TEAEs. Pre-treatment and post-treatment AEs will 
be described separately.  
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, this AE will be assumed as 
related to IMP. If the severity is missing for 1 of the treatment-emergent occurrences of an AE, 
the severity will be imputed with the maximal severity of the other occurrences. If the severity is 
missing for all the occurrences, the severity will be left as missing. 
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Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase.  
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 Gla-300 group/overall incidence. In case of equal frequencies of PTs within a SOC, the alphabetic order will 
be applied. 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.  
Analysis of all adverse events 
The overview of all TEAEs with the details below will be generated: 
• Any TEAE  
• Any severe TEAE 
• Any treatment emergent serious adverse event (SAE) 
• Any TEAE leading to death (death as an outcome of the AE as reported by the Investigator 
in the AE page) 
• Any TEAE leading to study discontinuation  
• Any TEAE leading to permanent discontinuation of IMP 
• Any treatment emergent AESI 
- 
Pregnancy  
- 
Symptomatic overdose 
- 
Alanine aminotransferase (ALT) increase 
• Any TEAE related to local intolerability at the injection site or hypersensitivity reaction 
• Any treatment-related TEAE 
The AE summaries of Table 6 will be generated with number (%) of participants experiencing at 
least one event. A bar chart will also be produced for the percentage (%) of participants 
experiencing common TEAEs (≥5%) in any treatment group, presented both overall and by SOC 
and PT. 
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Table 6 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HGLT, HLT and PT 
Common TEAE (≥5%)  
Primary SOC, HGLT, HLT and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
TEAE by maximal severity 
Primary SOC and PT 
Treatment emergent SAE 
Primary SOC and PT 
TEAE leading to permanent discontinuation of IMP 
Primary SOC and PT 
TEAE leading to study discontinuation 
Primary SOC and PT 
Treatment emergent AESI 
Primary SOC and PT 
TEAE related to local intolerability at the injection site or 
hypersensitivity reaction 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
Pretreatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment AE 
Overviewa 
 
Primary SOC and PT 
Post-treatment SAE 
Overviewa 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any severe AEs, any SAEs, any AEs leading to death, any AEs leading to study 
discontinuation, any AEs leading to permanent discontinuation of IMP, any AESIs, and any treatment-related AEs. 
Analysis of deaths 
In addition to the analyses of deaths included in Table 6 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods and reasons for death 
• Deaths in non-randomized participants or randomized but not treated participants 
Analysis of adverse events of special interest (AESIs)  
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 the trial by protocol amendment. All AESIs will be reported to the Sponsor in the 
same timeframe as SAEs (within 24 hours). 
The following AEs will be considered as AESIs in this trial:  
• Pregnancy of a female participant enrolled in the trial, as well as pregnancy occurring in a 
female partner of a male participant enrolled in the trial with study drug/NIMP. 
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• Symptomatic overdose (serious or nonserious) with the study drug/NIMP. 
• Increase in alanine aminotransferase (ALT; >3 × upper limit of normal [ULN]) 
Adverse events of special interest (AESIs) will be selected for analyses as indicated in Table 7. 
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. A bar chart will also be used to present the 
percentage (%) of participants experiencing at least one treatment-emergent AESI, overall and by 
each event of interest. 
Table 7 - Selections for AESIs  
AESIs  
Selection 
Pregnancy  
eCRF specific tick box on the AE page and Pregnancy All Items page 
Symptomatic overdose  
eCRF specific tick box on the AE page and Overdose page 
ALT increase 
eCRF specific tick box on the AE page 
Analysis of local intolerability at the study drug injection site or hypersensitivity reactions  
Any signs of local intolerability at the study drug injection site or hypersensitivity reactions 
should be recorded on the AE page of the eCRF. Number (%) of participants experiencing at least 
one event will be summarized, as well as at the primary SOC and PT level.  
4.7.4 Additional safety assessments  
4.7.4.1 Laboratory variables and vital signs  
The following laboratory variables and vital signs variables will be analyzed from baseline to 
Week 24 per Section 5.7. They will be converted into standard international units. 
• Hematology:  
- 
Red blood cells and platelets: erythrocytes, platelet count, leukocytes, hemoglobin, 
hematocrit 
• Clinical chemistry: 
- 
Metabolism: albumin 
- 
Electrolytes: sodium, potassium 
- 
Renal function: creatinine, eGFR, creatinine clearance. Creatinine clearance will be 
derived with the equation of Cockroft and Gault using weight assessed at the same 
visit as creatinine. The central laboratory should calculate eGFR using the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-EPI) equation: 
 eGFRcr = 142 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if 
female](6).  
- 
Liver function: ALT, aspartate aminotransferase (AST), alkaline phosphatase (ALP), 
total bilirubin, indirect bilirubin, direct bilirubin 
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• Urinalysis: 
- 
Quantitative analysis: pH, protein, ketones, leukocytes, blood/hemoglobin, glucose 
• Pregnancy test: urine or serum 
• Vital signs: body weight, heart rate, systolic blood pressure (SBP) and diastolic blood 
pressure (DBP) while in seated position 
The tests detailed above will be performed at the central laboratory, except urine pregnancy tests, 
which will be performed at sites using urine pregnancy test kits that are provided by PPD. 
Additional tests may be performed at a local or central laboratory at any time during the trial, as 
deemed necessary by the investigator or required by local regulations. If a test is used to evaluate 
an AE (diagnostic, follow-up, outcome), the results (including the disease progression of CKD) 
must be entered into the CRF. 
All laboratory tests with values that are considered clinically significantly abnormal during the 
trial should be repeated until the values return to normal/baseline or are no longer considered 
clinically significant by the investigator. Potentially clinically significant abnormalities (PCSA) 
will be flagged and the number and percentage of participants with PCSA will be presented.  
Quantitative analyses 
For all laboratory variables and vital signs above, descriptive statistics for results and changes 
from baseline will be provided for each analysis window, as well as the last value and the worst 
value (minimum and/or maximum value depending on the parameter) during the on-treatment 
period. These analyses will be performed using central measurements only (when available) for 
laboratory variables. A scatter plot of the worst post-baseline treatment-emergent value vs 
baseline value will also be presented by biological function and parameter. 
Analyses according to PCSA  
PCSA analyses will be performed based on the PCSA list in Section 5.5. For parameters for which 
no PCSA criteria are defined, similar analyses will be done using the normal range, if applicable.  
Analyses according to PCSA will be performed based on the worst value during the 
treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables and vital signs variables above, the incidence of participants with at least 
one PCSA during the treatment-emergent period will be summarized regardless of the baseline 
level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
In addition to summary tables, the percentage (%) of participants with at least one abnormality 
(PCSA) during the treatment-emergent period will be presented using bar charts, by biological 
function and parameter. 
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4.7.4.2 Product complaints  
All product complaint summaries during the on-treatment period (defined in Section 4.1) will be 
generated in the safety population and will include the number (%) of participants experiencing at 
least one event, the number of events and 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 
• Any product complaint leading to incorrect IMP dose administration 
In addition, the analyses 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  
All analyses are appropriately described in other areas of the SAP. 
4.9 
INTERIM ANALYSES  
No interim analyses are planned for this trial. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALT: 
alanine aminotransferase 
ALP:  
aspartate aminotransferase 
ANCOVA: 
analysis of covariance  
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
CGM: 
continuous glucose monitoring 
CKD: 
chronic kidney disease 
CKD-EPI:  
Chronic Kidney Disease Epidemiology Collaboration  
COVID-19: 
coronavirus disease 2019 
CV:  
coefficient of variation 
DBP: 
diastolic blood pressure 
DTP: 
direct-to-patient 
EASD: 
European Association for the Study of Diabetes 
eCRF: 
electronic case report form 
eDiary: 
electronic diary  
eGFR: 
estimated glomerular filtration rate 
EMA:  
European Medicines Agency 
FPG: 
fasting plasma glucose 
Gla-300: 
insuline glargine 300 U/mL 
GLP-1 RA: 
glucagon-like peptide-1 receptor antagonist 
GMI: 
Glucose Management Indicator 
HbA1c: 
glycated hemoglobin 
HCP:  
healthcare provider 
HLGT: 
high-level group term 
HLT: 
high-level term 
ICE: 
intercurrent event 
ICF: 
informed consent form 
IDeg-100: 
insulin degludec 100 U/mL 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
LLT: 
lower-level term 
LS:  
least-squares 
MAR: 
missing at random 
MCMC: 
Markov chain Monte Carlo 
MedDRA: 
medical dictionary for regulatory activities 
MI:  
multiple imputation 
MMRM:  
mixed-effect model with repeated measures 
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MNAR: 
missing not at random 
NIMP: 
non-investigational medicinal product 
OAD:  
oral antidiabetic drug 
OR: 
odds ratio 
PCSA: 
potentially clinically significant abnormality 
PPS: 
per protocol set 
PT: 
preferred term 
SAE:  
serious adverse event 
SAP: 
statistical analysis plan 
SAS: 
statistical analysis system     
SBP: 
systolic blood pressure 
SD: 
standard deviation 
SE: 
standard error 
SGLT-2i: 
sodium-glucose co-transporter-2 inhibitor 
SMPG: 
self-measured plasma glucose 
SOC: 
system organ class 
SoE: 
schedule of events 
SU:  
sulfonylureas 
T2DM: 
type 2 diabetes mellitus 
TAR: 
time above range 
TBR:  
time below range 
TEAE: 
treatment-emergent adverse event 
TIR: 
time in range 
TITR: 
time in tight range 
ULN: 
upper limit of normal 
WOCBP: 
woman of childbearing potential 
WHO-DD: 
World Health Organization-drug dictionary 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
Changes to protocol-planned analyses include the following:  
• Multiplicity adjustments on secondary endpoints (Section 4.1, Section 4.4.1.2, 
Section 4.6). 
• 
 compliance rules (Section 4.5.1). 
• Analysis of exploratory endpoints -
 (Section 4.5.2).  
Due to study early termination, planned analyses have been reduced in accordance with an 
abbreviated CSR. The list of tables, listings and figures supporting the abbreviated CSR are 
documented in Appendix 6 (Section 5.6) and focus on demographics, disease characteristics at 
baseline, exposure, participant disposition and safety. Primary and secondary efficacy data is 
descriptively summarized.  
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, MEDICAL (OR 
SURGICAL HISTORY), DISEASE CHARACTERISTICS AT BASELINE, PRIOR AND 
CONCOMITANT MEDICATIONS  
The following demographics and baseline characteristics, medical and surgical history and disease 
characteristics at baseline, and prior and concomitant medications will be summarized for the ITT 
population. Continuous data will be summarized using descriptive statistics. Categorical data will 
be summarized using counts and percentages. 
5.3.1 Demographics and baseline characteristics  
The following demographics and baseline characteristics will be summarized for the safety and 
ITT populations:  
• Weight (kg)  
• Height (cm) 
• Body mass index (BMI) in kg/m2 as quantitative variable documented in the eCRF and in 
categories (<30 kg/m2, ≥30 kg/m2) 
• Age in years as quantitative variable and in categories (<65 years, ≥65 years) 
• Sex (Male, Female)  
• Race (White, Black or African American, Not Reported, Unknown, Other, Multiple)  
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, Not Reported, Unknown, Other 
Ethnicity) 
• Country (Czech Republic, Hungary, Serbia, Poland, United States) 
Baseline safety and efficacy parameters (apart from those listed above) will be presented with the 
relevant safety and efficacy summaries.  
5.3.2 Medical (or surgical) history  
Medical (or surgical) history includes all 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. 
Medical and surgical history will be summarized by SOC and PT for the ITT population, sorted 
by internationally agreed order of SOC and by the decreasing frequency of PT within SOC. 
5.3.3 Disease characteristics at baseline  
Specific disease characteristics at baseline includes the following variables and variables related 
to diabetes history will be summarized for the Safety and ITT populations:  
• Baseline HbA1c as quantitative variable and in categories (<8.5%, ≥8.5%) 
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• Baseline FPG  
• Baseline SMPG 
• eGFR as quantitative variable and in categories (<45 mL/min/1.73 m2; 
≥45 mL/min/1.73 m2) 
• Previous use of anti-hyperglycemic therapy by medication categories (SU, Metformin, 
GLP-1Ras, DPPIV Inhibitors/Gliptins, SGLT2 inhibitors, TZD/Glitazones, Insulin, Other) 
• Anti-hyperglycemic therapy currently taken (Yes, No) 
• Age (years) at diagnosis of diabetes 
• Duration of diabetes (time from diagnosis (years))  
• History of gestational diabetes (Yes, No)  
Continuous variables will be summarized using descriptive statistics. Categorical disease 
characteristic variables will be summarized using count and percentages.  
5.3.4 Prior and concomitant medications  
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock.  
• Prior medications are those the participant used prior to first investigational medicinal 
product (IMP) intake. Prior medications can be discontinued before first IMP 
administration or can be ongoing during the treatment and/or post-treatment period. 
• Concomitant medications are any interventions received by the participant concomitantly 
to the IMP during the on-treatment period. A medication may be classified both as a prior 
and concomitant medication. Concomitant medications do not include medications started 
during the post-treatment period (as defined in Section 4.1) 
• Post-treatment medications are those the participant continued or started during the post-
treatment period (as defined in Section 4.1). 
• Any technical details related to computation, dates, or imputation for missing dates are 
described in Section 5.4.4).  
Prior, concomitant, and post-treatment medications will be summarized by anatomic and 
therapeutic levels defined by ATC (Anatomic Theraputic Chemical) classification for the ITT 
population and will be presented by treatment arm and overall.  
Prior medication summaries will be sorted by decreasing frequency of anatomic class (ATC1) and 
therapeutic class (ATC2) based on overall incidence. In case of equal frequency (anatomic or 
therapeutic categories), alphabetical order will be used. Participants will be counted once in each 
ATC category (anatomic or therapeutic) linked to the medication. A medication may be counted 
in several anatomic categories. 
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Concomitant and post-treatment medication summaries will be sorted by decreasing frequency of 
anatomic class (ATC1) followed by therapeutic class (ATC2) based on incidence in the Gla-300 
arm. In case of equal frequency regarding ATCs, alphabetical order will be used. Participants will 
be counted once in each ATC (anatomic or therapeutic categories) linked to the medication. A 
medication may be counted in several anatomic categories. 
5.3.4.1 Non-antidiabetic medications  
Prior, concomitant, and post-treatment non-antidiabetic medications will be summarized by 
anatomic class (ATC1) and therapeutic class (ATC2) for the ITT population and will be presented 
by treatment arm and overall. 
Prior medication summaries will be sorted by decreasing frequency of anatomic class (ATC1) and 
therapeutic class (ATC2) based on overall incidence. In case of equal frequency (anatomic or 
therapeutic categories), alphabetical order will be used. Participants will be counted once in each 
ATC category (anatomic or therapeutic) linked to the medication. A medication may be counted 
in several anatomic categories. 
Concomitant and post-treatment medication summaries will be sorted by decreasing frequency of 
anatomic class (ATC1) followed by therapeutic class (ATC2) based on incidence in the Gla-300 
arm. In case of equal frequency regarding ATCs, alphabetical order will be used. Participants will 
be counted once in each ATC (anatomic or therapeutic categories) linked to the medication. A 
medication may be counted in several anatomic categories. 
An individual listing sorted by treatment arm and subject number will be populated instead of a 
summary table if few non-antidiabetic medications are observed either prior or post treatment. 
5.3.4.2 Antidiabetic medications  
Prior, concomitant, and post-treatment antidiabetic medications will be summarized by 
pharmacological class (ATC3), chemical class (ATC4) and standardized medication name for the 
ITT population and will be presented by treatment arm and overall.  
The table for antidiabetic prior medications will be sorted by decreasing frequency of 
pharmacological class followed by chemical class and standardized medication name based on the 
overall incidence across treatment arm. In case of equal frequency, alphabetical order will be 
used.  
The tables for antidiabetic concomitant and post treatment medications will be sorted by 
decreasing frequency of pharmacological class followed by chemical class and standardized 
medication name based on the incidence in the Gla-300 treatment arm. In case of equal frequency, 
alphabetical order will be used.  
In addition, the following specific medications will be summarized:  
• Antidiabetic concomitant rescue medications will be presented by pharmacological class 
(ATC3), chemical class (ATC4) and standardized medication name. Table 9 below defines 
antidiabetic medications by pharamacological class (ATC3).  
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• Prohibited concomitant medications will be presented by prohibited medication category 
(as defined by deviation) and standardized medication name (see Table 8 below). 
Table 8 - Prohibited Medications  
Prohibited Medication Category 
Pharmacological Class 
(ATC3) 
Standardized Medication 
Name (ATC4)a 
Insulins and analogues 
A10AB, A10AC, A10AD, A10AE, 
A10AF 
 
Other blood glucose lowering drugs, excluding 
insulins 
A10BX 
Tirzepatide (ATC5: A10BX16) 
Peripherally acting antiobesity products 
A08AB 
 
Thyroid hormones 
H03AA 
 
Corticosteroids (excluding inhaled and topical) 
H02A, H02B 
 
Salycylic acid and derivatives 
N02BA 
 
Ascorbic acid (Vitamin C), including combinations 
A11GA, A11GB, 
G01AD, S01XA 
Ascorbic acid (G01AD03), Ascorbic 
acid (S01XA15) 
a Standardized medication names are provided where the prohibited medication is limited to certain medications within the provided ATC3 
class.  
A list of ATC3 codes to be used in identifying antidiabetic medications is shown in Table 9 
below. Prior, concomitant and post-treatment antidiabetic non-insulin and rescue therapies will 
also be summarized per standardized drug grouping name and standardized medication name. 
Table 9 - Antidiabetic Medications  
Standardized Drug Grouping Name 
Group ID 
Pharmacological Class (ATC3) 
Insulins and analogues 
100 
A10AB, A10AC, A10AD, A10AE, A10AF 
Biguanides 
101 
A10BA 
Sulphonamides 
102 
A10BC 
Other blood glucose lowering drugs 
103 
A10BX 
Other drugs used in diabetes 
104 
A10X 
Alpha glucosidase inhibitors 
105 
A10BF 
Thiazolidinediones 
106 
A10BG 
Dipeptidyl peptidase-4 inhibitors 
107 
A10BH 
Glucagon-like peptide-1 (GLP1) agonists 
168 
A10BJ 
SGLT2 inhibitors 
291 
A10BK 
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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 date, study day, and baseline  
For efficacy analyses, the reference date is a participant’s randomization date. For safety 
assessments, the reference date is a participant’s first treatment date. 
Study day is calculated as (Date of assessment - Reference date) + 1.  
Baseline is the last non-missing value recorded prior to or on the reference date.  
5.4.4 Missing data  
For relevant categorical tabulations in demographics, baseline characteristics and compliance 
summaries, the number of participants with missing data are counted in a category of “Missing” 
but no percentages will be calculated. “Missing” category will only be presented in summaries for 
variables where missing data occurs. The percentages on the other rows will be based on the 
number of non-missing observations. 
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, 
concomitantly, or post-treatment, it will be considered as a prior, concomitant, and post-treatment 
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. 
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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 will 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 Analysis windows for time points  
5.4.5.1 Main Study  
The following analysis windows will decide how the scheduled and/or unscheduled visits will be 
used in the by-visit analyses of efficacy and safety variables, excluding fasting SMPG 
(Section 4.4.1.1), SMPG 7-point profile (Section 4.4.1.1) , and basal insulin dosing data 
(Section 4.5.1). 
All non-missing measurements (scheduled or unscheduled) will be used if the measurement date 
is within the analysis window.  
After applying these time windows, if multiple assessments are associated to the same time point, 
the assessment closest from the targeted study day will be used. If the difference is a tie between 
multiple assessments, the value after the targeted study day will be used. If multiple valid values 
exist within a same day, then the first value of the day will be selected.  
If there is no measurement for a given parameter in an analysis window, data will be considered 
missing for the corresponding visit.  
Table 10 - Analysis window definition  
Scheduled post-baseline visit 
Targeted study day 
Analysis window in study days 
Week 4 (Visit 6) 
29 
Day 2 to Day 43 
Week 8 (Visit 10) 
57 
Day 44 to Day 71 
Week 12 (Visit 14) 
85 
Day 72 to 127 
Week 24 (Visit 17) 
169 
≥ Day128 
Study days are calculated considering Day 1 as the day of first administration of intervention (or the day of randomization for participant not 
exposed). 
 
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Unscheduled visits 
Unscheduled visit measurements of laboratory data and vital signs will be used for computation of 
baseline, the last on-treatment value, analysis according to PCSAs, and the shift summaries for 
safety. They will also be included in the by-visit summaries if they are windowed to scheduled 
post-baseline visits.  
5.5 
APPENDIX 5 CRITERIA FOR POTENTIALLY CLINICALLY SIGNIFICANT 
ABNORMALITIES  
Table 12 - Criteria for Potentially Clinically Significant Abnormalities  
Parameter 
PCSA 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3x ULN 
>5x ULN 
>10x ULN 
>20x ULN 
ALT and Total Bilirubin 
ALT >3x ULN and TBILI >2x ULN 
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Parameter 
PCSA 
eGFR (mL/min/1.73 m2) 
(Estimate of GFR based on an MDRD equation)  
 
<10  
<15 (kidney failure) 
≥40% decrease in eGFR from baseline 
≥50% decrease in eGFR from baseline 
Creatinine 
≥100% change from baseline 
Albumin (g/L) 
Change from baseline to: 
   <30  
   ≥30  
   >300  
Vital signs 
HR (bpm) 
≤50 and decrease from baseline ≥20  
≥120 and increase from baseline ≥20  
SBP (mmHg) 
≤95 and decrease from baseline ≥20  
≥160 and increase from baseline ≥20  
DBP (mmHg) 
≤45 and decrease from baseline ≥10  
≥110 and increase from baseline ≥10  
Weight  
≥5% increase from baseline  
≥5% decrease from baseline 
5.6 
APPENDIX 6 TABLE OF CONTENTS FOR ABBREVIATED CSR  
 
 
Title 
Analysis Set 
Table 
 
 
14.1.1.1 
Participant Disposition 
ITT Set 
14.1.1.2 
Analysis Sets 
Screened Set 
14.1.1.3 
Number of Participants Screened 
Screened Set 
14.1.1.4 
Number of Participants Screened by Country and Site 
Screened Set 
14.1.2 
Significant Protocol Deviations 
ITT Set 
14.1.3.1 
Demographics and Participant Characteristics at Baseline 
Safety Set 
14.1.3.2 
Disease Characteristics at Baseline 
Safety Set 
14.1.4 
Medical or Surgical History at Screening by Primary SOC 
and PT 
ITT Set 
14.1.5.1 
Extent of Study Treatment Exposure 
Safety Set 
14.1.5.2 
Treatment Compliance 
Safety Set 
14.1.5.3 
Dosing Summary 
Safety Set 
14.2.1.1 
Baseline Summary of Primary Endpoint: HbA1c Level 
ITT Set 
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Title 
Analysis Set 
14.2.1.2 
Baseline Summary of Primary Endpoint: HbA1c Level by 
Subgroups 
ITT Set 
14.2.2. 
Baseline Summary of Secondary Endpoints 
ITT Set 
14.3.1 
Overview of Adverse Event profile: Treatment-emergent 
Adverse Events 
Safety Set 
14.3.2 
Number (%) of Participants with TEAE(s) by Primary SOC, 
HLGT, HLT and PT 
Safety Set 
14.3.3. 
Participants with a Common TEAE (≥5%) in Any 
Treatment Group by Primary SOC, HLGT, HLT and PT 
Safety Set 
14.3.4 
Number (%) of Participants with TEAE(s) Related to IMP 
as per Investigator’s Judgment by Primary SOC and PT 
Safety Set 
14.3.5 
Number (%) of Participants with Treatment-emergent 
SAEs by Primary SOC and PT 
Safety Set 
14.3.6 
Number (%) of Participants Who Died by Study Period 
Safety Set 
14.3.7 
Overview of Hypoglycemic Events Overall and by 
Observation Period, ADA Level, and Diurnal Distribution 
Safety Set 
Figure 
 
 
14.2.1.1 
Box Plot of HbA1c Level by Analysis Visit (Observed 
Cases) 
ITT Set 
14.2.2.1 
Box Plot of FPG Level by Analysis Visit (Observed Cases) 
ITT Set 
14.2.2.2 
Box Plot of SMPG Level by Analysis Visit (Observed 
Cases) 
ITT Set 
14.2.2.3 
Line Plot of 7-point SMPG Profiles, Per Time Point within 
24-Hour Period by Analysis Visit (Observed Cases) 
ITT Set 
14.2.2.4 
Bar Chart of Percentage (%) of Participants Reaching 
HbA1c <7.0% at Week 24 (Observed Cases) 
ITT Set 
Listing 
 
 
16.2.1 
Participant Randomization List 
ITT Set 
16.2.2 
Listing of Participants with at Least One Protocol Deviation 
ITT Set 
16.2.3.1 
Listing of Participant Demographics 
Safety Set 
16.2.3.2 
Listing of Baseline Disease Characteristics 
Safety Set 
16.2.5.1 
Exposure to IMP 
Safety Set 
16.2.7.1 
Listing of all AEs 
Safety Set 
16.2.7.2 
Listing of all AEs leading to study discontinuation 
Safety Set 
16.2.7.3 
Listing of All Participants who Died During the Study 
Safety Set 
16.2.7.4 
Listing of On-treatment Hypoglycemic Events 
Safety SEt 
16.2.8 
Listing of Participants with HbA1c, SMPG, or FPG values 
at Week 24 
ITT Set 
 
 
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5.7 
SCHEDULE OF EVENTS  
5.7.1 Schedule of events for the main trial  
Table 13 - Schedule of events for the main trial  
Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography (including 
height) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Current medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationf 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
Study drug dispensing 
 
X 
 
X 
 
Xg 
 
X 
 
 
 
X 
 
SoloStar or FlexTouch pen 
instructionh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient eDiary setup 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient eDiary completion 
<------------------------------------------------------------------------------------------------------------X---------------------------------------------------------------------> 
 
Collection of eDiary 
 
X 
 
X 
 
 
 
X 
 
 
X 
X 
 
Glucose meter (dispensing 
and instruction) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Trial Period 
Screening 
Baseline/ 
Randomization 
Treatment 
Follow-Up 
Titrationa 
Maintenance 
 
Visitb 
1 
2 
3–5 
6 
7–9 
10 
11–13 
14 
15 
16 
17c 
Unscheduledd 
18 
Visit Type 
Clinic 
Clinic 
Phone 
Clinic 
Phone 
Phone 
Phone 
Clinic 
Phone 
Phone 
Clinic 
Clinic or Phone 
Phonee 
Week 
–2 
0 
1 to 3 
4 
5 to 7 
8 
9 to 11 
12 
16 
20 
24 
 
25 
Day 
–14 
0 
1 to 21 
28 
35 to 49 
56 
63 to 77 
84 
112 
140 
168 
 
175 
Window (Days) 
±2 
±2 
 
±3 
 
±3 
 
±3 
±3 
±3 
±3 
 
±3 
Collection of glucose meter 
(if mandatory by local 
regulation) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Daily dosing of Gla-300 or 
IDeg-100i 
 
<-------------------------------------------------------------------------------------------X--------------------------------------------------------------------> 
 
Study drug dose adjustments 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Study drug adherence and 
accountability 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
HbA1c 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
FPGj 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Fasting SMPGk 
 
<--------------------------------------------------------------------------X----------------------------------------------------------> 
 
 
7-point SMPGl 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Hypoglycemia eventsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Recording of AEs and SAEs 
(including AESIs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Product complaints 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs (including body 
weight)n 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
 
Clinical chemistryo 
Xp 
 
 
 
 
 
 
 
 
 
Xp 
 
 
Hematologyo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysiso 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine albumin: 
creatinine ratio 
Xp 
 
 
 
 
 
 
 
 
 
Xp 
 
 
Pregnancy testq 
X 
 
 
X 
 
 
 
X 
 
 
X 
 
 
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Abbreviations: AE, adverse event; AESI, adverse event of special interest; BMI, body mass index; 
; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology 
Collaboration; cr, creatinine; DBP, diastolic blood pressure; DTP, direct-to-patient; eDiary, electronic diary; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; Gla-300, insulin glargine 300 U/mL; 
HbA1c, glycosylated hemoglobin; HCP, healthcare provider; IDeg-100, insulin degludec 100 U/mL; IMP, investigational medicinal product; SAE, serious adverse event; SBP, systolic blood pressure; Scr, serum 
creatinine; SMPG, self-measured plasma glucose; WOCBP, women of childbearing potential. 
a During the titration period, the doses of Gla-300 and IDeg-100 will be adjusted using a recommended dose-adjustment algorithm. After randomization, the dose will be titrated at least weekly (but no more than 
every 3 days) until the patient reaches a target fasting SMPG value of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding hypoglycemia episodes. Thereafter, until the end of the trial, the doses of Gla-300 and 
IDeg-100 will be adjusted to maintain this glycemic target, if deemed appropriate by the investigator. Dose adjustments will be based on a median of fasting SMPG values from the last 3 measurements, including 
the value on the day of titration, measured by the patient using glucose meters and accessories supplied by the sponsor through a vendor. Best efforts should be made to reach the glycemic target by 8-12 weeks 
after randomization. 
b 
 
c At the end of the trial, patients should discuss with the investigator, in collaboration with their HCP, whether to continue on the Gla-300 or IDeg-100 treatment regimen or transition to an alternate antihyperglycemic 
therapy. All patients who withdraw from the trial prematurely will, as soon as possible, undergo all end-of-trial and follow-up assessments/procedures at a visit that should be identified as “the early trial 
discontinuation visit.” 
d An unscheduled visit can be planned anytime during the treatment period if study drug resupply is required. This will be a site visit or via phone contact with DTP-IMP delivery.  
The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial site. 
e This will be a phone contact, but could be a site visit if ongoing or new AEs emerge during the post-treatment period, if necessary. 
f 
A physical examination will be performed per standard of care to assess the health status of patients. A list of assessments is provided in Section 6.2.1 of the Protocol. 
g Study drug resupply at Visit 10 will be via phone contact with DTP-IMP delivery. The sponsor-approved courier company will need at least 72 hours’ notice to collect treatment kits from a trial site. 
h All patients will be trained by trial staff on how to use the pen correctly, how to store it, and how to change the needle to ensure that each patient is able to perform self-injection. An instruction leaflet will be 
provided to patients that explains how to use the disposable pen and needles. Training will be repeated during the treatment period as often as deemed necessary by site staff. 
i 
Gla-300 or IDeg-100 should be self-administered once daily between 6:00 PM and 8:00 PM throughout the treatment period. The investigator and patient will discuss and agree upon the injection time. Gla-300 or 
IDeg-100 will be administered after the fasting blood sample draw during site visits. The need for dose adjustment will be assessed at each visit. 
j 
For scheduled site visits, patients will be required to arrive having fasted without administering the study drug. Fasting is defined as no intake of food or drink, except water, in the 8 hours before blood sampling. 
k Fasting SMPG values will be used to titrate and adjust study drug doses and monitor glycemic levels. Patients will be required to measure fasting SMPG values (using the glucose meter supplied during the 
screening period) before breakfast and before administration of study drug once daily throughout the treatment period and to record the results in the eDiary.  
l 
The 7-point SMPG profile will be measured (and recorded in the patient’s eDiary) at the following 7 points: pre-prandial and 2 hours after starting breakfast, lunch, and dinner, and at bedtime.  
The 7-point SMPG profile will be performed over a single, 24-hour period, on at least 2 days within the week before selected site visits. 
m Hypoglycemia events will be evaluated based on the categories of interest described in Section 4.7.3. 
n This includes body weight, heart rate, SBP, and DBP. Height and body weight measurements at screening will be used to calculate BMI. 
o The list of clinical safety laboratory tests to be performed is provided in Section 4.7.4.1. Additional tests may be performed at a local or central laboratory at any time during the trial as deemed necessary by the 
investigator or required by local regulations. The central laboratory should calculate eGFR using the CKD-EPI equation: eGFRcr = 142 × min(Scr/κ, 1)α × max(Scr/κ, 1)-1.200 × 0.9938Age × 1.012 [if female] (6). 
p Creatinine and eGFR (clinical chemistry) and spot urine albumin: creatinine ratio will be measured for CKD monitoring. 
q This is only for WOCBP and is a urine pregnancy test. 
 
 
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6 
REFERENCES  
1. European Medicines Agency (EMA). Draft guidance. Guideline on clinical investigation of 
medicinal products in the treatment or prevention of diabetes mellitus. 2018 Jan 29 [cited 2022 
Feb 15]. Available from: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-
guideline-clinical-investigation-medicinal-products-treatment-prevention-diabetes-
mellitus_en.pdf 
2. Bergenstal RM, Beck RW, Close KL, Grunberger G, Sacks DB, Kowalski A, et al. Glucose 
Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose 
Monitoring. Diabetes Care [Internet]. November 2018 [cited 2022 July 19];41(11):2275-80. 
Available from: https://doi.org/10.2337/dc18-1581 
3. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95.  
4. Agiostratidou G, Anhalt H, Ball D, Blonde L, Gourgari E, Harriman KN, et al. Standardizing 
Clinically Meaningful Outcome Measures Beyond HbA1c for Type 1 Diabetes: A Consensus 
Report of the American Association of Clinical Endocrinologists, the American Association of 
Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF 
International, The Leona M. and Harry B. Helmsley Charitable Trust, the Pediatric Endocrine 
Society, and the T1D Exchange. Diabetes Care. 2017;40(12):1622-30. 
5. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes-
2021. Diabetes Care. 2021;44(Suppl 1):S73-84. 
6. National Kidney Foundation. CKD-EPI Creatinine Equation (2021) [Internet]. 2022 [cited 
2022 Mar 30]. Available from: https://www.kidney.org/content/ckd-epi-creatinine-equation-
2021 
 
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Statistical Analysis Plan (SAP) Client Approval Form 
 
Document Number: FORM-02894 v8.0 
Page 1 of 1 
Effective Date: 22 Nov 2021 
Printed on: 17 October 2023 
 
Client: 
Sanofi 
Protocol Number: 
LPS17007 
 
Document Description: 
Statistical Analysis Plan 
SAP Title: 
A 24-Week, Multicenter, Randomized, Open-Label, 
Parallel-Group Trial Comparing the Efficacy and Safety of 
Insulin Glargine 300 U/mL (Gla-300) and Insulin 
Degludec 100 U/mL (IDeg-100) in Insulin-Naïve People 
with Type 2 Diabetes Mellitus and Renal Impairment: 
TRENT Trial 
SAP Version Number: 
1.0 
Effective Date: 
18Oct2023 
 
Author(s): 
For PPD:  
  
 
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