A 12-week Randomized, Controlled Trial to Compare TOUJEO® and TRESIBA® in Terms of Glucose Values in Target Range and Variability During Continuous Glucose Monitoring in Patients With Type 1 Diabetes Mellitus
Phase: PHASE4
Conditions: Type 1 Diabetes Mellitus
Sponsor: Sanofi

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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
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 
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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: RDSD-002540 VERSION N° 2.0 (11-OCT-2018) based on TransCelerate CPT version 5 
Page 1 
CLINICAL TRIAL PROTOCOL 
Protocol title: 
A 12-week randomized controlled trial to compare 
TOUJEO® and TRESIBA® in terms of glucose values in 
target range and variability during continuous glucose 
monitoring in patients with type 1 diabetes mellitus 
Protocol number: 
LPS14947 
Amendment number: 
Original protocol 
Compound number 
(INN/Trademark): 
HOE901-U300 
(Insulin Glargine 300 U/mL/ Toujeo®) 
Short title: 
Comparison of glucose values and variability between 
TOUJEO and TRESIBA during continuous glucose 
monitoring in type 1 diabetes patients (inRange) 
Sponsor name: 
Legal registered 
address: 
Monitoring Team’s 
Representative Name 
and Contact Information 
Regulatory agency identifying number(s): 
EudraCT number: 
2017-002756-91 
IND number: 
Not applicable 
WHO number: 
U1111-1197-8171 
NCT number: 
Not applicable 
Approval Date: 
31 May 2019 
Total number of pages: 86 
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Clinical Trial Protocol 
LPS14947 - insulin glargine 300 U/mL 
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TABLE OF CONTENTS 
CLINICAL TRIAL PROTOCOL  ...................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
LIST OF FIGURES .......................................................................................................................................... 6 
1 
PROTOCOL SUMMARY ................................................................................................................. 7 
1.1 
SYNOPSIS ....................................................................................................................................... 7 
1.2 
SCHEMA ........................................................................................................................................ 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 14 
2 
INTRODUCTION ............................................................................................................................ 19 
2.1 
STUDY RATIONALE ...................................................................................................................... 19 
2.2 
BACKGROUND ............................................................................................................................. 19 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 21 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 22 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 23 
4 
STUDY DESIGN ............................................................................................................................ 25 
4.1 
OVERALL DESIGN ........................................................................................................................ 25 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 26 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 27 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 27 
5 
STUDY POPULATION .................................................................................................................. 28 
5.1 
INCLUSION CRITERIA .................................................................................................................. 28 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 29 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 30 
5.4 
SCREEN FAILURES ...................................................................................................................... 31 
6 
STUDY INTERVENTION ............................................................................................................... 32 
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6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 32 
6.1.1 
Devices........................................................................................................................................... 34 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ....................................................... 34 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 35 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 37 
6.4.1 
Drug accountability ......................................................................................................................... 37 
6.4.2 
Training to use injection devices .................................................................................................... 37 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 38 
6.6 
DOSE MODIFICATION .................................................................................................................. 38 
6.6.1 
Basal insulin ................................................................................................................................... 38 
6.6.1.1 
Starting dose .................................................................................................................................. 39 
6.6.1.2 
Dose adjustment ............................................................................................................................ 39 
6.6.2 
Mealtime insulin ............................................................................................................................. 40 
6.6.3 
Monitoring of insulin titration .......................................................................................................... 42 
6.6.4 
Evaluation of participants not meeting glycemic targets ................................................................ 42 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 42 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 43 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 43 
7.1.1 
Definitive discontinuation ............................................................................................................... 43 
7.1.2 
Temporary discontinuation ............................................................................................................. 44 
7.1.2.1 
Rechallenge ................................................................................................................................... 44 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 44 
7.3 
LOST TO FOLLOW UP.................................................................................................................. 45 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 46 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 46 
8.1.1 
Continuous glucose monitoring (CGM) .......................................................................................... 46 
8.1.1.1 
CGM performance .......................................................................................................................... 46 
8.1.1.2 
CGM qualification and data transfer .............................................................................................. 47 
8.1.2 
Glycated hemoglobin A1c .............................................................................................................. 48 
8.1.3 
Fasting plasma glucose ................................................................................................................. 48 
8.1.4 
Self-monitoring of plasma glucose ................................................................................................. 48 
8.1.5 
Insulin dose (including IMP during the treatment period) .............................................................. 50 
8.1.6 
Patient-reported Outcomes (PROs) ............................................................................................... 51 
8.1.6.1 
DTSQs............................................................................................................................................ 51 
8.1.6.2 
DTSQc............................................................................................................................................ 51 
8.1.6.3 
MOS Sleep ..................................................................................................................................... 52 
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8.1.6.4 
WPAI .............................................................................................................................................. 52 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 53 
8.2.1 
Physical examinations.................................................................................................................... 53 
8.2.2 
Vital signs ....................................................................................................................................... 53 
8.2.3 
Clinical safety laboratory assessments .......................................................................................... 53 
8.2.4 
Hypoglycemia ................................................................................................................................. 54 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 55 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 56 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 56 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 56 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 56 
8.3.5 
Pregnancy ...................................................................................................................................... 57 
8.3.6 
Guidelines for reporting product complaints .................................................................................. 57 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 57 
8.5 
PHARMACOKINETICS .................................................................................................................. 58 
8.6 
PHARMACODYNAMICS ............................................................................................................... 58 
8.7 
GENETICS ..................................................................................................................................... 58 
8.8 
BIOMARKERS ............................................................................................................................... 58 
8.9 
HEALTH ECONOMICS .................................................................................................................. 58 
9 
STATISTICAL CONSIDERATIONS  ............................................................................................. 59 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 59 
9.2 
SAMPLE SIZE DETERMINATION  ................................................................................................ 59 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 60 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 60 
9.4.1 
Efficacy analyses ........................................................................................................................... 60 
9.4.2 
Safety analyses .............................................................................................................................. 62 
9.4.3 
Other analyses ............................................................................................................................... 63 
9.5 
INTERIM ANALYSES  ................................................................................................................... 63 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 64 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 64 
10.1.1 
Regulatory and Ethical Considerations .......................................................................................... 64 
10.1.2 
Informed Consent Process ............................................................................................................ 64 
10.1.3 
Data Protection .............................................................................................................................. 65 
10.1.4 
Committees Structure .................................................................................................................... 65 
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10.1.5 
Dissemination of Clinical Study Data ............................................................................................. 66 
10.1.6 
Data Quality Assurance ................................................................................................................. 66 
10.1.7 
Source documents ......................................................................................................................... 67 
10.1.8 
Study and Site Closure .................................................................................................................. 67 
10.1.9 
Publication Policy ........................................................................................................................... 67 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 68 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING................................................. 69 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 73 
10.5 
APPENDIX 5: QUESTIONNAIRE .................................................................................................. 77 
10.5.1 
The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs)  ............................ 77 
10.5.2 
The Diabetes Treatment Satisfaction Questionnaire Change Version .......................................... 78 
10.5.3 
MOS Sleep ..................................................................................................................................... 79 
10.5.4 
WPAI .............................................................................................................................................. 81 
10.6 
APPENDIX 6: ADA HYPOGLYCEMIA DEFINITIONS ................................................................... 82 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  ............................................................. 83 
10.8 
APPENDIX 8: ABBREVIATIONS ................................................................................................... 83 
11 
REFERENCES ............................................................................................................................... 84 
 
LIST OF TABLES 
Table 1 - Objectives and endpoints ............................................................................................................... 22 
Table 2 - Overview of study interventions administered ............................................................................... 32 
Table 3 - Basal insulin dose adjustments ...................................................................................................... 39 
Table 4 - Rapid-acting insulin dose adjustment ............................................................................................ 41 
Table 5 - Carb counting: insulin-to-carbohydrate ratio .................................................................................. 41 
Table 6 - Populations for analyses ................................................................................................................ 60 
Table 7 - Efficacy analyses ........................................................................................................................... 61 
Table 8 - Safety analyses .............................................................................................................................. 62 
Table 9 - Protocol-required laboratory assessments .................................................................................... 68 
 
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LIST OF FIGURES 
Figure 1 - Graphical study design ................................................................................................................. 13 
 
 
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Clinical Trial Protocol 
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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Protocol title: A 12-week randomized controlled trial to compare TOUJEO® and TRESIBA® in 
terms of glucose values in target range and variability during continuous glucose 
monitoring in patients with type 1 diabetes mellitus 
Short title: 
Comparison of glucose values and variability between TOUJEO and TRESIBA 
during continuous glucose monitoring in type 1 diabetes patients (inRange) 
Rationale: 
The fluctuations in blood glucose, regular short-duration periods of hyperglycemia and 
hypoglycemia, which are not detected by the measurements of glycated hemoglobin (HbA1c), 
may possibly contribute to vascular pathological processes and diabetic complications.  
Insulin glargine U300 (HOE901-U300, Toujeo®) is a more concentrated formulation of insulin 
glargine U100 (HOE901) which showed a prolonged and flatter glucose-lowering activity (up to 
36 hours) compared to Lantus (Insulin glargine U100), resulting in less circadian fluctuation in 
blood glucose levels (1). Given these features of the pharmacokinetic (PK)/pharmacodynamics 
(PD) profiles, Toujeo is considered to be well suitable for constant, peakless 24-hour basal insulin 
supply in diabetes management, with the expectation of less hypoglycemic risk at equal to tighter 
blood glucose control. 
Tresiba® is a basal insulin that forms soluble multi-hexamers upon subcutaneous (SC) injection, 
resulting in a depot from which insulin degludec is continuously and slowly absorbed into the 
circulation leading to a flat and stable glucose-lowering-effect. This recombinant analog of human 
insulin provides basal insulin supply beyond 42 hours after injection in euglycemic clamp 
conditions in type 1 diabetes (2).  
The present study LPS14947 is designed to further explore similarities and differences between 
Toujeo and Tresiba in terms of an effect on continuous glucose profile, while the conventional 
glycemic control as measured by HbA1c is anticipated to be similar between the 2 treatments. 
Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
To demonstrate the noninferiority of insulin glargine 300 U/mL 
in comparison to insulin degludec 100 U/mL on glycemic 
control and variability in participants with diabetes mellitus 
 
Percent time in glucose range of ≥70 to ≤180 mg/dL (≥3.9 to 
≤10 mmol/L) at Week 12, obtained using continuous glucose 
monitoring (CGM) 
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Secondary 
To evaluate the glycemic control and variability parameters in 
each treatment group at Week 12 using CGM 
At Week 12, the following endpoints will be assessed: 
 
Glucose total CV  
 
Glucose within-day and between-day CV  
Other secondary endpoints: 
 
Change from baseline to Week 12 in HbA1c 
 
Change from baseline to Week 12 in central lab FPG 
 
Percent time and mean hours per day with 
glucose<70mg/dL (on all time and during the night 
[00:00 to 05:59]) 
 
Percent time and mean hours per day with 
glucose>180mg/dL 
 
To evaluate the safety of insulin glargine 300 U/mL in 
comparison to insulin degludec 100 U/mL  
Number of participants with adverse events (see Section 8.3)  
Number of participants with at least one hypoglycemic event 
from baseline to Week 12 
Number of hypoglycemic events per participant year from 
baseline to Week 12 
Overall design: 
This is a multicenter, randomized, active-controlled, parallel-group, 12-week open-label study to 
compare the efficacy of Toujeo with Tresiba using 20-day CGM glucose profiles at Week 12. The 
CGM during study period will be blinded to both the Investigators and patients. 
Study population will consist of participants with type 1 diabetes mellitus (T1DM), treated with 
multiple daily injections (MDI) using basal insulin once daily and rapid acting insulin analogs for 
at least one year, and having HbA1c ≥ 7% and ≤ 10% at screening (see full list of inclusion and 
exclusion criteria in Section 5).  
Number of participants: 
Approximately 338 patients will be randomly assigned to study intervention for an estimated total 
of 131 evaluable participants per intervention group (with the assumption of a non-evaluability 
rate of 22%). 
Intervention groups and duration: 
The study is planned to randomize 338 patients in 2 parallel treatment groups: 
 
Toujeo group, n=169 patients. 
 
Tresiba group, n=169 patients. 
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The duration of the study per patient will be around 18 weeks (1 or 2 weeks of screening followed 
by a 4-week run-in period, a 12-week treatment period and a 2 to 4 days follow-up period). 
Study interventions 
Investigational medicinal products 
 
Formulation:  
Test drug: Toujeo (insulin glargine 300 U/mL) is supplied as a sterile, non-pyrogenic, 
clear, colorless solution for SC injection in the Toujeo SoloStar prefilled, disposable pen. 
Each Toujeo SoloStar contains in total 450 units of insulin glargine (1.5 mL of 300 U/mL 
insulin glargine solution). 
Control drug: Tresiba is supplied as a sterile, non-pyrogenic, clear, colorless solution in 
the marketed Tresiba FlexTouch prefilled (disposable) pen (insulin degludec 100 U/mL 
solution for SC injection). Each Tresiba FlexTouch contains in total 300 units of insulin 
degludec (3.0 mL of 100 U/mL insulin degludec solutions). 
 
Route of administration: subcutaneous. 
 
Dose regimen: At randomization, patients will switch from their current basal insulin to 
either Toujeo or Tresiba in the morning. The initiation doses of Toujeo and Tresiba will be 
the patient’s current doses of their basal-insulin analogs. During the titration phase 
(expected to be up to Week 8), doses of either Toujeo or Tresiba will be titrated to achieve 
glycemic targets without hypoglycemia. The dose will be titrated at least weekly (but no 
more often than every 3 days), until the patient reaches a target fasting SMPG of ≥70 to 
<100 mg/dL (≥3.9 to <5.6 mmol/L) while avoiding hypoglycemia episodes. Dose 
adjustments are based on a median of fasting SMPG values from the last 3 days, which 
includes the value measured on the day of titration, as measured by the patient using 
glucometers and accessories supplied by the Sponsor. Sponsor will ensure adequate 
monitoring of basal insulin titration. 
 
a Median refers to intermediate SMPG value (the value between the lowest and the highest SMPG values when the values are ranked in a 
growing order). 
b Prior to additional basal insulin titration, mealtime insulin should be titrated to achieve a bedtime and pre-breakfast glucose delta <50 mg/dL, 
if so considered helpful by Investigator. 
 
Mediana fasting pre-breakfast SMPG values (last 3 days) 
 
Basal insulin dose adjustments (U/day)b  
≥140 mg/dL (≥7.8 mmol/L) 
+4 units  
≥100 and <140 mg/dL (≥5.6 and <7.8 mmol/L) 
+2 units  
≥70 and <100 mg/dL (≥3.9 and 
<5.6 mmol/L) 
No change 
≥56 and <70 mg/dL (≥3.1 and <3.9 mmol/L) 
-2 units 
<56 mg/dL (<3.1 mmol/L) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or one severe hypoglycemic episode 
-4 units or at the discretion of the Investigator or 
medically qualified designee 
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Noninvestigational medicinal products(s) 
 
Formulation: rapid-acting (mealtime) insulin analog (eg, insulin glulisine, insulin lispro or 
insulin aspart). The cost of the mealtime insulin analogue may be reimbursed if not 
covered by health insurance and if allowed by local regulations. Alternatively, the sponsor 
provided insulin glulisine may be offered. 
 
Route of administration: subcutaneous. 
 
Dose regimen: The injection time and frequency of rapid-acting (mealtime) insulin will be 
at the Investigator’s discretion, in accordance with the National Product Label. During the 
study, the doses of the mealtime insulin analog should be actively titrated to achieve and 
maintain the 2 hour postprandial SMPG in the range ≥130 to ≤180 mg/dL (≥7.2 to 
<10 mmol/L) while avoiding hypoglycemia. Dose adjustment of mealtime insulin can be 
based on a pattern of post-meal SMPG data from the prior 3 days (simple titration) OR the 
carbohydrate content of the meal. Sponsor will ensure adequate monitoring of mealtime 
insulin titration.  
Simple titration: Titration of mealtime insulin based on a pattern of post-meal glucose 
median <130 / >180 mg/dL in the prior 3 days using the table below. 
 
Mealtime dose of Insulin 
Pattern of Postprandial Plasma 
Glucose values <130 mg/dLa 
Postprandial Plasma Glucose 
values >180 mg/dLa 
≤10 units 
Decrease dose by 1 unit 
Increase dose by 1 unit 
≥11-19 units 
Decrease dose by 2 units 
Increase dose by 2 units 
≥20 units 
Decrease dose by 3 units 
Increase dose by 3 units 
a If more than half of the mealtime plasma glucose (2-hours postprandial plasma glucose) values for the week were above target. 
OR 
 
Carb counting: (insulin-to-carbohydrate ratio) group. 
Starting recommendation 1 unit to 15 grams carbs 
Consider calculating insulin to carb (I:C) ratio = 500/total daily dose (TDD) of insulin. 
 
Mealtime dose of Insulin 
Pattern of Postprandial Plasma 
Glucose values <130 mg/dLa 
Pattern of Postprandial Plasma 
Glucose values >180 mg/dLa 
1 unit/20 g 
Decrease to 1 unit/25 g 
Increase to 1 unit/15 g 
1 unit/15 g 
Decrease to 1 unit/20 g 
Increase to 1 unit/10 g 
1 unit/10 g 
Decrease to 1 unit/15 g 
Increase to 2 unit/15 g 
2 unit/15 g 
Decrease to 1 unit/10 g 
Increase to 3 unit/15 g 
3 unit/15 g 
Decrease to 2 unit/15 g 
Increase to 4 unit/15 g 
a If more than half of the mealtime plasma glucose values for the prior 3 days were above target. 
 
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Statistical considerations: 
 
Sample size  
The sample size calculation is based on the percent time spent in glucose range of ≥70 to 
≤180 mg/dL (≥3.9 to ≤10 mmol/L) at Week 12, assessed from CGM measurements obtained 
from Weeks 10 to 12. 
For this criterion of percent time in range, there is no predefined non-inferiority margin. 
A relative non-inferiority margin of 10% is considered. 
Let m1 and m0 be the true means for the Toujeo and Tresiba groups, respectively. 
The non-inferiority null hypothesis would be H0: m1-m0 ≤ -0.1*m0 or H0: m1-0.9*m0 ≤0 
and the alternative hypothesis (H1): m1=m0. 
Toujeo would be considered non-inferior to Tresiba if the lower limit of the 95% confidence 
interval (CI) for the adjusted difference estimate of m1-0.9*m0 at Week 12 is > 0. 
To ensure 90% power, the sample size should satisfy: 
1.96 −(0.1 ∗𝑚0)
√1.81 ∗𝑆𝐷2
𝑛
= − 1.282 
Where -1.282 is the 10th percentile of a standard normal distribution and standard deviation 
(SD) the common SD. 
which leads to: 𝑛=
(1.96+1.282)2∗1.81∗𝑆𝐷2
(0.1∗𝑚0)2
 
Assuming a common SD of 14.7%, an average percent time in range in the Tresiba treatment 
group of 56% (value from LPS14587), no true difference between both arms under H1, and a 
relative non-inferiority of 10%, a sample size of 131 evaluable patients per treatment group 
would provide at least 90% power to show non-inferiority of Toujeo with respect to Tresiba 
on the percentage of time plasma glucose within the range of ≥70 to ≤180 mg/dL at Week 12. 
With the assumption of a non-evaluability rate of 22%, 338 patients (169 per treatment arm) 
will have to be randomized. 
 
 
Primary analysis: 
The primary endpoint (percent time in glucose range of ≥70 to ≤180 mg/dL [≥3.9 to 
≤10 mmol/L] at Week 12) using available data from the 12-week randomized period will be 
analyzed using an analysis of covariance (ANCOVA model including the fixed categorical 
effects of treatment group (Toujeo, Tresiba), randomization stratum of screening HbA1c 
(<8.0% versus ≥8.0%), as well as, the continuous fixed covariate of baseline percent time in 
range value. This procedure will provide baseline adjusted least-squares means estimates at 
Week 12 for both treatment groups, as well as, the differences of these estimates, with their 
corresponding standard errors (SEs) and 95% CI. 
To assess non-inferiority, the lower bound of the two-sided 95% CI for the adjusted difference 
estimate of m1 - 0.9*m0 at Week 12 will be compared to 0. 
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Clinical Trial Protocol 
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Non-inferiority will be demonstrated if the lower bound of the two-sided 95% CI of the 
adjusted difference estimate of m1 - 0.9*m0 at Week 12 on the intent to treat (ITT) population 
is >0. 
 
Analysis of secondary endpoints: 
The CGM endpoints will be analyzed using the same model as described for the primary 
endpoint using the ITT population. 
Change in HbA1c will be analyzed using an ANCOVA model including the fixed categorical 
effects of treatment group (Toujeo, Tresiba), as well as, the continuous fixed covariate of 
baseline HbA1c value. 
Change in FPG will be analyzed using ANCOVA model including the fixed categorical effects 
of treatment group (Toujeo, Tresiba), the randomization stratum of HbA1c at screening 
(<8.0%, ≥8.0%), as well as, the continuous fixed covariate of baseline FPG value. 
Change from baseline in 7-point SMPG profiles (preprandial and 2-hour postprandial plasma 
glucose at breakfast, lunch and dinner, and at bedtime) to Week 12 will be described by 
treatment group using mean and SD. 
To control the type I error, a hierarchical step-down testing procedure described by Hochberg 
and Tamhane (3) will be applied for the primary efficacy endpoint and the main secondary 
endpoint: 
- 
Step 1 proceeds to assess non-inferiority of Toujeo versus Tresiba on the percent time 
in range in 70-180 mg/dl, 
- 
Step 2: only if step 1 is demonstrated, then non-inferiority of Toujeo versus Tresiba on 
the glucose total CV will be tested with a relative non-inferiority margin of 10%, 
- 
Step 3: only if step 2 is demonstrated, then difference between Toujeo and Tresiba on 
the percent time in range in 70-180 mg/dl will be tested.  
No multiplicity adjustment will be made on other secondary/other efficacy variables; 95% CI 
and P-values presented for these endpoints will be done for descriptive purpose only. 
Data Monitoring Committee: No
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Clinical Trial Protocol 
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1.2 
SCHEMA 
Figure 1 - Graphical study design 
 
TOUJEO QD morning
TRESIBA QD morning
Open label treatment period: 12 weeks*
1:1
2-arms, RCT
T1DM (N =338)
Adult patients with T1 diabetes, age 
between 18 and 70 years
HbA1c  ≥7%  - ≤10%
MDI regimen with any QD basal insulin 
and rapid acting analogues
Prior basal: no TOUJEO or TRESIBA in 
the last 30 days.
R
Run-in
(stabilization of insulin regimen + 
CGM )
4 weeks 
W1 0 -W1 2 : CGM
W1 2 : 7 -po int
SMPG
Sta biliza tio n o f 
Insulin
W -4 /-3
CGM W-3 /-1
7 -po int SMPG 
(befo re R)
Screening
(1  to  2  weeks) 
Basal insulin titration: 8 weeks*
* Telephone calls to monitor insulin 
titration weekly between site visits for all 
patients, unless attending the study site for 
sensor replacement. Option to come to site 
on D(-)10 and D74 for sensor replacement. 
 
Abbreviations: CGM = continuous glucose monitoring, HbA1c = glycated hemoglobin, , MDI = multiple daily injection, R = randomized, SMPG = self-monitoring of plasma glucose, T1 diabetes = type 1 diabetes. 
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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
Procedure 
Screening 
(weeks) 
Run-in (weeks) 
 
 
Intervention period (weeks) 
Follow up 
Notes 
-6/-5 
-4 
-3 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOTc 
2 to 4 
days after 
last IMP 
dose 
Visit Windows:  
Site visits : ±3 days  
Phone call visits : 
±1 day  
relative to Visit 6 
Visita 
1 
2 
3 
4 
 
5 
 
6 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
15 
16 
 
17 
 
18b 
 
19d 
 
 
Day 
-42/-35 
-28 
-20 
-14 
-7 
1 
7 
14 
21 
28 
35 
42 
48 
56 
64 
71 
78 
84 
 
86-88 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To be repeated in 
case of rescreening 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical examination 
including height and weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, surgical and 
diabetes history 
Method of mealtime insulin 
titration 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Current method at 
screening and the one 
to be followed during 
treatment period at 
randomization 
Vital signs and body weight  
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Vital signs include 
heart rate and blood 
pressure (sitting 
position) 
Dispensation/collection of 
study diary 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
 
 
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Procedure 
Screening 
(weeks) 
Run-in (weeks) 
 
 
Intervention period (weeks) 
Follow up 
Notes 
-6/-5 
-4 
-3 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOTc 
2 to 4 
days after 
last IMP 
dose 
Visit Windows:  
Site visits : ±3 days  
Phone call visits : 
±1 day  
relative to Visit 6 
Visita 
1 
2 
3 
4 
 
5 
 
6 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
15 
16 
 
17 
 
18b 
 
19d 
 
 
Day 
-42/-35 
-28 
-20 
-14 
-7 
1 
7 
14 
21 
28 
35 
42 
48 
56 
64 
71 
78 
84 
 
86-88 
 
Dispensation of study 
intervention 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
IMP compliance check 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
Collecting and 
counting used and 
unused pens 
IRT calle 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
Randomization 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation and review of 
basal and mealtime insulin 
dose 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Prior and concomitant 
medication 
X 
X 
X 
 
 
X 
 
 
 
 
“ 
 
 
X 
 
 
 
X 
X 
X 
 
CGM device dispensation ; 
blinded CGM and training 
including insertion of CGM 
sensor  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
If required, 
Investigators can 
arrange for patient’s to 
attend the site after 
the first 10 days of 
CGM for the sensor to 
be replaced at the 
study site. 
CGM recordingf 
 
 
20days 
 
 
 
 
 
 
 
 
 
20 days 
X 
 
 
 
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Procedure 
Screening 
(weeks) 
Run-in (weeks) 
 
 
Intervention period (weeks) 
Follow up 
Notes 
-6/-5 
-4 
-3 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOTc 
2 to 4 
days after 
last IMP 
dose 
Visit Windows:  
Site visits : ±3 days  
Phone call visits : 
±1 day  
relative to Visit 6 
Visita 
1 
2 
3 
4 
 
5 
 
6 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
15 
16 
 
17 
 
18b 
 
19d 
 
 
Day 
-42/-35 
-28 
-20 
-14 
-7 
1 
7 
14 
21 
28 
35 
42 
48 
56 
64 
71 
78 
84 
 
86-88 
 
Collect CGM device and 
upload CGM data 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Upload CGM data to 
the site computer with 
QuintilesIMS Study 
Management Suite 
Software 
Training: Glucometer, SMPG 
profiles, study diary 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glucometer dispensation 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting SMPGg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Values of last 3 
measurements before 
each visit must be 
recorded in eCRF 
2hPPG  
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Regularly as 
instructed by 
investigator 
 
7-point SMPG 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
SMPG data upload to site's 
PC 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
X 
X 
Server independent 
from eCRF 
Re-training: Glucometer, 
SMPG profiles, study diary 
 
X 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
 
 
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Procedure 
Screening 
(weeks) 
Run-in (weeks) 
 
 
Intervention period (weeks) 
Follow up 
Notes 
-6/-5 
-4 
-3 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOTc 
2 to 4 
days after 
last IMP 
dose 
Visit Windows:  
Site visits : ±3 days  
Phone call visits : 
±1 day  
relative to Visit 6 
Visita 
1 
2 
3 
4 
 
5 
 
6 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
15 
16 
 
17 
 
18b 
 
19d 
 
 
Day 
-42/-35 
-28 
-20 
-14 
-7 
1 
7 
14 
21 
28 
35 
42 
48 
56 
64 
71 
78 
84 
 
86-88 
 
HbA1c, FPG 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Xh 
X 
 
Central lab 
h:In case of premature 
EOT, : HbA1c, FPG to 
be measured  at 
Week 12 
C-peptide 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Central lab 
 
Hematology, clinical 
chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
See Appendix 2, 
Section 10.2 
Pregnancy test (WOCBP 
only) 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Serum pregnancy test 
for screening; urine 
pregnancy test for 
subsequent 
monitoring (if positive 
to be confirmed by a 
serum test). 
AE/SAE 
To be assessed and reported if any throughout the study 
 
Hypoglycemia recording 
To be assessed and reported if any throughout the study 
 
DTSQs 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
DTSQc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
MOS-sleep 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
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Procedure 
Screening 
(weeks) 
Run-in (weeks) 
 
 
Intervention period (weeks) 
Follow up 
Notes 
-6/-5 
-4 
-3 
-2 
-1 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
EOTc 
2 to 4 
days after 
last IMP 
dose 
Visit Windows:  
Site visits : ±3 days  
Phone call visits : 
±1 day  
relative to Visit 6 
Visita 
1 
2 
3 
4 
 
5 
 
6 
7 
 
8 
 
9 
 
10 
 
11 
 
12 
 
13 
 
14 
15 
16 
 
17 
 
18b 
 
19d 
 
 
Day 
-42/-35 
-28 
-20 
-14 
-7 
1 
7 
14 
21 
28 
35 
42 
48 
56 
64 
71 
78 
84 
 
86-88 
 
WPAI 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
a Telephone calls to monitor insulin titration should be scheduled by the Investigator for Weekly in between of site visits for all patients, unless the patient is attending the study site for sensor replacement. Option to 
come to site on D-10 and D74 for sensor replacement. 
b Visit 18 will occur at Week 12 regardless of the treatment end date, and procedures ticked below should be done 
c EOT (End Of Treatment) visit will occur in case of premature discontinuation of study treatment before Visit 18 at week 12 and related procedures ticked below should be applied. If at the time of such premature 
discontinuation there is ongoing CGM recording, it should be completed, and EoT vist done thereafter. Afterward, the patients should continue in the study up to the scheduled date of study completion. See 
Section 7.1 
d If EOT visit occurs beyond 2 to 4 days after last administration of study drug then Visit 8 will not be required. EOT and safety follow up can be done at the same time, if occurs within 2 to 4 days after last IMP dose. 
e The Investigator should contact IRT either at Visit 18 or  at EOT visit in case of premature end of treatment (whichever occurs first), to register end of treatment. 
f 
For each 20 day CGM period to be fully evaluable for CGM it is necessary to obtain a minimum of 10 days (not necessarily consecutive) of useable CGM data. Useable CGM data for a day/a 24-hour CGM profile 
are defined as: at least 80% time of records per 24 hours; no gap (missing data) lasting for ≥2 hours per 24 hours besides the warm-up time for the sensor after insertion. 
g SMPG to be performed by the patients from run-in period and throughout the study duration: 
1. 
Fasting (pre-breakfast/pre-injection) SMPG: daily until dose stabilization of basal insulin has been completed and fasting SMPG goal is reached. Thereafter, the number of fasting SMPG checks can be 
reduced according to the Investigator’s judgment, however at least 3 fasting (pre-breakfast) SMPG measurements per week should be done. 
2. 
SMPG values throughout the study, starting after Visit 2. Patients should test their SMPG following the Investigator’s instructions for mealtime insulin titration. 
3. 
2hPPG (post prandial plasma glucose); regularly as instructed by investigator to guide meal time insulin titration;  
4. 
7-point SMPG profile (before and 2 hours after breakfast, lunch and dinner, and at bedtime): at least ONE day during the week that precedes Visits 6  and 18 
Patients should be instructed to self-assess plasma glucose levels whenever they experience any symptoms of hypoglycemia; see ‘SMPG during symptomatic hypoglycemia’ in Section 8.1.4 for further 
instructions. 
 
Abbreviations: AE = adverse event, FPG = fasting plasma glucose, HbA1c = glycated hemoglobin, IMP = investigational medicinal product, IRT= interactive response technology, CGM = continuous glucose 
monitoring, EOT = end of treatment, PC = personal computer, R = randomization, SMPG = self-monitoring of plasma glucose, SAE = serious adverse event, WOCBP = women of childbearing potential.
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2 
INTRODUCTION 
The fluctuations in blood glucose, regular short-duration periods of hyperglycemia and 
hypoglycemia, which are not detected by the measurements of HbA1c, may possibly contribute to 
vascular pathological processes and diabetic complications. This association may be independent 
of average glucose exposure expressed by HbA1c. This hypothesis remains controversial, but 
stems from the observation that intensive (versus standard) glucose control in the diabetes control 
and complications trial (DCCT) was associated with reduced risk for retinopathy after correcting 
for HbA1c (4). Supportive observations report that the coefficient of variation (CV) of fasting 
plasma glucose (FPG) independently predicted mortality in type 2 diabetes mellitus (T2DM) (5). 
Potential mechanisms that might link oscillating blood glucose with vascular pathology include 
oxidative stress and inflammatory processes, with enhanced apoptosis of vascular endothelial 
cells (6). 
2.1 
STUDY RATIONALE 
In registration trials (EDITION and BEGIN), both Toujeo and Tresiba took Lantus as active 
comparator and demonstrated comparable efficacy and lower hypoglycemia risk. Toujeo and 
Tresiba are both described to have advantages over Lantus in their PK and PD profiles after once 
daily dosing regimens by providing a flatter fluctuation of PK exposure and a more evenly 
distributed GIR, which is considered desirable for a basal insulin. 
The present study LPS14947 is designed to further explore similarities and differences between 
Toujeo and Tresiba in terms of the effect on continuous glucose profile, while the conventional 
glycemic control as measured by HbA1c is anticipated to be similar between the 2 treatments. 
2.2 
BACKGROUND 
Insulin glargine U300 (HOE901-U300) is a more concentrated formulation of insulin glargine 
U100 (HOE901), 21A-Gly-31B-32B-Di-Arg human insulin, a recombinant analog of human 
insulin providing a 24 hour basal insulin supply after a single-dose SC injection. Insulin glargine 
U100 has been marketed as Lantus® for more than 15 years. Its efficacy and safety are 
well-known through extensive data collection involving over 100 000 patients in clinical studies, 
including randomized, controlled clinical trials and the results of post marketing surveillance 
arising from approximately 30 million patient-years of clinical experience. The more sustained 
release of insulin glargine Toujeo (insulin glargine U300) compared to insulin glargine 100 U/mL 
is attributable to the reduction of the injection volume by two thirds that results in a smaller 
precipitate surface area. Further information on Toujeo, including important clinical trials 
performed pre and post registration, can be found in the National Product Label (7). 
As observed in euglycemic clamp studies in patients with type 1 diabetes (PKD10086, PKD11627 
and TDR11626) after a single dose or multiple doses in healthy subjects or patients with T1DM, 
there are differences between Lantus and Toujeo in PK/PD profiles. The prolonged and flatter 
profile of the glucose-lowering activity of Toujeo (up to 36 hours) results in more constant 
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glycemic control within a 24 hour injection interval and beyond, resulting in less circadian 
fluctuation in blood glucose levels and affording greater flexibility in dosing time (1). Given these 
features of the PK/PD profiles, Toujeo is considered to be well suitable for constant, peakless 
24-hour basal insulin supply in diabetes management, with the expectation of less hypoglycemic 
risk at equal to tighter blood glucose control. 
Clinical implication of Toujeo in management of type 1 diabetes was investigated in clinical 
studies in patients with T1DM. The EDITION-4 phase 3 trial in patients with T1DM showed 
similar therapeutic efficacy between Toujeo and Lantus with respect to glucose lowering, while a 
slightly lower risk of hypoglycemia was observed for Toujeo. Confirmed or severe nocturnal 
hypoglycemia was generally lower with Toujeo compared with Lantus, the incidence of 
confirmed or severe hypoglycemia at any time of day was equal or lower (8). 
PDY12777 was a small-scale (59 patients divided into 4-treatment arms) exploratory study using 
continuous glucose monitoring system (CGM), which provided sufficient data for diurnal glucose 
patterns associated with Toujeo or Lantus treatment. CGM analysis in participants with T1DM 
showed better glucose stability and lower intra-patient glucose variability with Toujeo than 
Lantus. These differences were more evident with the morning injection regimen. Moreover, the 
incidence of confirmed or severe hypoglycemic events was numerically lower with Toujeo than 
with Lantus. However, neither of the two studies was sufficiently powered to demonstrate reduced 
rates of hypoglycemia with Toujeo (9). 
Tresiba is a basal insulin that forms soluble multi-hexamers upon subcutaneous injection, 
resulting in a depot from which insulin degludec is continuously and slowly absorbed into the 
circulation leading to a flat and stable glucose-lowering-effect. During a period of 24 hours with 
once-daily treatment, the glucose-lowering effect of Tresiba, was evenly distributed between the 
first and second 12 hours. This recombinant analog of human insulin provides basal insulin supply 
beyond 42 hours after injection in euglycemic clamp conditions in type 1 diabetes (2).  
It has been approved in the US, European Union, Japan and other parts of the world. Further 
information on Tresiba can be found in the National Product Label (10). 
The efficacy and safety of Tresiba were demonstrated in BEGIN program. The impact of Tresiba 
on HbA1c was comparable with insulin Lantus but with reduced risk of hypoglycemia mainly 
during the protocol defined nocturnal period (11). 
A trial comparing the efficacy of insulin degludec with insulin glargine on glycemic control using 
CGM in patients with type 1 diabetes has shown that time within the glycemic target range 
(>70 mg/dL [>3.9 mmol/L] and <130 mg/dL [<7.2 mmol/L]) measured by CGM in the last 
4 hours of each dosing interval during the last 2 weeks of the 6-week treatment period was 
1.39 hours (SD 0.71) and 1.09 hours (0.77) respectively in insulin degludec and insulin glargine 
U100 arms respectively (12). 
Study LPS14585 compared the PD and PK properties of 0.4 and 0.6 U/kg/day insulin glargine 
(Toujeo) with the same dose levels of insulin degludec (Tresiba). At a dose level of 0.4 U/kg/day 
at steady state, the individual fluctuations of the glucose infusion rate (GIR) over the dosing 
interval of 24 hours (GIR-smFL0-24) were significantly lower following treatment with Toujeo 
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compared to insulin degludec. The point estimate (90% CI) for the ratio of the PD parameter 
GIR-smFL0-24 for Toujeo versus insulin degludec was 0.80 (0.66 to 0.96) with a corresponding 
p-value of 0.047, indicating 20% less within-day variability of the glucodynamic profile for 
Toujeo versus insulin degludec in this clinically relevant dose (0.4 U/kg/day) for T1DM patients. 
In a recent comparative RCT (BRIGHT trial) where Toujeo was directly compared to Tresiba in 
previously insulin-naïve patients with T2DM, non-inferiority was shown in efficacy while 
hypoglycemia was found to be lower for Toujeo in the insulin titration period (week 0-12) with 
comparable rates in the maintenance period (week 13-24) (13). 
2.3 
BENEFIT/RISK ASSESSMENT 
Within the context of this Phase 4 study, a favorable risk-benefit assessment for the 
Investigational medicinal products (IMPs) (Toujeo and Tresiba) is already well established. The 
use of both drugs in this study is according to the approved National Product Label. 
With the exception of minimal laboratory assessments at screening, the study procedures 
(including the use of CGM) are consistent with the standard-of-care for these patients. The risks 
arising from the minimal blood sampling required by the protocol and also for the CGM sensor 
placement (limited to infrequent occurrence of local skin reaction) are low. 
Potential benefits to participants arise from the opportunity for treatment optimization and the 
availability of the CGM data following unblinding. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of Toujeo and Tresiba may be found in the Summary of Product Characteristics. 
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3 
OBJECTIVES AND ENDPOINTS 
Table 1 - Objectives and endpoints 
Objectives 
Endpoints 
Primary 
To demonstrate the noninferiority of insulin glargine 300 U/mL 
in comparison to insulin degludec 100 U/mL on glycemic 
control and variability in participants with diabetes mellitus 
Percent time in glucose range of ≥70 to ≤180 mg/dL (≥3.9 to 
≤10 mmol/L) at Week 12, obtained using continuous glucose 
monitoring (CGM) 
Secondary 
To evaluate the glycemic control and variability parameters in 
each treatment group at Week 12 using CGM 
At Week 12, the following endpoints will be assessed: 
 
Glucose total CV  
 
Glucose within-day and between-day CV  
Other secondary endpoints: 
 
Change from baseline to Week 12 in HbA1c 
 
Change from baseline to Week 12 in central lab FPG 
 
Percent time and mean hours per day with 
glucose<70mg/dL (on all time and during the night 
[00:00 to 05:59]) 
 
Percent time and mean hours per day with 
glucose>180mg/dL 
To evaluate the safety of insulin glargine 300 U/mL in 
comparison to insulin degludec 100 U/mL  
Number of participants with adverse events (see Section 8.3)  
Number of participants with at least one hypoglycemic event 
from baseline to Week 12 
Number of hypoglycemic events per participant year from 
baseline to Week 12 
Tertiary/exploratory 
To explore the glycemic control and variability parameters in 
each treatment group at Week 12 using CGM 
Mean hours per day in the glucose range of ≥70 to ≤180 mg/dL 
(≥3.9 to ≤10 mmol/L) 
Percent time and mean hours per day in the glucose range of 
≥70 to ≤140 mg/dL (≥3.9 to ≤7.8 mmol/L) (on all-time and 
during the night [00:00 to 05:59]) 
Nocturnal percent time in glucose range of ≥70 to ≤180 mg/dL 
(≥3.9 to ≤10 mmol/L) at Week 12, obtained using CGM 
Percent time and mean hours per day with glucose: <54 mg/dL, 
(on all time and during the night [00:00 to 05:59]) 
Percent time with glucose <70 mg/dL within the 12 hours after 
basal insulin injection 
Percent time and mean hours per day with glucose >250 mg/dL 
Mean glucose profile over 24-hour period 
24h-AUC 
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Objectives 
Endpoints 
Daily insulin doses (total daily insulin, total basal insulin, total 
bolus insulin, ratio of basal to bolus insulin dose) in units and 
U/kg body weight 
Change from baseline to week 12 in patient-reported outcomes 
(treatment satisfaction, sleep quality and quantity, and 
productivity)  
7-point SMPG profiles (preprandial and 2-hour postprandial 
plasma glucose at breakfast, lunch dinner and bedtime) at 
Week 12 and change in 7-point SMPG profiles from baseline to 
Week 12 
3.1 
APPROPRIATENESS OF MEASUREMENTS 
The primary efficacy endpoint is based on the CGM recording to be collected during 
Weeks 10-12, representing the last 3 weeks of the 12 week IMP (either Toujeo or Tresiba) 
treatment period by which time stable doses are anticipated (ie, IMP titration phase expected to be 
up to Week 8, see Section 6.6.1.2). 
Secondary analyses will be performed to evaluate the therapeutic feature of a flatter and longer 
duration of Toujeo compared to Tresiba over at least 24 hours, which should result in more 
sustained glycemic control, and less hypoglycemia during nighttime. The assessment will be 
measured by the secondary and exploratory endpoints of: the incidence rate of nocturnal 
documented symptomatic hypoglycemia, and the variability analyses of CGM profiles. 
The CGM system allows frequent glucose measurements (every 5 minutes) and the ability to 
analyze glucose distributions in real time (14, 15). Use of this approach in a clinical study 
provides the opportunity to better understand glucose metabolism associated with the study IMP. 
This approach has been employed previously in studies of the efficacy of long-acting insulins in 
patients with diabetes. 
Mealtime insulin titration will also be implemented to achieve the postprandial SMPG targets. 
Thus, the glycemic control measured by laboratory HbA1c and FPG at Week 12 is expected to be 
similar between the two treatments.  
Frequent SMPG assessment values will be used to guide the insulin dose titration and to support 
the analyses of 7-point SMPG profile and hypoglycemia reports. At Visits 6, 14, 15 and 18 the 
SMPG data will be uploaded from the glucometer onto the site computer so that the Investigator 
and study staff are able to check the patient’s comprehension and compliance with dose 
adjustments and diary completion and to identify potential non-reported episodes of 
hypoglycemia. Safety analyses include a thorough hypoglycemia analysis on incidence rate, 
proportion of patients with hypoglycemia and the diurnal distribution of hypoglycemia. These 
analyses will be performed based on the SMPG and the hypoglycemic events reported by the 
patients. Patients will be instructed to measure SMPG whenever they feel hypoglycemic. This 
aims to detect and confirm as many hypoglycemic episodes as possible. 
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Sponsor will implement the monitoring of titration for both basal and meal time insulins to ensure 
optimal dosing.  
Patient-Reported Outcomes (PRO):  
Patients will complete self-reported questionnaires at designated time points in the study: 
The Diabetes Treatment Satisfaction Questionnaire Status and Change Versions (DTSQs and 
DTSQc, respectively) (16, 17) will be used to evaluate patient satisfaction with treatment and 
patient perception of blood glucose control over a several-week period.  
The MOS Sleep questionnaire will be used to measure patient perception on key aspects of sleep 
(18). The WPAI will be used to measure absenteeism, presenteeism and work productivity (19).  
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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a multicenter, randomized, active-controlled, parallel-group, 12-week open-label study. 
The study consists of a 1- or 2–week screening period, followed by a 4-week run-in period, and a 
12-week randomized treatment period. 
During the first 2 weeks of the run-in period (Weeks -4 and -3), patients will undergo treatment 
stabilization of their current basal and mealtime insulin treatment, and will be trained and tested 
on how to perform study-related procedures. During the (-)3 – (-)1 weeks of run-in, patients will 
wear a CGM device, blinded both to patients and Investigators. This will be the baseline CGM 
period, when during 20 consecutive days, a minimum of (10 days, not necessarily consecutive) of 
useable CGM data must be generated, to be eligible for randomization. 
Patients satisfying the study inclusion/exclusion criteria (including CGM performance 
requirements) will be randomized in a 1:1 ratio to morning injections of either Toujeo or Tresiba, 
which will replace the patient’s current basal insulin. 
An interactive response technology (IRT) will be configured and randomization will be stratified 
by HbA1c at screening (<8.0%; ≥8.0%). 
During the randomized treatment period, CGM data (blinded to both patients and Investigators) 
will be collected during Weeks 9-12 during 20 consecutive days. 
The basal insulin injection will be once daily in the morning, defined as the time period between 
waking up and breakfast. The injection time will be discussed between the Investigators and 
patients at randomization and should be kept consistent at the same time each day. 
During the entire study starting after the screening period, patients will perform SMPG as 
specified in the study flow chart. The SMPG readings will be used to guide insulin dose titration 
for optimal glycemic control.  
Appropriate dose titration of basal and mealtime insulin will be implemented as described in the 
dose regimen section. 
At the end of the study, the patients will be followed-up from 2 to 4 days after last IMP dose to 
collect posttreatment safety information. 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The fluctuations in blood glucose, regular short-duration periods of hyperglycemia and 
hypoglycemia, which are not detected by the measurements of HbA1c, may possibly contribute to 
vascular pathological processes and diabetic complications. This association may be independent 
of average glucose exposure expressed by HbA1c. This hypothesis remains controversial, but 
stems from the observation that intensive (versus standard) glucose control in the DCCT was 
associated with reduced risk for retinopathy after correcting for HbA1c (4). Supportive 
observations report that the coefficient of variation of FPG independently predicted mortality in 
T2DM (5). Potential mechanisms that might link oscillating blood glucose with vascular 
pathology include oxidative stress and inflammatory processes, with enhanced apoptosis of 
vascular endothelial cells (6). 
This is a randomized, active-controlled, 12-week open-label study to compare the efficacy of 
Toujeo with Tresiba using CGM glucose profiles, sampling ambulatory glucose level every 
5-minutes over a 20-day period at Week 12. The CGM during study period will be blinded to both 
the Investigators and patients. 
Eligible patients will be randomized to either Toujeo or Tresiba, both given once-daily by SC 
injection in the morning. Patients allocated to Toujeo or Tresiba groups will switch from their 
previous basal insulin. During 4 weeks of the run-in period, patients will be required to titrate 
their basal and mealtime insulin to optimize the fasting and 2-hour postprandial self-monitoring of 
plasma glucose (SMPG) targets. The baseline CGM will be performed during the last 3 weeks of 
run-in.  
The primary objective of the study is to explore the percent of time in target CGM glucose range 
of 70-180 mg/dL with Toujeo versus Tresiba treatment at 12 weeks of treatment. In addition, all 
hypoglycemia incidence and distribution (24 hours and nocturnal) will be analyzed according to 
the American Diabetes Association (ADA) classification (severe, documented symptomatic, 
asymptomatic, probable and relative) (20). Glucose stability and variability will be assessed 
between and within each group via measurements of glucose CV. 
A relatively homogenous patient population will be selected, reducing potential confounding 
effects, so that the true differences in the therapeutic effects of Toujeo versus Tresiba can be 
assessed. The study population includes patients 18-70 years of age with T1DM, on a basal plus 
mealtime insulin regimen for at least one year, and HbA1c level ≥7% and <10%. Patients must be 
on a stable dose of basal/bolus insulin regimen for 30 days before screening. 
Repeat assessments of selected PROs will be performed during the study as the exploratory 
analyses (including patient satisfaction with treatment and patient perception of blood glucose 
control assessed by Diabetes Treatment Satisfaction Questionnaire [status and change 
version - DTSQs and DTSQc], MOS Sleep Scale to measure key aspects of sleep and the Work 
Productivity and Activity Impairment Questionnaire [WPAI]- Diabetes; assessing the impairment 
on daily work and activities due to diabetes) in order to reveal any potential link between 
improvement in continues glucose profile and patient well-being. 
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4.3 
JUSTIFICATION FOR DOSE 
During the first 2 weeks of the run-in period (Weeks -4 and -3), patients will be required to titrate 
their basal and mealtime insulin to stabilize the fasting and 2-hour postprandial SMPG targets of 
≥70 to <100 mg/dL (≥3.9 to <5.6 mmol/L) while avoiding hypoglycemia episodes. 
At randomization, the initiation doses of Toujeo and Tresiba will be the patient’s current doses of 
their basal insulin on a unit-to-unit basis. 
Dose adjustments will be based on a median of fasting SMPG values from the last 3 days, which 
will include the value measured on the day of titration, measured by the patient using glucometers 
and accessories supplied by the Sponsor. Appropriate dose titration of IMP and mealtime insulin 
is expected to be up to Week 8. 
During the randomized treatment period, IMP injection will be administered once daily each 
morning at the same time. 
4.4 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he/she has completed all phases of the 
study including a 2 to 4 day follow-up period. 
The end of the study is defined as the date of the “last patient last visit” planned with the protocol, 
including the follow-up visit. 
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5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be 18 to 70 years of age inclusive, at the time of signing the informed 
consent. 
Type of participant and disease characteristics 
I 02. Participants with T1DM. 
I 03. Participants treated with multiple daily injections (MDI) using basal insulin analog once 
daily and rapid acting insulin analogs for at least one year. 
I 04. HbA1c ≥7% (48 mmol/mol) and ≤ 10% (86 mmol/mol) at screening. 
Sex 
I 05. Male or Female 
a) Female participants: A female participant is eligible to participate if she is not pregnant 
(see Appendix 4 [Section 10.4]), not breastfeeding, and at least one of the following 
conditions applies: 
- 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4), 
OR 
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 (Section 10.4) 
during the intervention period. 
Informed Consent 
I 06. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1.2) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. 
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5.2 
EXCLUSION CRITERIA  
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Any clinically significant abnormality identified either in medical history or during 
screening evaluation (eg, physical examination, laboratory tests, ECG, vital signs) , or any 
AE during screening period which, in the judgment of the investigator, would preclude 
safe completion of the study or constrains efficacy assessment. 
E 02. End stage renal disease defined as estimated glomerular filtration rate (GFR) modification 
of diet in renal disease (MDRD) <15 mL/min/1.73 m² or on renal replacement treatment. 
E 03. Laboratory findings at screening: 
 
ALT or AST >3 x ULN or total bilirubin >1.5 x ULN (except in case of documented 
Gilbert’s syndrome). 
 
Fasting C-peptide >0.2 nmol/L. 
E 04. Retinopathy or maculopathy with one of the following treatments, either recent (within 
3 months prior to screening) or planned: intravitreal injections or laser or vitrectomy 
surgery. 
E 05. Body weight change ≥5 kg within 3 months prior to screening 
Prior/concomitant therapy 
E 06. Participants not on stable dose of basal insulin analog (±20% total daily dose) for at least 
30 days prior to screening. 
E 07. Participants having received Toujeo or Tresiba as basal insulin within 30 days prior to 
screening. 
E 08. Participants not using the same insulins (both basal and rapid) within 30 days prior to 
screening. 
E 09. Participants having received basal insulin dose ≥0.6 U/kg body weight within 30 days prior 
to screening. 
E 10. Participants having received any glucose lowering drugs (including any premixed insulins, 
human regular insulin as mealtime insulins, any others injectable or oral), other than basal 
and rapid insulin analogs, within 3 months prior to screening. 
E 11. Participants having received glucocorticoids (excluding topical application or inhaled 
form) for more than 10 days within 3 months prior to screening. 
E 12. Participants having used insulin pump within 6 months prior to screening. 
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E 13. Participants who will need real time, flash or implantable CGM for routine care any time 
during study participation. 
Prior/concurrent clinical study experience 
E 14. Exposure to any investigational drug in the last 4 weeks or 5 half-lives, whichever is 
longer, prior to screening or concomitant enrollment in any other clinical study involving 
an investigational study treatment. 
Diagnostic assessments 
Not applicable. 
Other exclusions 
E 15. Any contraindication to use of Toujeo, Tresiba and rapid insulin analogs according to the 
national product label. 
E 16. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
E 17. Night shift workers. 
E 18. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or subjects who are legally institutionalized. 
E 19. Participants dependent on the Sponsor or Investigator (in conjunction with section 1.61 of 
the ICH-GCP Ordinance E6). 
E 20. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
Additional criteria at the end of the run-in period 
E 21. Participants unwilling or unable to comply with study procedures as outlined in the 
protocol. 
E 22. Participants who withdraw consent during the screening (starting from signed ICF). 
E 23. Inappropriate CGM use during run-in period evidenced by failure to obtain a minimum of 
(10 days, not necessarily consecutive) of useable CGM data by the end of run-in (see 
Section 8.1.1.2 for the definition of useable CGM data). 
5.3 
LIFESTYLE CONSIDERATIONS 
Lifestyle and diet therapy provided before the time of screening is to be continued during the 
study. Dietary and lifestyle counseling will be given by a healthcare professional and compliance 
will be checked as per SoA (Section 1.3) and should be consistent with international or local 
guidelines for patients with T1DM (with regard to the distribution of calories among 
carbohydrates, proteins, and fats, exercise, etc).  
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5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond 
to queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened in cases where original screen failure was due to reasons expected to change at 
rescreening and based upon the Investigator’s clinical judgment. Rescreened patients will be 
subject to the screening visit procedures/assessments (see following paragraphs) including new 
informed consent signed and allocation of a new patient number. 
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6 
STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED 
Table 2 - Overview of study interventions administered 
Study 
intervention name 
Toujeo 
Tresiba 
Dosage formulation 
Toujeo (insulin glargine 300 U/mL) is supplied as 
a sterile, non-pyrogenic, clear, colorless solution 
for SC injection in the Toujeo SoloStar prefilled, 
disposable pen. 
Tresiba (insulin degludec 100 U/mL) is supplied 
as a sterile, non-pyrogenic, clear, colorless 
solution for SC injection in the marketed Tresiba 
FlexTouch prefilled, disposable pen. 
Unit dose 
strength(s)/Dosage 
level(s) 
Each Toujeo SoloStar contains in total 450 units 
of insulin glargine (1.5 mL of 300 U/mL insulin 
glargine solution). Mixing of Toujeo with other 
insulin products or dilution is not allowed 
Each Tresiba FlexTouch contains in total 
300 units of insulin degludec (3 mL of 100 U/mL 
insulin degludec solution). Mixing of Tresiba with 
other insulin products or dilution is not allowed. 
Route of administration 
SC self-injection 
SC self-injection 
Dosing instructions 
Toujeo will be self-administered by SC injection 
once daily in the morninga, which is defined as 
the time period between waking up and 
prebreakfast. The clock time for the morning 
injection (hh:mm) will be established at the 
discretion of the patient/Investigator at the time of 
randomization and will be maintained for the 
duration of the study. 
Injection site should be alternated between the 
left and right anterolateral and left and right 
posterolateral abdominal wall or thighs or upper 
armsb.  
Tresiba will be self-administered by SC injection 
once daily in the morninga, which is defined as 
the time period between waking up and 
prebreakfast. The clock time for the morning 
injection (hh:mm) will be established at the 
discretion of the patient/Investigator at the time 
of randomization and will be maintained for the 
duration of the study. 
Injection site should be alternated between the 
left and right anterolateral and left and right 
posterolateral abdominal wall or thighs or upper 
armsb.  
Packaging and labeling 
Toujeo SoloStar pens will be supplied as open 
label treatment kits containing 5 Toujeo SoloStar 
pens. Each SoloStar pen will be labeled as 
required per country requirement. Treatment 
labels will indicate the treatment number used for 
treatment allocation. The Investigator’s name, the 
patient number and visit number will be entered 
manually by the site staff on the treatment box 
label prior to dispensing. 
Tresiba FlexTouch pens will be supplied as open 
label treatment kits containing 5 Tresiba 
FlexTouch pens. Each FlexTouch pen will be 
labeled as required per country requirement. 
Treatment labels will indicate the treatment 
number used for treatment allocation. The 
Investigator’s name, the patient number and visit 
number will be entered manually by the site staff 
on the treatment box label prior to dispensing. 
a Patients taking their current basal insulin at any time (eg, evening) other than in the morning should switch their injection time to the morning 
at randomization. The instruction on changing injection time should be given by the Investigator in accordance with the National Product 
Label of the patient’s current basal insulin. On the day of switching injection time, the total dose of current basal insulin and the pre breakfast 
(if applicable) rapid action insulin may need to be reduced based on the physician’s medical judgment. For example, on the day before 
changing injection time, the dose of the current basal insulin may be changed to approximately 1/2 to 2/3 of the total daily dose, which would 
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then be injected in the evening as the patient’s usual injection time. On the following day, the dose of randomly assigned basal insulin (IMP) 
will be equal to the total daily current basal insulin dose and injected in the morning before breakfast. 
b Within a given area, location should be changed (rotated) at each time to prevent injection site skin reactions.The injection sites for IMP and 
noninvestigational medicinal product (NIMP) should be different so that, if any, an injection site reaction can be attributed specifically either to 
IMP (Toujeo or Tresiba) or NIMP (mealtime insulin). 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
An instruction leaflet, which explains how to use the disposable pen and needles, will be provided 
for Toujeo and Tresiba. All patients will be trained by study staff at Visit 6 (randomization) on 
how to use the pen correctly, how to rotate injection site to avoid skin reactions, how to store the 
pen and how to change the needle. Training will be repeated as often as deemed necessary by 
study site staff during the treatment period. For the duration of the treatment, patients will be 
required to use the same type of study drug disposable pens and needles. Each patient will be 
supplied with the appropriate number of pens according to the dispensing scheme indicated in the 
SoA (see Section 1.2). 
Toujeo (insulin glargine 300 U/mL) 
Toujeo will be self-administered with the prefilled, disposable Toujeo SoloStar pen specifically 
labeled for use in the study. This pen allows dose setting in the range of 1–80 units with minimum 
of 1 unit increment. The dose of Toujeo is titrated according to the patient’s need for insulin 
glargine. 
The following pen needles will be provided for use with the disposable injection pen devices: 
 
BD Ultra Fine Needles 31 G x 5 mm. 
 
BD Ultra Fine Needles 31 G x 8 mm. 
Tresiba (insulin degludec 100 U/mL) 
Tresiba will be self-administered with the prefilled, disposable Tresiba FlexTouch pen specifically 
labeled for use in this study. This pen allows dose setting in the range of 1–80 units with 
minimum of 1 unit increment. The dose of Tresiba is titrated according to the patient’s need for 
insulin degludec 
The following pen needles will be provided for use with the disposable injection pen devices: 
 
BD Ultra Fine Needles 31 G x 5 mm. 
 
BD Ultra Fine Needles 31 G x 8 mm. 
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NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
The protocol-mandated background therapy is mealtime insulin analog, ie, rapid insulin analogs 
(eg, insulin glulisine, insulin lispro or insulin aspart). Patients in both treatment groups will 
continue with their short-acting mealtime insulin analogue which has been used for at least 
30 days before the screening visit and which will be continued throughout the study. The cost of 
the mealtime insulin analogue may be reimbursed if not covered by health insurance and if 
allowed by local regulations. Alternatively, the sponsor provided insulin glulisine may be offered. 
Dose adjustment of mealtime insulin can be based on a pattern of post-meal SMPG data from the 
prior 3 days (simple titration) OR the carbohydrate content of the meal. The injection sites should 
be different from the IMP (Toujeo or Tresiba) for the fast-acting mealtime insulin analogs so that 
any injection site reactions can be attributed specifically either to the fast-acting insulin or to the 
IMP. Changes in the body areas used for injection of basal (current during run-in or IMP during 
the randomized treatment period) and mealtime insulin should be avoided as far as possible during 
the study. 
6.1.1 Devices 
CGM  
Dexcom G6 device will be used for continuous glucose monitoring. 
 
Glucometers  
Roche Accucheck glucometers will be provided and used for SMPG measurements by patients.  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
Investigators or other authorized persons (eg, Pharmacists) are responsible for storing the 
IMP/NIMP in a secure and safe place in accordance with local regulations, labeling specifications, 
policies, and procedures. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance with 
the labeled storage conditions with access limited to the Investigator and authorized site staff. 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records). 
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Any quality issue noticed with the receipt or use of an IMP/NIMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure (see  
Section 8.3.6). 
A potential defect in the quality of IMP/NIMP/device may be subject to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor, in order to recall the IMP/NIMP/device and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP/device to a third party (except for 
DTP shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP/NIMP/device to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP/device in any other manner. 
The expiry date is mentioned on the IMPs labels, and storage conditions are written on the IMPs 
labels and in the instruction leaflet. Patients are responsible for the correct storage of “not in-use” 
and “in-use” pens after it is dispensed at the site. 
All used, partially-used or unused treatments will be retrieved by the Sponsor. A detailed 
treatment log of the returned IMP will be established with the Investigator (or the Pharmacist) and 
countersigned by the Investigator and the monitoring team. 
The Investigator will not destroy any IMP unless the Sponsor provides written authorization.  
A potential defect in the quality of IMP may initiate a recall procedure by the Sponsor. In this 
case, the Investigator will be responsible for promptly addressing any request made by the 
Sponsor, in order to recall IMP and eliminate potential hazards. 
As NIMP will not be provided by the Sponsor, return and destruction will not be required. The 
cost of the mealtime insulin analogue may be reimbursed if not covered by health insurance and if 
allowed by local regulations. Alternatively, the sponsor provided insulin glulisine may be offered. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
As Toujeo and the control drug Tresiba are distinguishable, this study is an open-label design, and 
no attempt will be made to blind the randomly assigned study treatment. 
The Clinical Supplies Trial Supply Operations Manager will provide the treatment kit number list 
and the Study Biostatistician will provide the randomization scheme to the IRT. IRT will then 
generate the patient randomization list according to which it will allocate patients to either 
treatment arm. 
The IMPs will be provided in open-label boxes and each type of kit is identified with a treatment 
number. 
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At the screening visit, the Investigator or designee will contact the IRT center to receive the 
patient number. This patient number is composed of a 12-digit number containing the 3-digit 
country code, 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 can be re-screened once before randomization in case of non-eligibility or in cases where 
original screen failure was due to reasons expected to change at rescreening and based upon the 
Investigator’s clinical judgment. Re-screened patients will be subject to the screening visit 
procedures/assessments including new informed consent signed and allocation of a new patient 
number.  
Before randomization, baseline CGM results with accompanying CGM summary report certifying 
compliance with requirements MUST be available. In order for a patient to be randomized the 
baseline CGM performance (during Weeks -3 to -1) must reflect at least 10 days (not necessarily 
consecutive) of useable 24-hour CGM data (see Section 8.1.1.2 for the definition of useable data). 
At Visit 6, only after patient eligibility is confirmed, the Investigator or designee will call the IRT 
for patient randomization and first treatment kit(s) allocation. 
Only eligible patients will be randomized at a 1:1 ratio to receive Toujeo or Tresiba for 12 weeks. 
Randomization will be stratified by HbA1c at screening (<8.0%; ≥8.0%).  
A randomized patient is defined as a patient who is registered and assigned with a randomized 
treatment arm from the IRT, as documented from IRT log file, regardless of whether the treatment 
kit was used or not. 
The IRT will be contacted at each time a treatment kit(s) allocation is necessary, ie, at Visit 6 
(randomization) and also at Visit 14.  
A patient cannot be randomized more than once to the study. 
Complete details of potential instances requiring the site to contact the IRT are provided in 
Section 1.3. 
Compensation for lack of blinding 
Given the open-label administration of study treatments (basal insulin during the treatment 
period), the assessment of outcomes will be based on objectively collected data, which will be 
blinded for CGM (primary and secondary endpoints) and open for SMPG data (secondary 
endpoints). 
Neither the patient, the Investigator nor the Sponsor will have access to the individual data for the 
primary efficacy parameter (CGM records) obtained from each patient so as to avoid patients and 
Investigators making treatment decisions based on the data for the primary endpoint. The CGM 
receiver’s screen will be blocked of displaying data. The CGM data will be uploaded to a separate 
server which assures maintenance of the blind with vendor software and a report summary with 
daily CGM performance will be available immediately. Investigators will not be able to see the 
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recorded glucose values, nor will the report include any real glucose data. However, transfers of 
CGM related to the Sponsor team will be performed during the study for data review purpose, 
with the name of the IMP treatment masked. 
The SMPG records in the patient diaries (and complete data at study visits where there is a 
download of SMPG data) enable Investigators to monitor the patients comprehension of the study 
requirements, identify unreported episodes of hypoglycemia, and also to guide the dose of basal 
(current during run-in, IMP during the randomized treatment period) and mealtime insulin dosage; 
hence these data are not blinded for the Investigator and the patient as they are required for 
managing the patient’s care during the study.  
The Sponsor study team, except individuals who have access to patients’ source documents (eg, 
local monitoring team, auditors) will remain blinded to the treatment arm of individual patients 
throughout the study up to the database lock. All analyses and data review before database lock 
will be performed blindly. Supplemental documentation will detail the exact measures to be kept 
in place to manage the risk of inadvertent unblinding of the study team. 
6.4 
STUDY INTERVENTION COMPLIANCE 
6.4.1 Drug accountability 
A Treatment Log Form for returned and dispensed IMP will be kept for each patient. Patients will 
return to the site with used and unused IMP at Visits 14 and 18. The Investigator or delegate will 
inspect IMP remaining in the returned packs and compare to dosing records documented in the 
patients’ diaries. Discrepancies will be addressed to the patient for clarification on treatment 
compliance. The Investigator will complete the appropriate Treatment Log Form based on the 
used/unused IMP (study drug pens) returned. 
6.4.2 Training to use injection devices 
An instruction leaflet, which explains how to use the disposable pen and needles, will be provided 
for Toujeo and Tresiba. All patients will be trained by study staff at Visit 6 (randomization) on 
how to use the pen correctly, how to rotate injection site to avoid skin reactions, how to store the 
pen and how to change the needle. Training will be repeated as often as deemed necessary by 
study site staff during the treatment period. For the duration of the treatment, patients will be 
required to use the same type of study drug disposable pens and needles. Each patient will be 
supplied with the appropriate number of pens according to the dispensing scheme indicated in the 
SoA (see Section 1.3). 
Patients must be reminded by study staff of the following instructions: ‘Injection pens should 
never be shared with others, even if the needle is changed. Always use a new needle for each 
injection to help ensure sterility and prevent blocked needles. Do not reuse or share needles with 
another person’.  
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6.5 
CONCOMITANT THERAPY 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
 
Reason for use. 
 
Dates of administration including start and end dates. 
 
Dosage information including dose and frequency. 
During the study, the following medications are prohibited. 
 
Any glucose-lowering agents other than: 
- 
 the IMP (Toujeo or Tresiba), 
- 
the patient’s current background basal insulin analog during the run-in period (which 
may not be changed during the study), 
- 
the patient’s existing mealtime insulin (which may not be changed during the study).  
This includes oral or injectable glucose lowering agents, other type of basal insulin 
(eg, NPH), pre-mixed insulin, and human regular insulin, 
 
Insulin pump therapy is not allowed during the course of the study. 
 
Initiation of any weight loss drugs is not allowed; previous treatment with weight loss 
drugs can be continued and doses must remain stable throughout the study. 
 
Systemic glucocorticoids for more than 10 consecutive days (topical or inhaled 
applications are allowed). 
Other medications which are unlikely to interfere with the IMP and the study variables are 
allowed as needed and discussed with the Investigator. However, doses of chronically 
administered medicines should be kept fixed during the trial if at all possible. 
6.6 
DOSE MODIFICATION 
Note: During the first 2 weeks of the run-in period, patients will be required to titrate their basal 
and mealtime insulin to stabilize the fasting and 2-hour postprandial self-monitoring of plasma 
glucose (SMPG) targets.  
6.6.1 Basal insulin 
The patient’s basal insulin dose will be titrated with the objective of reaching a target fasting 
SMPG of ≥70 to <100 mg/dL (≥3.9 to <5.6 mmol/L) while avoiding hypoglycemia episodes 
(ie, this is identical to the algorithm to be used for IMP see Section 6.6.1.2). Note: fasting SMPG 
should be taken within 30 minutes prior to injection of current basal insulin (if applicable) and 
before breakfast. 
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6.6.1.1 Starting dose 
At randomization, the initiation doses of Toujeo and Tresiba will be the patient’s current doses of 
their basal insulin on a unit-to-unit basis. 
The first injection of IMP should occur on the day of randomization (Visit 6) under the 
supervision of the Investigator or the designated study staff. If for any reason, the patient could 
not inject the first dose at the study site, the first dose can be administered in the morning of the 
next day and the date and time will be documented in the electronic case report form (eCRF) for 
randomized basal insulin (IMP). 
6.6.1.2 Dose adjustment 
6.6.1.2.1 Dose adjustments based on target fasting SMPG  
During the titration phase (expected to be up to Week 8), doses of IMP (either Toujeo or Tresiba) 
will be titrated to achieve glycemic targets without hypoglycemia according to the algorithm 
outlined in Table 3. 
The IMP dose will be titrated at least weekly (but no more often than every 3 days), until the 
patient reaches a target fasting SMPG of ≥70 to <100 mg/dL (≥3.9 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 days, which 
will include the value measured on the day of titration, measured by the patient using glucometers 
and accessories supplied by the Sponsor. 
Table 3 - Basal insulin dose adjustments 
Mediana fasting pre-breakfast SMPG values 
(last 3 days)  
Basal insulin dose adjustments (U/day)b 
≥140 mg/dL (≥ 7.8 mmol/L) 
+4 units 
≥100 and < 140 mg/dL (≥5.6 and <7.8 mmol/L) 
+2 units 
≥70 and <100 mg/dL (≥3.9 and 
<5.6 mmol/L) 
No change 
≥56 and <70 mg/dL (≥3.1 and <3.9 mmol/L) 
-2 units 
<56 mg/dL (<3.1 mmol/L) or occurrence of 2 (or more) 
symptomatic hypoglycemic episodes or 1 severe 
hypoglycemic episode 
-4 units or at the discretion of the Investigator or medically 
qualified designee 
Abbreviation: SMPG = self-monitoring of plasma glucose 
a Median refers to intermediate SMPG value (the value between the lowest and the highest SMPG values when the values are ranked in a 
growing order). 
b Prior to additional basal insulin titration, mealtime insulin should be titrated to achieve a bedtime and pre-breakfast glucose delta <50 mg/dL, 
if so considered helpful by the Investigator. 
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Regular SMPG is very important in order to achieve blood glucose targets. It is necessary to 
perform daily fasting/pre-breakfast SMPG and postprandial measurements (Section 8.1.4) to 
support the titration. More frequent SMPG at other time-point may be needed at the Investigator’s 
discretion. 
Patients will be familiarized with the adjustment schedule so that they will be able to monitor the 
dose adjustment with the assistance of the Investigator or medically qualified designee. During the 
study, contacts between the Investigator and patient are scheduled to assess the response to 
treatment and to decide on dose adjustment. During these visits, patients will report their SMPG 
data, insulin doses and hypoglycemia to the study site. 
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 their IMP insulin dose adjustments in between the scheduled visits without prior 
consultation of the site personnel. 
The best efforts should be made to reach the target glucose by 8 weeks after randomization; 
thereafter, the dose should be maintained until the end of the study. If required, minimal dose 
adjustments may be considered at the discretion of the Investigator or medically qualified 
designee to achieve fasting SMPG target.  
6.6.1.2.2 Dose adjustment in cases of hypoglycemia 
Dose adjustment in cases of hypoglycemia will be as follows (refer to Section 8.2.4 for 
hypoglycemia definitions): 
 
Upward titration is to be stopped for 1 week after a case of severe hypoglycemia 
(requiring assistance) or ≥2 episodes of documented symptomatic hypoglycemia within a 
week, unless there was a manageable factor (eg, omission of a meal or overdosed insulin) 
for the event. 
 
Doses of basal insulin (IMP during the randomized treatment period and patient’s current 
medication during the run-in period) or mealtime insulin may be reduced or modified at 
any time for hypoglycemia during the study. 
 
Small decreases of the basal insulin dose (eg, 1 unit) are at the discretion of the 
Investigator or medically qualified designee, if SMPG is below 70 mg/dL (3.9 mmol/L) or 
if relevant hypoglycemia occurs.  
 
Patients who experienced mild to moderate hypoglycemia as a result of a missed meal, 
unusual exercise or alcohol use will be counseled on the correction of those behaviors and 
should not reduce their insulin dose.  
6.6.2 Mealtime insulin 
From Visit 2, the injection time (in relation to the meal intake) and frequency of mealtime insulin 
(ie, rapid-acting insulins: insulin glulisine, insulin lispro or insulin aspart) will be at the 
Investigator’s discretion, in accordance with the relevant National Product Labels. 
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The dose of the mealtime insulin analogs will be actively titrated to achieve a target of 2-hour 
postprandial plasma glucose. The dose adjustment regimen can be titrated based on a pattern of 
postprandial plasma glucose results of SMPG from the prior 3 days (simple titration based on a 
pattern of post-meal glucose median <130/>180 mg/dL) or based on the carbohydrate content of 
the meal (carb counting).  
The titration goal is a 2-hour postprandial SMPG in the range of ≥130 to ≤180 mg/dL (≥7.2 to 
≤10 mmol/L) while avoiding hypoglycemia. For the purpose of this protocol, 2-hour postprandial 
is defined as 2 hours after the start of the meal. 
Dose of mealtime insulin will be recorded in the patient’s diary and eCRF. Note: It is essential 
that this data is captured on the day of randomization. 
While basal insulin doses are increased, mealtime insulin doses may be reduced to avoid daytime 
hypoglycemia as deemed appropriate by the Investigator. 
Appropriate adjustment in mealtime insulin will continue throughout the study (Visits 2 to 18). 
The two regimens are described in Table 4 and Table 5. 
Table 4 - Rapid-acting insulin dose adjustment 
Mealtime dose of insulin 
Pattern of postprandial plasma 
glucose values <130 mg/dLa 
Postprandial plasma glucose 
values >180 mg/dLa 
≤10 units 
Decrease dose by 1 unit 
Increase dose by 1 unit 
≥11-19 units 
Decrease dose by 2 units 
Increase dose by 2 units 
≥20 units 
Decrease dose by 3 units 
Increase dose by 3 units 
a If more than half of the mealtime plasma glucose (2-hour postprandial plasma) values for the week were above target. 
Table 5 - Carb counting: insulin-to-carbohydrate ratio 
Mealtime dose of insulin 
Pattern of postprandial plasma 
glucose values <130 mg/dLa 
Pattern of postprandial plasma 
glucose values >180 mg/dLa 
1 unit/20 g 
Decrease to 1 unit/25 g 
Increase to 1 unit/15 g 
1 unit/15 g 
Decrease to 1 unit/20 g 
Increase to 1 unit/10 g 
1 unit/10 g 
Decrease to 1 unit/15 g 
Increase to 2 unit/15 g 
2 unit/15 g 
Decrease to 1 unit/10 g 
Increase to 3 unit/15 g 
3 unit/15 g 
Decrease to 2 unit/15 g 
Increase to 4 unit/15 g 
a If more than half of the mealtime plasma glucose values for the prior 3 days were above target 
Starting recommendation 1 unit to 15 grams carbs 
Consider calculating insulin to carb (I:C) ratio = 500/total daily dose (TDD) of insulin. 
Investigators will also be provided with an initial guideline of 1800/TDD as a correction factor to be used if applicable at the Investigators’ discretion. 
Dietary modifications (eg, snacks) will be made by the Investigator, dietician or other medically 
qualified person based on his/her best judgment. 
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6.6.3 Monitoring of insulin titration 
Sponsor will ensure the adequate monitoring of basal and mealtime insulin titration. The 
monitoring will be described in the Insulin-Dosing Supervision Manual. 
6.6.4 Evaluation of participants not meeting glycemic targets 
In case the target fasting glycemic goal cannot be achieved in spite of successive IMP dose 
titration over 8 weeks, the Investigator should ensure that no reasonable explanation exists for 
insufficient glucose control and in particular that: 
 
Plasma glucose was actually measured in fasting condition (eg, before breakfast within 
30 minutes window prior to injection). 
 
IMP and mealtime insulin are properly injected. 
 
There is no inter-current disease which may jeopardize glycemic control (eg, infectious 
disease). 
 
Compliance to diet and lifestyle is appropriate. 
 
If any of the above can reasonably explain the insufficient glycemic control, the 
Investigator should take appropriate action, eg,: 
- 
Adjust the IMP dose and mealtime insulin dose, 
- 
Check the compliance of IMP and mealtime insulin injection, 
- 
Evaluate and treat intercurrent disease (to be reported in AE)/ SAE/concomitant 
medication parts of the eCRF, 
- 
Organize a specific interview with a Registered Dietician or other medically qualified 
person to discuss with the patients on the absolute need to be compliant to diet and 
lifestyle recommendations. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY 
Intervention after the end of the study treatment is at the discretion of the Investigator or other 
treating physician.  
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  
7.1.1 Definitive discontinuation 
The IMP should be continued whenever possible.  
In case the IMP is stopped, it should be determined whether the stop can be made temporarily; 
definitive IMP discontinuation should be a last resort. Any IMP discontinuation must be fully 
documented in the eCRF. In any case, the participant should remain in the study as long as 
possible. 
Definitive intervention discontinuation is any intervention discontinuation associated with the 
definitive decision from the Investigator not to re-expose the participant to the IMP at any time 
during the study, or from the participant not to be re-exposed to the IMP whatever the reason. 
List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reason(s) for treatment discontinuation and this should be documented in the eCRF. 
The patients may withdraw from treatment with IMP in case of the following: 
 
At patient’s own request, ie, withdrawal of the consent for treatment. 
 
If, in the Investigator's opinion, continuation with the administration of IMP would be 
detrimental to the patient's well-being. 
 
At the specific request of the Sponsor. 
A patient must withdraw from treatment with IMP in either of the following cases: 
 
Intercurrent condition that requires discontinuation of IMP. 
 
Pregnancy in female participants. 
 
Necessity to use prohibited therapy (see Section 6.5) 
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 
See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
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Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP (Visit 18). If 
CGM assessment is ongoing it should be completed as planned for the ongoing 2-week period. 
After that patients should remain in the study and complete all relevant scheduled study 
assessments. Whenever possible, CGM should be performed on Weeks 10 - 12, and patient return 
for the planned Visit 18. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs or for other reason.  
For all temporary treatment discontinuations, duration must be recorded by the Investigator in the 
appropriate pages of the eCRF. 
7.1.2.1 Rechallenge 
In case of treatment interruption due to an AE, reinitiation of treatment with the IMP will be done 
under close and appropriate clinical/and or laboratory monitoring once the Investigator will have 
considered according to his/her best medical judgment that the responsibility of the IMP(s) in the 
occurrence of the concerned event was unlikely and if the selection criteria for the study are still 
met (refer to Section 5.1 and Section 5.2).  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, 
compliance, or administrative reasons. 
 If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
 If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
 See SoA for data to be collected at the time of study discontinuation and follow-up and for 
any further evaluations that need to be completed. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
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The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, eg, 
medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused.  
7.3 
LOST TO FOLLOW UP 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
 
Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
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8 
STUDY ASSESSMENTS AND PROCEDURES 
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.  
 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 Continuous glucose monitoring (CGM) 
A CGM system is a device that records interstitial glucose levels continuously throughout the day 
and night via a subcutaneous sensor. During the study, patients will use the Dexcom G6® CGM 
system with software (DexCom, Inc., San Diego, CA), an approved device with single-use 
disposable electrochemical sensing elements designed for up to 10 days of continuous use with 
measurement of glucose levels in interstitial fluid in 5-minute intervals. 
All patients must use the CGM device provided by the Sponsor during the CGM collection 
periods. Additionally, patients cannot initiate personal (non-study) real time, flash or implantable 
CGM system during the study (see E 13). 
8.1.1.1 CGM performance 
Two (2) sets of CGM will be conducted by the study patients. Baseline CGM will start at Visit 3 
(Week -3) and stop at randomization visit (Visit 6). During the randomized treatment period, an 
endpoint CGM recording during Weeks 9, 10, 11 and 12 [Days 64 to 84]) will be done. Patients 
must be well trained to understand the importance of the CGM performance and compliance with 
the manufacture’s (DexCom) instructions. 
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All patients will undergo training, delivered by the investigational site personnel, at Visit 2 
regardless of previous experience with CGM. After the training, patients should understand the 
process of CGM and how to handle the CGM device at home, the distance of receiver and effect 
of temperature on the device etc. If the patient is not sufficiently compliant with the study 
procedures, all necessary training has to be repeated by the site staff. 
Patients, Investigators, and study personnel will be blinded to the CGM data. The CGM receiver’s 
screen will be blocked of displaying data. Neither patients nor Investigators will be able to see the 
glucose values. 
At Visit 3 and Visit 15, the insertion of CGM sensor will occur under the supervision of 
Investigators or designees. Patients will be instructed to insert the sensor into the belly (abdomen) 
at least 8 cm (3 inches) away from the insulin injection sites.  
After the CGM sensor being inserted, and the transmitter being attached, patients will stay in the 
study site as long as needed to explain the use of CGM. During the next 19 days when the patients 
are operating the CGM, they must: 
 
Carry the CGM receiver with them all the time; the receiver must be placed within 20 feet 
(6 meters) from the patients’ body in order to capture the data measured by the device. 
 
After 10 days of wearing the device, patients must remove and replace the sensor 
themselves. Note: If required, Investigators can arrange for patients to attend the site after 
the first 10 days of CGM for the sensor to be replaced at the study site. 
Patients will receive a user guide of instruction included in the DexCom G6 device kit. Technique 
support via a 24/7 help-line service for trouble shooting will be provided by the manufacturer, 
DexCom. The patients should immediately contact the sites if they encounter any device 
malfunction or device related events eg, sensor fracture. The Investigator or a site staff will help 
patients contact the DexCom service line for problem solving.  
After the end of the study, the patients and their Investigator will receive a standardized analysis 
(eg, Ambulatory Glucose Profile) of their personal two 20-day CGM-periods.  
8.1.1.2 CGM qualification and data transfer 
CGM qualification 
There are 2 periods of CGM in this study. During each CGM period, patients will wear the CGM 
for 20 consecutive days to generate a minimum of (10 days, not necessarily consecutive) of 
useable CGM records. Useable CGM data for a day/a 24-hour CGM profile are defined as:  
 
At least 80% time of records per 24 hours.  
 
No gap (missing data) lasting for ≥2 hours per 24 hours besides the warm-up time for the 
sensor after insertion. 
Note: Only patients with 10 days out of 20 of qualified CGM records will proceed to 
randomization and other CGM recording periods. 
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CGM data transfer 
The CGM data will be uploaded to a separate server which assures maintenance of the blind with 
vendor software (QuintilesIMS Study Management Suite) and a data acceptability report with 
daily CGM performance will be available immediately. This will be performed at the end of the 
20-day CGM period and may additionally be generated in the event of a patient returning to the 
site for replacement of the sensor after the first 10 days of CGM. Investigators will not be able to 
see the recorded glucose values, nor will the report include any real glucose data. The CGM 
summary will be used for the Investigators to review the patient’s daily performances and 
determine the quality of CGM and will be considered as source documents). 
Use of CGM data for future analysis 
After the database lock anonymized CGM data may be transferred to a third party for future 
analysis and modeling of glycemic values.  
8.1.2 Glycated hemoglobin A1c 
Glycated hemoglobin A1c is assayed at screening (Visit 1; Week -6/-5), randomization Visit 6 
and Visit 18 (Week 12). For the eligibility and efficacy assessments of the study, HbA1c is 
measured by a certified level I “National Glycohemoglobin Standardization Program”, or 
equivalent certification as per specific country regulations, central laboratory. The screening value 
will be transferred into the IRT for stratification purpose during the patient randomization at the 
Visit 6. 
8.1.3 Fasting plasma glucose 
Fasting plasma glucose is measured at a central laboratory. Blood samples for FPG measurement 
are taken at screening (Week -6/-5), randomization Visit 6 and at Visit 18 (Week 12). 
8.1.4 Self-monitoring of plasma glucose 
Plasma glucose values will be self-measured by the patients using the Sponsor-provided 
glucometers and corresponding supplies (lancet, control solutions, test strips, etc). Patients should 
not use their own glucometers during the study period starting after Visit 2 (Week -4). 
Self-monitoring plasma glucose performance 
At Visit 2, the patients will be shown how to accurately measure plasma glucose values with the 
blood glucometers. The Investigator or a member of the investigational staff will explain the need 
to measure glucose at the times requested for profiles and how to correctly record the values and 
times. Training will be repeated as often as necessary at the study visits and the investigational 
staff will review the study diary at each visit. 
The schedule for performing SMPG is specified in Section 1.3. 
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Self-monitoring of plasma glucose readings will be used to guide the basal and mealtime insulin 
titration to reach glucose targets. The Investigators should review the SMPG records at each visit 
and also ask the pattern of fasting and postprandial SMPG so that they can provide instruction to 
the patients for appropriate insulin dose adjustment. Investigators may request more frequent 
blood glucose test and/or at specific time eg, midnight, if needed, to help the patients optimize 
insulin dosage. The SMPG records will be the patient’s study diary entries (available at each 
visit). The SMPG summary report downloaded at Visits 6, 14, 15 and 18 will also be available to 
Investigators. 
Investigators will record SMPG values and insulin doses during weekly telephone contacts as 
well.  
Fasting self-monitoring of plasma glucose 
After randomization, before breakfast SMPG = Pre-injection SMPG 
Pre-injection SMPG: Within 30 minutes prior to injection of Toujeo or Tresiba before breakfast 
on the day of the first injection of the IMP (Day 1/Visit 6) and daily until uptitration has been 
completed and fasting pre-breakfast SMPG is stable in the target range, and then, at least 3 fasting 
measurements per week. 
2 hours PPG will be measured by patient regularly as instructed by investigator to guide the 
dosing of meal time insulin.  
7-point SMPG profiles 
Before (pre-injection after randomization) and 2 hours after breakfast; lunch; dinner, and at 
bedtime: at least 1 day during the week that precedes Visits 6 and 18. Note: 7-point SMPG profile 
should also be pre-injection during the run-in period in cases where the patient’s current basal 
insulin is administered in the morning. 
SMPG during symptomatic hypoglycemia 
Whenever the patients feel hypoglycemic symptoms, plasma glucose should be measured by the 
patient (or others, if applicable), if possible. Patients should be instructed to self-assess plasma 
glucose levels prior to carbohydrate intake/administration of glucose whenever symptomatic 
hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue prior to confirmation with the SMPG. 
Patients have to document hypoglycemic events appropriately in their diaries and contact the 
Investigator as soon as possible following severe events for review and for decision on any 
necessary actions to be taken. 
All hypoglycemia episodes will be documented on the “hypoglycemia specific form” in the eCRF. 
This includes all symptomatic hypoglycemia events and asymptomatic hypoglycemia. 
Investigators should review the SMPG diary entries (and when available also data stored in the 
glucometer) to assess data for episodes of hypoglycemia, ie, to confirm episodes reported by 
patients in the diary and also to identify any episodes that were not reported in the diary). 
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Hypoglycemia events fulfilling the criteria of a SAE will also be documented on the AE and SAE 
form in the eCRF. 
Recording of SMPG data 
Patients will document their SMPG values with the testing times in the Sponsor-provided diary. If 
for any reason, SMPG is recorded by the patient in a non-Sponsor provided diary, the Investigator 
(or designee) and patient will sign/initial the data so that the diary can be kept in the study source 
documents. 
At on-site Visits 6, 14, and 18, SMPG data stored in the individual’s glucometer will be uploaded 
to the site’s computer. A summary including all measured glucose values will be promptly 
available for the Investigator (or designee) to review. SMPG data will be uploaded to site’s PC 
(server independent from eCRF). At a minimum, for SMPG data that are captured in the eCRF, 
including the values recorded during weekly telephone contacts, the Investigators or study staff 
must verify the accuracy with the data that are uploaded from the glucometer. Once an error is 
identified, only the corrected data should be entered in the eCRF and erroneous data in the diary 
will be corrected by the patient and initialed. 
Use of SMPG data for future analysis 
The SMPG data from the glucometer will be uploaded to an independent server and will not be 
captured in the clinical database (which will comprise SMPG data that is transcribed from the 
study diary).  
The downloaded SMPG data will not be analyzed or reported in the clinical study report. 
After the database lock anonymized SMPG data may be transferred to third party for future 
analysis and modeling of glycemic values. 
8.1.5 Insulin dose (including IMP during the treatment period) 
Insulin dose and injection time for both basal insulin (ie, patient’s current basal insulin prior to 
randomization or IMP [Toujeo or Tresiba] after randomization) and mealtime insulin will be 
documented in the study diary on a daily basis. All doses of mealtime insulin analog during the 
day as taken for all meals and all snacks must be recorded. 
 
At Weeks 4, 8, and 12, the following data will be entered in the eCRF: 
- 
The dose the patient was taking prior to the visit and the dose taken after the visit (so 
as to reveal any dose adjustments made at the visit), 
- 
All available data on the injection time and doses administered will be entered in the 
eCRF, 1 week before on site visit, including missed injection, 
- 
Missed injections. 
 
In case of symptomatic hypoglycemia, the dose and injection time should be entered in the 
eCRF on the specific hypoglycemia form. 
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 
All available data of dose and injection time on the last 3 days before permanently IMP 
treatment discontinuation. 
 
Data on SMPG values and dose of basal and rapid acting insulin, obtained verbally during 
weekly telephone contacts. 
8.1.6 Patient-reported Outcomes (PROs) 
The patient-reported outcome (PRO) questionnaires in this study are the Treatment Satisfaction 
Questionnaire (DTSQs and DTSQc versions), the MOS Sleep and the Work Productivity and 
Activity Impairment Questionnaire (WPAI).  
The patients will be requested to complete all the questionnaires by themselves during selected 
clinical visits (see study SoA), independently from investigator, site staff and any help from 
friends or relatives. For validity purposes, patients will be asked to answer all the questions of the 
questionnaires at the start of the visit in a quiet place, and while on site to return the completed 
questionnaires on the same day. 
In case of premature discontinuation of study treatment, all the PRO questionnaires will be 
completed by the patients as normally planned at 12 weeks.  
8.1.6.1 DTSQs 
The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) will be used to 
evaluate patient satisfaction with treatment and patient perception of blood glucose control over a 
several week period (16). The DTSQs is a validated questionnaire comprised of 8 questions which 
are answered on a Likert scale from 0 to 6.  Responses to 6 of the items will be summed to 
produce a Total Treatment Satisfaction score ranging from 0 (no satisfaction) to 36 (high 
satisfaction with treatment). The 2 items of ‘perceived frequency of ‘hyperglycemia’ (Item 2) and 
‘perceived frequency of hypoglycemia’ (Item 3) are scored separately ranging from 0 (none of the 
time) to 6 (most of the time). The DTSQs will be completed by the patients at baseline and 
Week 12. Mean differences in scores from baseline and between groups will be evaluated to 
understand the impact of treatment on patient satisfaction. 
The DTSQs is available in appendix 5 (Section 10.5). 
8.1.6.2 DTSQc 
The Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) was developed 
from the original DTSQ to evaluate the change in treatment satisfaction at a specific time point. 
The DTSQc instructions and response options differ from those of the DTSQs to produce 
measures of relative change in satisfaction rather than measures of absolute satisfaction.  
It will be used to measure patient perception of change in treatment satisfaction at 12 weeks. 
Scores for DTSQc treatment satisfaction items range from −3 to +3, and the sum of the treatment 
satisfaction score range from −18 to +18. Positive scores are indicative of improvement in 
treatment satisfaction, whereas negative scores are indicative of deterioration in treatment 
satisfaction since start of the study. Perceived frequency of hyperglycemia and hypoglycemia 
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scores range from −3 to +3, with negative scores indicating fewer problems with blood glucose 
levels and positive scores indicating more problems than before. DTSQc will be completed by the 
patients at 12 weeks after the DTSQs (status version). To control for baseline scores, DTSQs will 
be used as a measure of treatment satisfaction at baseline. 
The DTSQc is available in appendix 5 (Section 10.5). 
8.1.6.3 MOS Sleep 
Originally developed for use in the Medical Outcomes Study (MOS), the MOS Sleep Scale is a 
brief, self-administered generic assessment designed to measure key aspects of sleep, such as 
disturbance, adequacy, somnolence, and quantity. 
The 12-item acute revised version of the MOS Sleep will be used in this study with a past week 
recall period and 5-point likert response options (appendix 5 in Section 10.5.3). 
The 12-item MOS Sleep Scale assessment yields scores on six subscales (18, 21):  
 
Sleep Disturbance (4-item subscale on sleep initiation problems, and sleep maintenance 
problems). 
 
Snoring (single-item subscale). 
 
Shortness of Breath or Headache (single-item subscale asking about the frequency of 
awakening with shortness of breath or with a headache). 
 
Sleep Adequacy (2-item subscale asking about frequency of awakening fresh and rested in 
the morning and getting the amount of sleep needed). 
 
Daily Somnolence (3-item subscale). 
 
Sleep Quantity (single-item subscale representing the average number of hours slept). 
 
One Sleep Problems Index is also calculated based on 9 of the items. 
Responses to all but the open-ended sleep quantity item are transformed to scores on a 
0-100 metric, with higher item scores reflecting more of the attribute implied by the scale name. 
Scores on the multi-item subscales and indexes also range from 0 to 100. 
The MOS Sleep will be completed by the patients at baseline and Week12. 
8.1.6.4 WPAI  
The WPAI is a 6-item validated questionnaire assessing the amount of absenteeism, presenteeism 
and daily activity impairment attributable to a specific health problem (WPAI:SHP version V2.0) 
(19). An adapted version of the WPAI:SHP will be used where the term PROBLEM was replaced 
by DIABETES, as requested by the authors.  
The WPAI:Diabetes will be completed by the patients at baseline and Week 12. 
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8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations 
A complete physical examination will include, at a minimum, assessments of the [Cardiovascular, 
Respiratory, Gastrointestinal and Neurological] systems. Height and weight will also be measured 
and recorded. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Vital signs 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
systolic and diastolic blood pressure and pulse. 
Blood pressure (mmHg) should be measured when the patient is quiet and seated and with their 
arm outstretched in line with mid-sternum and supported. Measurement should be taken under 
standardized conditions, approximately at the same time of the day, on the same arm, with the 
same device and the values are to be recorded in the eCRF. Devices for blood pressure 
measurement should be regularly recalibrated according to manufacturers’ instructions. 
Heart rate (bpm) will be measured at the time of the measurement of blood pressure. 
8.2.3 Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.  
The Investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the Investigator to be more severe than expected for the participant’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the Investigator or medical monitor. 
 
If such values do not return to normal/baseline within a period of time judged reasonable 
by the Investigator, the etiology should be identified and the Sponsor notified. 
 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.  
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 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.  
8.2.4 Hypoglycemia 
Hypoglycemia will be reported on the specific hypoglycemia event information form of the 
e-CRF. Hypoglycemia fulfilling the seriousness criteria will be documented in addition on the 
SAE form in the e-CRF. 
The SMPG values will be used for the confirmation of hypoglycemia (ie, episodes both reported 
and not-reported by patients in the diary).  
Hypoglycemic events will be categorized (20, 22, 23, 24) as follows: 
 
Severe hypoglycemia: Severe hypoglycemia is an event requiring assistance of another 
person to actively administer carbohydrate, glucagon, or other resuscitative actions. These 
episodes may be associated with sufficient neuroglycopenia to induce seizure, 
unconsciousness or coma. Plasma glucose measurements may not be available during such 
an event, but neurological recovery attributable to the restoration of plasma glucose to 
normal is considered sufficient evidence that the event was induced by a low plasma 
glucose concentration. The definition of severe symptomatic hypoglycemia includes all 
episodes in which neurological impairment was severe enough to prevent self-treatment 
and which were thus thought to place participants at risk for injury to themselves or others. 
Note that “requiring assistance of another person” means that the participant could not 
help himself or herself. Assisting a participant out of kindness, when assistance is not 
required, should not be considered a “requiring assistance” incident.  Severe hypoglycemia 
will qualify as an SAE only if it fulfills SAE criteria (see Section 10.3). For example, 
events of seizure, unconsciousness or coma must be reported as SAEs. 
 
Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia is an 
event during which typical symptoms of hypoglycemia are accompanied by a measured 
plasma glucose concentration less than 3.9 mmol/L (70 mg/dL). Clinical symptoms that 
are considered to result from a hypoglycemic episode are, eg, increased sweating, 
nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
 
Asymptomatic hypoglycemia: Asymptomatic hypoglycemia is an event not accompanied 
by typical symptoms of hypoglycemia but with a measured plasma glucose concentration 
less than 3.9 mmol/L (70 mg/dL). 
In addition to the threshold of plasma glucose of less than  3.9 mmol/L (70 mg/dL), documented 
hypoglycemia with a measured plasma glucose concentration less than 3.0 mmol/L (54 mg/dL) 
will also be analyzed (20, 24). 
Hypoglycemic events will be evaluated regardless the time of onset during the study and time of 
the day. 
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In addition, hypoglycemia events will be evaluated at the following time periods defined by time 
of the day: 
 
Nocturnal hypoglycemia: any hypoglycemia of the above categories that occurs between 
00:00 and 05:59, regardless of whether participant was awake or woke up because of the 
event. 
 
Daytime hypoglycemia: any hypoglycemia of the above categories that occurs between 
06:00 and 23:59. 
Note: CGM values will not be taken into account for the purpose of hypoglycemia. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
The AESIs are listed below: 
 
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP;  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]), 
- 
In the event of pregnancy in a female participant, IMP should be discontinued, 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
 
Symptomatic overdose (serious or non-serious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant (not based on systematic 
drug count) and defined as any dose administration which, in the Investigator’s 
opinion based on clinical judgment is considered significantly greater than the 
prescribed dose of insulin. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
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The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention or the study (see Section 7).  
8.3.1 Time period and frequency for collecting AE and SAE information  
All SAEs will be collected from the signing of the informed consent form (ICF) until the 
follow-up visit at the time points specified in the SoA (Section 1.3). 
All AE will be collected from the signing of the ICF until the follow-up visit at the time points 
specified in the SoA (Section 1.3). 
All SAEs and AESI will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be reasonably 
related to the study intervention or study participation, the Investigator must promptly notify the 
Sponsor. 
8.3.2 Method of detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3 Follow-up of AEs and SAEs 
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts.  At the pre-specified study end-date, all SAEs, [and non-
serious AEs of special interest (as defined in Section 8.3)], will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3). Further information on follow-up procedures is given in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs 
 
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
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 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
 
Adverse events that are considered expected will be specified in the product prescribing 
information. 
 
An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.  
8.3.5 Pregnancy 
 
Details of all pregnancies in female participants and female partners of male participants 
occurring after the start of study intervention and until the end of the study will be 
collected and followed until the outcome. 
 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 Guidelines for reporting product complaints 
Any defect in the IMP/NIMP/device must be reported as soon as possible by the Investigator to 
the monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
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3. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS 
PK parameters are not evaluated in this study. 
8.6 
PHARMACODYNAMICS 
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
GENETICS 
Genetics are not evaluated in this study. 
8.8 
BIOMARKERS 
Biomarkers are not evaluated in this study. 
8.9 
HEALTH ECONOMICS 
Health economics are not evaluated in this study. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
The objective is to show non-inferiority of Toujeo versus Tresiba in patients with type 1 diabetes 
on the percent time in glucose range of ≥70 to ≤180 mg/dL (≥3.9 to ≤10 mmol/L) at Week 12 
obtained using CGM. 
9.2 
SAMPLE SIZE DETERMINATION  
The sample size calculation is based on the percent time spent in glucose range of ≥70 to 
≤180 mg/dL (≥3.9 to ≤10 mmol/L) at Week 12, assessed from CGM measurements obtained 
during Weeks 10, 11 and 12. 
For this criterion of percent time in range, there is no predefined non-inferiority margin. A relative 
non-inferiority margin of 10% is considered. 
Let m1 and m0 be the true means for the Toujeo and Tresiba groups, respectively.  
The non-inferiority null hypothesis would be H0: m1-m0 ≤ -0.1*m0 or H0: m1-0.9*m0 ≤0 and the 
alternative hypothesis (H1): m1=m0. 
Toujeo would be considered non-inferior to Tresiba if the lower limit of the 95% CI for the 
adjusted difference estimate of m1-0.9*m0 at Week 12 is >0. 
To ensure 90% power, the sample size should satisfy: 
1.96 −(0.1 ∗𝑚0)
√1.81 ∗𝑆𝐷2
𝑛
= − 1.282 
Where -1.282 is the 10th percentile of a standard normal distribution and SD the common SD. 
Which leads to: 
𝑛= (1.96 + 1.282)2 ∗1.81 ∗𝑆𝐷2
(0.1 ∗𝑚0)2
 
Assuming a common SD of 14.7%, an average percent time in range in the Tresiba treatment 
group of 56% (value from LPS14587), no true difference between both arms under H1, and a 
relative non-inferiority of 10%, a sample size of 131 evaluable patients per treatment group would 
provide at least 90% power to show non-inferiority of Toujeo with respect to Tresiba on the 
percentage of time plasma glucose within the range of ≥70 to ≤180 mg/dL at Week 12. 
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With the assumption of a non-evaluability rate of 22% 338 participants (169 per treatment arm) 
will have to be randomized.  
Patient is evaluable for the primary endpoint if he/she as at least 10 days of useable CGM data 
(not necessarily consecutives) at Week 12 (see Section 8.1.1.2 for definition of useable data). 
9.3 
POPULATIONS FOR ANALYSES 
For purposes of analysis, the following populations are defined (Table 6): 
Table 6 - Populations for analyses 
Population 
Description 
ITT 
All randomized (patients who signed ICF and with a treatment arm allocated before first IMP and 
recorded in the IRT database) participants, irrespective of the treatment actually being received, 
analyzed according to the treatment group allocated by randomization. 
PP 
The PP population is a subset of ITT population with no major protocol deviations. Participants included 
in this population will fulfill at least the criteria below: 
 
randomized and received only the treatment allocated at the randomization 
 
did not permanently discontinue treatment 
The PP population will be fully defined in the SAP. 
Safety 
All randomized participants who received at least one dose of IMP, regardless of the amount of 
treatment administered. Patients will be analyzed according to the treatment actually received. 
ICF: informed consent form; IRT: interactive response technology; ITT: intent to treat; PP: per protocol; SAP: statistical analysis plan 
9.4 
STATISTICAL ANALYSES 
The SAP will be developed and finalized before database lock and will describe the participant 
populations to be included in the analyses, and procedures for accounting for missing, unused, and 
spurious data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. 
9.4.1 Efficacy analyses 
All efficacy analyses will be performed on the ITT population. Sensitivity analyses will be 
performed on the PP population on a selection of endpoints. 
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Table 7 - Efficacy analyses 
Endpoint 
Statistical Analysis Methods 
Primary: Percent time in glucose 
range of ≥70 to ≤180 mg/dL (≥3.9 to 
≤10 mmol/L) at Week 12, obtained 
using CGM 
Primary endpoint using available data from the 12-week randomized period will be 
analyzed using an ANCOVA model including the fixed categorical effects of treatment 
group (Toujeo, Tresiba), randomization stratum of screening HbA1c (<8.0% versus 
≥8.0%), as well as, the continuous fixed covariate of baseline percent time in range value. 
This procedure will provide baseline adjusted least-squares means estimates at Week 12 
for both treatment groups, as well as, the differences of these estimates, with their 
corresponding standard errors (SEs) and 95% CIs. 
To assess non-inferiority, the lower bound of the two-sided 95% CI for the adjusted 
difference estimate of m1 - 0.9*m0 at Week 12 will be compared to 0. 
Non-inferiority will be demonstrated if the lower bound of the two-sided 95% CI of the 
adjusted difference estimate of m1 - 0.9*m0 at Week 12 on the ITT population is >0. 
A sensitivity analysis will be performed using the PP population. 
Let m1 and m0 be the true means for the Toujeo and Tresiba groups, respectively. 
To assess non-inferiority, the lower bound of the two-sided 95% CI for the adjusted 
difference estimate of m1 - 0.9*m0 at Week 12 will be compared to 0. 
Non-inferiority will be demonstrated if the lower bound of the two-sided 95% CI of the 
adjusted difference estimate of m1 - 0.9*m0 at Week 12 on the ITT population is >0. 
A sensitivity analysis will be performed using the PP population. 
Secondary: CGM endpoints at 
Week 12 (see Section 3) 
CGM endpoints will be analyzed using the same model as described for the primary 
endpoint using the ITT population. 
Exploratory analysis will be performed on within day glucose CV to summarize the 
treatment effects across subgroup defined by within day CV<36% vs. >=36% at baseline. 
Secondary 
 
 
Change from baseline to 
Week 12 in HbA1c 
Change in HbA1c will be analyzed using an analysis of covariance (ANCOVA) model 
including fixed categorigal effect of treatment group (Toujeo, Tresiba), as well as, the 
continuous fixed covariate of baseline HbA1c value.  
 
Change from baseline to 
Week 12 in central lab FPG 
Change in FPG will be analyzed using ANCOVA model including the randomization 
stratum of HbA1c at screening (<8.0%, ≥8.0%), treatment group (Toujeo, Tresiba), as 
well as, the continuous fixed covariate of baseline FPG value. 
Exploratory 
[Will be described in the statistical analysis plan finalized before database lock] 
 
To control the type I error, a hierarchical step-down testing procedure described by Hochberg and 
Tamhane (3) will be applied for the primary efficacy endpoint and the main secondary endpoint: 
 
Step 1 proceeds to assess non-inferiority of Toujeo versus Tresiba on the percent time in 
range in 70-180 mg/dl. 
 
Step 2: only if step 1 is demonstrated, then non-inferiority of Toujeo versus Tresiba  on the 
glucose total CV will be tested with a relative non-inferiority margin of 10%. 
 
Step 3: only if step 2 is demonstrated, then difference between Toujeo and Tresiba on the 
percent time in range in 70-180 mg/dl will be tested. 
No multiplicity adjustment will be made on other secondary/other efficacy variables; 95% CI and 
P-values presented for these endpoints will be done for descriptive purpose only. 
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9.4.2 Safety analyses 
All safety analyses will be performed on the Safety Population.  
The summary of safety results will be presented by treatment group.  
The baseline value is defined generally as the last available value before randomization. 
For all safety data, the observation period will be divided as follows: 
 
The pre-treatment phase is defined as the time from when the patients sign the informed 
consent to randomization. 
 
The on-treatment phase is defined as the time from the first injection of the open label 
IMP (included) up to 2 days after the last injection of IMP. 
 
The post-treatment phase is defined as the time after the on-treatment phase until the end 
of the study (Follow up Visit).  
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became serious during 
the on-treatment phase. 
Table 8 - Safety analyses 
Endpoint 
Statistical Analysis Methods 
Secondary: 
 
 
Number of 
participants with AEs 
TEAEs, treatment-emergent SAEs, TEAEs leading to death, and TEAEs leading to treatment 
discontinuation will be summarized by treatment group for the 12-week on-treatment period. 
All adverse events will be coded to a “preferred term” (PT) and “high-level group term” (HLGT), 
“high level term” (HLT) and associated 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 by SOC (sorted by internationally agreed order), 
HLGT, HLT and PT sorted in alphabetical order, and for each treatment group, the number (n) 
and percentage (%) of patients experiencing at least one AE. 
Multiple occurrences of the same event in the same patient will be counted only once in the 
tables within a treatment period. The denominator for computation of percentages is the safety 
population within treatment group. 
 
Number of 
participants with at 
least one 
hypoglycemic event 
from baseline to 
Week 12 
The number and incidence of patients experiencing at least one hypoglycemic event will be 
presented per treatment group and type of hypoglycemic event (see Section 8.2.4) and 
according to time of occurrence (nocturnal [ie, 00:00 to 05:59], any time of day and daytime 
[ie, 06:00 to 23:59]) during the 12-week on treatment period. The Odds Ratio and its 
corresponding 95% CI of Toujeo arm over Tresiba arm for each hypoglycemic event (nocturnal 
and any time of the day) will be estimated by a logistic regression model. 
 
Number of 
hypoglycemic events 
per participant year 
from baseline to 
Week 12. 
The rate of hypoglycemic events (in patient-year of exposure) will be determined per treatment 
group and type of hypoglycemic event (see Section 8.2.4), and according to time of occurrence 
(nocturnal [ie, 00:00 to 05:59], any time of the day) during the 12-week on treatment period. 
Exploratory 
Not applicable 
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9.4.3 Other analyses  
Not applicable. 
9.5 
INTERIM ANALYSES  
No interim analysis is planned during the study. 
 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1.1 Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines, 
- 
Applicable laws and regulations. 
 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.  
 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
 
The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC, 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures, 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations. 
10.1.2 Informed Consent Process 
 
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.  
 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
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 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.  
 
Participants who are rescreened are required to sign a new ICF. 
10.1.3 Data Protection 
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation).  
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names or 
any information which would make the participant identifiable will not be transferred.  
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant.  
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
10.1.4 Committees Structure 
The steering committee is composed of scientists with clinical and methodological expertise in 
diabetes and conduct of clinical trials. This committee, led by a chairman, is responsible for 
producing and conducting a scientifically sound study and for ensuring accurate reporting of the 
study. In that capacity, the steering committee must address scientific issues encountered during 
the study. 
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10.1.5 Dissemination of Clinical Study Data 
Sanofi shares information about clinical trials and results on publically accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials.  Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.6 Data Quality Assurance 
 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
 
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
 
The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.  
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 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.  
10.1.7 Source documents 
 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
 
Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.8 Study and Site Closure 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor's procedures, or GCP guidelines. 
 
Inadequate recruitment of participants by the Investigator. 
 
Discontinuation of further study intervention development. 
10.1.9 Publication Policy 
 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments.  
 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
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 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS 
The tests detailed in Table 9 will be performed by the central laboratory.  
 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 9 - Protocol-required laboratory assessments 
Laboratory 
assessments 
 
Parameters 
Hematology 
Platelet count  
Red blood cell (RBC) count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count  
 
Clinical chemistry 
Uric acid 
Potassium 
Aspartate 
aminotransferase (AST)/ 
Serum glutamic-
oxaloacetic transaminase 
(SGOT) 
Total bilirubin (in case 
of values above the 
normal range, 
differentiation in 
conjugated and non-
conjugated bilirubin) 
 
Creatinine 
 
 
Sodium 
Alanine 
aminotransferase 
 (ALT)/ Serum glutamic-
pyruvic transaminase 
(SGPT) 
Estimated creatinine 
clearance 
 
FPG 
HbA1c 
Blood urea nitrogen 
(BUN) 
Alkaline phosphatase 
 
 
 
Other screening tests 
 
C peptide 
 
Serum human chorionic gonadotropin (hCG) pregnancy test (for 
women of childbearing potential at screening) 
 
Urine hCG pregnancy test for WOCBP at Visit-6 and 18 (to be 
confirmed with serum test if positive) 
 
The results of central laboratory tests will be uploaded to the clinical database. Investigators will 
receive the reports from central laboratory and must document their review of each laboratory 
safety report. 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
DEFINITION OF AE 
AE definition 
 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease), eg: 
- 
Symptomatic and/or,  
- 
Requiring either corrective treatment or consultation, and/or,  
- 
Leading to IMP discontinuation or modification of dosing, and/or,  
- 
Fulfilling a seriousness criterion, and/or,  
- 
Defined as an AESI. 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfil the definition of an AE or SAE.  
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of 
efficacy" or "failure of expected pharmacological action" also constitutes an AE or SAE. 
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Events NOT meeting the AE definition 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
d) Results in persistent disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
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- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e) Is a congenital anomaly/birth defect 
f) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These events should usually be 
considered serious. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
RECORDING AND FOLLOW-UP OF AE AND/OR SAE 
AE and SAE recording 
 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
 
The Investigator will then record all relevant AE/SAE information in the CRF. 
 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the AE/SAE CRF page. 
 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
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 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
 
The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
 
The Investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
 
If a participant dies during participation in the study 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 completed CRF. 
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 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor’s representative via an electronic data collection tool 
 
The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
 
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
 
After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form (see next section) or to 
the Sponsor’s representative by telephone. 
 
Contacts for SAE reporting can be found in a separate document. 
SAE reporting to the Sponsor’s representative via paper CRF 
 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor’s representative. 
 
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
 
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
 
Contacts for SAE reporting can be found in a separate document. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION 
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
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Women in the following categories are not considered WOCBP 
1. Premenarchal
2. Premenopausal female with 1 of the following:
-
Documented hysterectomy,
-
Documented bilateral salpingectomy,
-
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion
should be applied to determining study entry.
Note:  Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal
range may be used to confirm a postmenopausal state in women not using hormonal
contraception or hormonal replacement therapy (HRT). However, in the absence of
12 months of amenorrhea, confirmation with more than one FSH measurement is
required,
-
Females on HRT and whose menopausal status is in doubt will be required to use one
of the non-estrogen hormonal highly effective contraception methods if they wish to
continue their HRT during the study. Otherwise, they must discontinue HRT to allow
confirmation of postmenopausal status before study enrollment.
CONTRACEPTION GUIDANCE 
Female participants 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly. 

Implantable progestogen-only hormone contraception associated with inhibition of ovulationb

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS) b

Bilateral tubal occlusion

Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner of the woman of childbearing potential and the absence of sperm has been
confirmed. If not, an additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 90 days.)
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Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition 
of ovulationc 
 oral 
 intravaginal 
 transdermal 
 injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
 oral 
 injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
ACCEPTABLE METHODSd 
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary 
mode of action 
 Male or female condom with or without spermicidee 
 Cervical cap, diaphragm, or sponge with spermicide 
 A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide 
(double-barrier methods)c 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
contraceptive methods are limited to those which inhibit ovulation as the primary mode of action. 
d) Considered effective, but not highly effective - failure rate of ≥1% per year.  Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception.  
e) Male condom and female condom should not be used together (due to risk of failure with friction). 
COLLECTION OF PREGNANCY INFORMATION:  
Male participants with partners who become pregnant  
 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
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 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure.  
Female participants who become pregnant  
 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for the procedure. 
 
Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. Any post-study pregnancy related SAE considered reasonably related to 
the study intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting.  
Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention. 
 
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10.5 
APPENDIX 5: QUESTIONNAIRE 
10.5.1 The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs)  
 
 
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10.5.2 The Diabetes Treatment Satisfaction Questionnaire Change Version  
 
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10.5.3 MOS Sleep 
 
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10.5.4 WPAI 
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10.6 
APPENDIX 6: ADA HYPOGLYCEMIA DEFINITIONS 
In this study, hypoglycemia is categorized according to the American Diabetes Association 
workgroup on hypoglycemia classification:  
 
Defining and Reporting Hypoglycemia in Diabetes: A Report from American diabetes 
Association Workgroup on hypoglycemia Diabetes Care. 2005 May;28(5):1245-9.  
 
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. 
In addition to the threshold of ≤70 mg/dL (≤3.9 mmol/L), hypoglycemia episodes with a plasma 
glucose of <54 mg/dL (<3.0 mmol/L) will be analyzed separately:  
International Hypoglycemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L 
(54 mg/dL) Should Be Reported in Clinical Trials: A Joint Position Statement of the American 
Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 
2017; 40(1): 155-157. 
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.8 
APPENDIX 8: ABBREVIATIONS 
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ANCOVA: 
analysis of covariance 
CGM: 
continuous glucose monitoring 
CI: 
confidence interval 
CV: 
coefficient of variation 
DCCT: 
Diabetes Control and Complications Trial 
eCRF: 
electronic case report form 
FPG: 
fasting plasma glucose 
GIR: 
glucose infusion rate 
HbA1c: 
glycated hemoglobin A1c 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent to treat 
PD: 
Pharmacodynamics 
PK: 
Pharmacokinetics 
SAE: 
serious adverse event 
SC: 
subcutaneous 
SD: 
standard deviation 
SE: 
standard errors 
SMPG: 
self-monitoring of plasma glucose 
T1DM: 
type 1 diabetes mellitus 
 
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11 
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24. International Hypoglycaemia Study Group. Glucose Concentrations of Less Than 3.0 mmol/L 
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2017 Jan;40(1):155-157. 
 
 
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