Conditions: Type 1 Diabetes Mellitus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 15
Healthy volunteers: no

Brief summary:
Primary Objective:

To evaluate the effect of virtual approach via novel technologies versus traditional study conduct on glycemic control in terms of glycated hemoglobin (HbA1c).

Secondary Objective:

To evaluate the appropriate utilization of virtual approach via novel technologies during the study and to assess the effect of the virtual versus traditional study conduct on multiple outcomes in terms of study methodology and diabetes management.

Detailed description:
The study had a maximum study duration of 29 weeks, which consisted of a 3-week screening period (including a possible 1-week delay in first investigational medicinal product \[IMP\] administration after randomization in virtual group due to shipment of IMP and the virtual devices), a 24-week treatment period, and 1-week post-treatment safety follow-up period.

Arms:
arm 1: Participants included in this virtual trial approach group did not visit the study sites during the study course. All study assessments, including vital signs, weight, laboratory variables, etc., were completed via the Bluetooth devices that instantly transfer the digital data. arm 2: Participants included in this traditional trial approach group visited the study site, followed the study visit schedules for all study assessments that was performed either in-person or phone visits.

Interventions: intervention 1: Insulin glargine, 300 units per milliliter (U/mL) intervention 2: Background therapy: Rapid Acting meal time insulin analogs (Humalog, Novolog or Apidra)
Intervention descriptions: intervention 1: Self-administered subcutaneous injection using prefilled pen once daily for 24 weeks. Dose titration to achieve fasting self-monitoring of plasma glucose (SMPG) level between 80 and 130 milligram per deciliter (mg/dL). intervention 2: Subcutaneous injection.

Protocol document:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-002579 VERSION N°14.0 (04-FEB-2016) 
Page 1 
CLINICAL TRIAL PROTOCOL 
COMPOUND: Toujeo®/insulin glargine 300 U/mL/HOE901-U300 
Evaluation of virtual versus traditional study conduct in a 6-month, multicenter, 
randomized, open-label, 2-parallel group pilot study in adult patients with Type 1 
diabetes mellitus 
STUDY NUMBER: MSC15146 
STUDY NAME: eStudy 
EudraCT
Not applicable
IND Number(s) 
Not applicable 
Version Number: 
1  
WHO universal trial number: 
U1111-1188-5647 
Date: 
13-Mar-2017 
Total number of pages: 
243 
(electronic 1.0)
NCT03260868


Clinical Trial Protocol  
13-Mar-2017 
MSC15146 - insulin glargine 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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Clinical Trial Protocol  
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MSC15146 - insulin glargine 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
 
COMPOUND: Toujeo®/Insulin Glargine 
300 U/mL/HOE901-U300 
STUDY No.: MSC15146 
STUDY NAME: eStudy 
TITLE 
Evaluation of virtual versus traditional study conduct in a 6 month, 
multicenter, randomized, open-label, 2-parallel group pilot study in 
adult patients with Type 1 diabetes mellitus (T1DM) 
INVESTIGATOR/TRIAL LOCATION 
The United States of America, Canada 
PHASE OF DEVELOPMENT 
Phase 4 
STUDY OBJECTIVE(S) 
 
Primary objective: 
To evaluate the effect of virtual approach via novel technologies 
versus traditional study conduct on glycemic control in terms of 
glycated hemoglobin A1c (HbA1c). 
Secondary objectives: 
To evaluate the appropriate utilization of virtual approach via novel 
technologies during the study and to assess the effect of the virtual 
versus traditional study conduct on multiple outcomes in terms of 
study methodology and diabetes control. 
• 
Study methodology with the two approaches: 
- 
Patient satisfaction with the trial experience via a 
patient reported outcome (PRO) 
- 
Impact of clinical trial participation via a PRO 
- 
Patient burden with the clinical trial experience via a 
PRO 
- 
Resource use via a PRO 
- 
Medication and key study activity compliance 
- 
Patient retention  
• 
Diabetes control with the two approaches: 
- 
Diabetes related PROs 
- 
Glycemic control (HbA1c, fasting plasma glucose 
[FPG], self-monitoring of plasma glucose [SMPG]) 
• 
Patient care with the two approaches: 
- 
Doctor/site-patient relationship 
- 
Site satisfaction with provisioned care 
- 
Patient experience in the clinical trial via a qualitative 
exit interview  
• 
Safety assessment managed by the two approaches 
including: 
- 
Hypoglycemic events 
- 
Adverse events (AEs) 
STUDY DESIGN 
A 28-week, randomized, open-label, 2 approach groups, multicenter, 
pilot study 
The study consists of 3 periods: 
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An up-to-3-week screening period, which includes 2 steps to 
complete the consent in person, the eligibility assessment and the 
shipment of study material. 
Patients with T1DM currently treated with insulin glargine 100 U/mL 
(eg, Lantus or Basaglar) plus rapid-acting analog insulin and with 
internet access will eSign the consent on the study website. 
Screening procedures will be performed in person by medical 
professionals provided by Homecare services (via The Medical 
Research Network [MRN]) in collaboration with the investigators. 
The investigators will then complete the eligibility assessments at the 
end of screening, the randomization, and the shipment of study 
material.  
Eligible patients will be randomized 1:1 (virtual:traditional) into 
2 study groups to receive the same investigational medicinal product 
(IMP, Toujeo) but follow either a traditional trial approach or a 
remote, virtual approach for completion of all study procedures. 
Stratification factors for randomization include study site and HbA1c 
<7.6% or ≥7.6%.  
Thus, patients randomized to the virtual group will not visit the study 
sites during the entire study course, except for a physical 
examination before IMP initiation. All other study assessments, 
including vital signs, weight, lab variables, etc, will be completed via 
Bluetooth devices that instantly transfer the digital data, available for 
investigators’ view. Video chat between the patients and 
investigators/designees may occur for safety reason in addition to 
the planned study visits. 
A 24-week treatment period. 
Patients in both groups will receive the same study treatment with 
Toujeo as the basal insulin plus their existing rapid-acting insulin 
analogs (Humalog, Novolog, or Apidra) to manage their diabetes. 
Toujeo dose will be titrated to target the fasting SMPG between 
80 and 130 mg/dL; meal-time insulin analogs will be adjusted 
following investigators’ instructions to maintain postprandial SMPG 
within a range of 130 to 180 mg/dL.  
All patients will monitor their plasma glucose via the study-provided 
glucose meter. The SMPG values will be used to guide the insulin 
dose adjustment and document the hyper- or hypoglycemic events. 
A 1-week posttreatment period to collect any posttreatment safety 
information.  
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Patients with T1DM diagnosed at least one year before the 
screening visit. 
• 
Patients who are treated with multi-dose insulin using 
insulin glargine 100 U/mL (eg, Lantus or Basaglar) as 
basal insulin and rapid acting insulin analogues as bolus 
insulin 
• 
Patient with access to or experience with mobile 
technology (eg, tablet or smartphone) 
• 
eSign the consent on the study web portal 
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Exclusion criteria: 
• 
Age <18 years at screening (Visit 1 – Step 1) 
• 
Type 2 diabetes mellitus 
• 
HbA1c <5.4% or ≥9.0% at screening (Visit 1-Step 2) 
• 
Patients who received less than 6 months treatment with 
any basal plus mealtime insulin 
• 
Use of any basal  insulins other than insulin glargine 
100 U/mL (eg, Lantus or Basaglar)  within 3 months before 
screening 
• 
Use of an insulin pump within 6 months before screening 
• 
Use of meal-time insulin other than rapid-acting insulin 
analogs (Humalog, Novolog, or Apidra), eg, human regular 
insulin, within 30 days before screening 
• 
Use of systemic glucocorticoids (excluding topical 
application or inhaled forms) for one week or more within 
3 months before screening 
• 
Patients experienced with any severe hypoglycemic 
episode resulting in seizure, unconsciousness, or coma, 
and/or leading to hospitalization during the past 6 months 
before screening 
• 
Patients with insufficient smartphone skills or unwilling to 
properly use the virtual tools deemed by the investigator 
based on the observation over the digital screening 
procedure 
• 
Mental disorders or any neurologic disorder that would 
affect patient’s ability to meet the study requirements, or 
patients deemed unlikely to safely manage insulin dosage 
by the Investigators 
• 
Known hypersensitivity/intolerance to insulin glargine, 
rapid-acting insulin analogs or any of their excipients 
• 
Pregnant or breast-feeding women, or women who intend 
to become pregnant during the study period 
Total expected number of patients 
150 randomized patients (75 patients in virtual group, 75 patients in 
traditional group) 
STUDY TREATMENTs 
 
Investigational medicinal product 
Toujeo (insulin glargine 300 U/mL, HOE901-U300) 
Formulation: 
Toujeo (insulin glargine-U300) will be supplied as a sterile, 
nonpyrogenic, clear, colorless solution in the Toujeo SoloStar® 
prefilled (disposable) pen (insulin glargine 300 units/mL solution for 
subcutaneous [SC] injection). 
Each Toujeo SoloStar contains in total 450 units of insulin glargine 
(1.5 mL of 300 units/mL insulin glargine solution). This pen allows 
dose setting in the range of 1 to 80 units with a minimum of 1 unit 
increment. 
Dilution or mixing of Toujeo with other insulin products is not 
allowed.  
Route of administration: 
Subcutaneous injection once daily (self-administration) 
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Dose regimen: 
Starting dose of Toujeo is the patient’s existing insulin glargine 
100 U/mL dose prior to Day 1. Toujeo will be titrated based on 
self-measured, fasting (prebreakfast/preinjection) plasma glucose 
levels (target range 80 to 130 mg/dL; 4.4 to 7.2 mmol/L) while 
avoiding hypoglycemia.  
Noninvestigational medicinal products 
Patients in both treatment groups will continue with their existing 
rapid-acting mealtime insulin analogs (Humalog, Novolog, or Apidra) 
during the study. 
Formulation: 
Solution for SC injection 
Route(s) of administration: 
Subcutaneous injection 
Dose regimen: 
Dosing of the rapid-acting mealtime insulin will be adjusted based on 
the pattern of mean postmeal SMPG level or based on the 
carbohydrate content of the meal (carb counting) as per instruction 
of the investigator; target range for 2-hour postprandial plasma 
glucose is 130 to 180 mg/dL (7.2 to 10.0 mmol/L). 
ENDPOINT(S) 
 
Primary endpoint: 
Changes in HbA1c from baseline to Week 24  
Secondary endpoints: 
Study methodology assessment with the two approaches: 
• 
Patient satisfaction with trial experience PRO: Was it 
Worth It (WIWI) Questionnaire at Week 24 
• 
The effect of the trial on a patients’ ability to work and 
perform regular activities PRO: Work Productivity and 
Impairment-study participation (WPAI-SP), change from 
baseline to Week 24 
• 
Patient burden with the trial participation: (PRO: Overall 
Study Experience-Participation [OSEP]), change from 
baseline to Week 24 (OSEP part 1-diabetes appraisal)/at 
Week 24 (OSEP part 2-study appraisal) 
• 
Patient-reported healthcare resource utilization: resource 
use questionnaire (RUQ) over the 24 week treatment 
period  
• 
Medication and key study activity compliance from 
baseline to Week 24: 
- 
The exposure time to basal insulin (Toujeo) and 
percentage of actual dose over the prescribed dose 
- 
The number of times the patient used the Bluetooth 
devices, in accordance with the study instructions 
- 
The number of times the patient completed the blood 
draw visit, in accordance with the study instructions 
- 
Patient withdrawal from baseline to Week 24 
Diabetes control with the two approaches: 
• 
Diabetes related PROs, changes from baseline to Week 
24 in: 
- 
Diabetes Treatment Satisfaction Questionnaire status 
(DTSQs) 
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- 
Diabetes Treatment Satisfaction Questionnaire 
change (DTSQc), administered on Week 24 only 
- 
Hypoglycemia Fear Survey-II (HFS-II) 
- 
Diabetes Distress Scale (DDS) 
• 
HbA1c: change from baseline to Week 16 
• 
FPG: change from baseline to Week 16 and Week 24 
• 
Change in 7-point SMPG profiles, mean and per time-point 
from baseline to Week 16 and Week 24, 
• 
Insulin doses 
Patient care with the two approaches: 
• 
Study-specific resource requirements: Overall Study 
Experience-Sites (OSES) questionnaire part 1 (resource 
requirements) over the 24 week treatment period 
• 
Site-perceived patient relationship and satisfaction: OSES 
questionnaire part 2 at Week 24  
• 
Patient interview in a subset of patients at Week 24 
Safety assessment managed by the two approaches: 
• 
Hypoglycemic events and incidence rate (as per the 
American Diabetes Association (ADA) classification) 
during the 24-week period in each group 
• 
Adverse events (including Injection site reactions and 
hypersensitivity), Serious AEs (SAEs) and Product 
Technical Complaints (PTCs) 
ASSESSMENT SCHEDULE 
See study flowchart in Section 1.2. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
This is a pilot study, consequently no formal sample size calculation 
was done. 
The sample size was not powered for confirmatory testing, only 
descriptive statistics will be provided. 
Number of patients per trial approach group: randomization using a 
ratio 1 (virtual):1 (traditional). 
Nevertheless, a precision calculation based on the 2-sided 95% 
confidence interval (CI) shows that the change in HbA1c from 
baseline in virtual approach, the change in HbA1c from baseline in 
traditional approach and the difference in HbA1c change between 
the two approaches will be estimated with a precision of 
approximately 0.37%, using a standard deviation (SD) of 1.1 and 
taking into account an up to 10% rate of non-evaluable patients for 
HbA1c. 
General aspects of the analyses: 
Except if defined below, the baseline value will be the last available 
value prior to the first injection of IMP. 
Analysis population: 
The primary population for all non-safety endpoints will be the Intent-
To-Treat (ITT) population, which will comprise all randomized 
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Page 8 
patients, irrespective of the trial approach group being used, 
analyzed according to the approach group allocated by 
randomization.  
The safety population is defined as all randomized patients who did 
actually receive at least one dose of Toujeo, regardless of the 
amount of Toujeo administered. 
Primary analysis: 
The primary efficacy endpoint (change in HbA1c from baseline to 
Week 24) will be analyzed using a mixed-effect model with repeated 
measures (MMRM) approach, using the missing at random 
framework carried out via SAS PROC MIXED using adequate 
contrasts. The model will include fixed categorical effects of trial 
approach group, visit, trial approach-by-visit interaction, 
randomization stratum of site; and the continuous fixed covariates of 
baseline HbA1c value and baseline HbA1c value-by-visit interaction. 
Analysis of secondary endpoints: 
A descriptive summary will be provided for each endpoint per 
approach group. Additional statistical analyses are summarized 
below. 
Analysis of study methodology 
The change in WPAI-SP and OSEP part 1 scores from baseline to 
Week 24 will be analyzed using an analysis of covariance 
(ANCOVA). WIWI and OSEP part 2 scores will be compared at 
Week 24 between approach groups using an analysis of variance 
(ANOVA). 
The total and average resource utilization per patient will be 
calculated on all on-treatment questionnaires using the RUQ. 
Duration of IMP exposure will be summarized descriptively and 
categorically (by periods) by numbers and percentages. 
The number of times the patient used the Bluetooth devices and the 
number of times the patient completed the blood draw visit will be 
summarized only in the virtual approach group. 
Patient withdrawal from baseline to Week 24 will be analyzed 
descriptively and using a Kaplan-Meier plots/estimates of the 
cumulative incidence of study discontinuation. 
Analysis of diabetes control 
The change in DTSQs, HFS-II, and DDS scores from baseline to 
Week 24 will be analyzed using an ANCOVA. DTSQc scores at 
Week 24 will be compared between approach groups using an 
ANCOVA. 
The change in HbA1c from baseline to Week 16 will be described in 
each trial approach group and analyzed using the same model as 
done for primary endpoint 
The change in FPG, and 7-point SMPG from baseline to Week 24 
will be described in each trial approach group and analyzed using an 
MMRM approach. 
Analysis of patient care 
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Overall Study Experience-Sites (OSES) part 1 will be compared 
between approach groups using an ANCOVA; OSES part 2 will be 
compared between approach groups using an ANOVA. 
Patient experience via a qualitative exit interview will be analyzed via 
an expert qualitative research analysis group.  
Safety analyses: 
Safety analyses will be descriptive, based on the safety population. 
The baseline value for safety endpoints will be the last available 
value prior to the first injection of IMP. 
The following safety parameters will be analyzed: 
• 
Hypoglycemia 
- 
Hypoglycemia event (categories as defined by the 
ADA Workgroup on Hypoglycemia: severe, 
documented symptomatic, asymptomatic, probable 
symptomatic, relative, and nocturnal) 
- 
Number and percentage of patients experiencing at 
least one hypoglycemic events by categories (any, 
severe, documented symptomatic) 
- 
Number and rate per patient-year of hypoglycemic 
events by categories (any, severe, and documented 
symptomatic) 
Hypoglycemia analyses will be performed at any time, 
nocturnal (00:00-05:59) and daytime. 
• 
AEs 
• 
SAEs 
• 
Deaths 
• 
Adverse events of special interest (AESIs) 
• 
Injection site reaction and hypersensitivity reaction 
• 
PTCs 
• 
Vital signs 
The observation period of safety data will be divided into 
3 segments: 
• 
The pre-treatment period is defined as the time between 
the date of the informed consent and the date of first 
injection of open-label IMP 
• 
The treatment-emergent AE (TEAE) period is defined as 
the time from the first injection of IMP up to 2 days after 
the last injection of IMP 
• 
The posttreatment period is defined as the time starting 
3 days after the last injection of IMP 
DURATION OF STUDY PERIOD (per 
patient)  
The study consists of: 
• 
A 3-week screening period, including 1 week between 
randomization and first IMP administration due to shipment 
of IMP and the Bluetooth devices for virtual group and the 
appointment making with the site for the traditional group 
• 
A 24-week treatment period 
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Page 10 
• 
A 1-week posttreatment safety follow-up period after 
treatment completion or premature discontinuation of study 
treatment 
In total the maximum study duration for one patient will be 
approximately 28 weeks. 
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Page 11 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
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Page 12 
1.2 
STUDY FLOW CHART 
(
 = virtual visits;    = phone call visits; P = on-site in-person visits) 
 
Screening  
Randomization  
Treatment period 
Follow-up 
Visits  
1 
Step-1a 
1 
Step-2b 
2  
Step-1c 
2  
Step-2d
3  
 
  
4 
 
 
5 
 
 
6 
 
 
7 
8 
 
 
9  
10 
 
 
11 
 
 
12 
EOTg 
13 
EOS 
 
Traditional group  
 
P 
 
 
 
P 
 
P 
 
P 
 
P 
 
Virtual group  
 
(Digital screening) 
 
P & 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks  
-3 
-2 
-1 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
1 week 
Window (day) 
 
 
-/+ 4 
 
-/+ 3 
-/+ 3 
-/+ 3 
-/+ 4 
-/+3 
-/+ 4 
-/+ 3 
-/+ 4 
-/+ 3 
-/+ 3 
+/-2 
Informed Consent (eConsent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Schedule Homecare visit  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interactive response technology (IRT) calls 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Inclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video chat with Investigator and site staff 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history; diabetes 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication(s) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationd 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh and body weight 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virtual material/device shipment 
(Bluetooth devices)e 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation/collection of e-diary 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening  
Randomization  
Treatment period 
Follow-up 
Visits  
1 
Step-1a 
1 
Step-2b 
2  
Step-1c 
2  
Step-2d
3  
 
  
4 
 
 
5 
 
 
6 
 
 
7 
8 
 
 
9  
10 
 
 
11 
 
 
12 
EOTg 
13 
EOS 
 
Traditional group  
 
P 
 
 
 
P 
 
P 
 
P 
 
P 
 
Virtual group  
 
(Digital screening) 
 
P & 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks  
-3 
-2 
-1 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
1 week 
Window (day) 
 
 
-/+ 4 
 
-/+ 3 
-/+ 3 
-/+ 3 
-/+ 4 
-/+3 
-/+ 4 
-/+ 3 
-/+ 4 
-/+ 3 
-/+ 3 
+/-2 
Randomization via IRT call  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Video chat with investigator and site staff 
via the virtual devicee 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Allocation of study medication (IMP) 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
First IMP (Toujeo) injectione 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation and review of IMP and 
NIMP dosesf 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IMP compliance check; collecting & 
counting used & unused pens 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Diet and lifestyle counselling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Glucose meter shipmentc 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
7-Point SMPGi 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
5-point SMPGi 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Upload SMPG to PCj 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
AE/SAE 
 
To be assessed and reported (if any) since consent throughout the study (report SAE to the sponsor within 24 hours) 
Hypoglycemia recording 
 
 
To be assessed and reported (if any) since randomization throughout the study 
Injection site reactions, PTCs 
 
 
To be assessed and reported (if any) since randomization throughout the study 
Central Laboratoryk,e 
 
HbA1c, FPG 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Hematology, clinical biochemistryl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening  
Randomization  
Treatment period 
Follow-up 
Visits  
1 
Step-1a 
1 
Step-2b 
2  
Step-1c 
2  
Step-2d
3  
 
  
4 
 
 
5 
 
 
6 
 
 
7 
8 
 
 
9  
10 
 
 
11 
 
 
12 
EOTg 
13 
EOS 
 
Traditional group  
 
P 
 
 
 
P 
 
P 
 
P 
 
P 
 
Virtual group  
 
(Digital screening) 
 
P & 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks  
-3 
-2 
-1 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
1 week 
Window (day) 
 
 
-/+ 4 
 
-/+ 3 
-/+ 3 
-/+ 3 
-/+ 4 
-/+3 
-/+ 4 
-/+ 3 
-/+ 4 
-/+ 3 
-/+ 3 
+/-2 
Urine analysism 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP only)n 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
PROs and other questionnaireso 
 
Diabetes related PROs: DTSQs, DDS, 
HFS-II 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Diabetes related PRO: DTSQc 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Was it Worth It (WIWI) Questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Work Productivity and Impairment Study 
Participation (WPAI-SP) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Overall Study Experience - Participation 
(OSEP) part 1 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Overall Study Experience - Participation 
(OSEP) part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Resource Use Questionnaire (RUQ) 
 
 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Overall Study Experience - Sites (OSES) 
– part 1 (resource requirements) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall Study Experience – Sites (OSES) 
– part 2 (relationship, satisfaction) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Qualitative exit interviewp 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a Prior to Visit 1, patients will be contacted by the sites or guided by the multi-channel digital recruiters to the eConsent web portal (Parallel 6 Website). Informed consent process will be completed electronically by 
the candidate trial patients.  During the eConsent process, the study purpose, virtual tools for participation, and other protocol requirements will be introduced and discussed with the patients in the text or 
audio/video manner.  After eSigning and counter-eSigning by the patient and the investigator, the enrolment IRT call will be made and the patient ID assigned.  
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b Assessments at Visit 1- Step 2 will be performed in-person by Homecare health professional (The MRN) in corporation with the study investigators and designees. This visit can occur at the patient’s home, at 
work, or at any location providing the adequate space and level of privacy. Patient identification will be further verified and confirmed.   
c At the end of screening, investigators will determine the eligibility of the screened patients for participation. The randomization IRT call will be made at the Visit 2- Step 1. Patients will be informed by the study sites 
of their randomization group and Visit 2- Step 2 will be scheduled for the baseline assessments within 1 week (+/- 4 days). 
Glucose meters with Bluetooth access and associated accessories (lancet, control solutions, test strips, etc), e-diaries features, and instructions will be shipped to all eligible patients. Patients will use the study 
provided glucose meters throughout the study.  
d Physical examination will be performed at the in-person visit in the traditional group. In the virtual group, physical examination will be performed on-site, in-person, between randomization IRT call and the first IMP 
administration. All other assessments will occur remotely on the day of the first IMP administration (Day 1). 
e Only for patients randomized in virtual group: 
• 
They will receive the Bluetooth devices for their remote participation and the IMP (Toujeo®) before Visit 2-Step 2. 
• 
Shortly after randomization (IRT call), they will be scheduled for an in-person visit to allow for the initiation physical examination performed by the investigator. 
• 
They will be further trained on the Bluetooth devices utilization. 
• 
The IMP starting date and dose will be instructed by the investigator at the time of Visit 2-Step 2. The first IMP (Day 1) data will be documented with the dose in the e-CRF. 
• 
All study assessments, including vital signs and weight, will be done via the Bluetooth devices by the patients at home.   
• 
Patients located in the United States (US) will receive a laboratory requisition and have their blood drawn at any local Quest®. For patients located in Canada, blood draw will be performed by the Homecare 
via The MRN.  
• 
Unscheduled on-site visits or Homecare physician visits (depending on the patient’s location) only for safety assessment could be scheduled as deemed necessary by the investigator (ie, performance of 
physical examinations is critical to determine a diagnosis or further evaluation procedure for an AE). 
f 
IMP dose will be titrated at the investigator’s discretion to achieve the fasting glycemic target while avoiding hypoglycemia 
g EOT assessments will also be performed for any patients who prematurely discontinue the study treatment.  Patients should continue the study procedure as planned up to the EOS after IMP discontinuation.  
h Heart rate and blood pressure (sitting position)  
i 
7-point SMPG profile (before [preinjection after randomization] and 2 hours after breakfast, lunch and dinner, and at bedtime): at least ONE day during the weeks before Visit 2-Step 2 (Week 0), Visit 10 (Week 16), 
and Visit 12 ( Week 24) 
5-point SMPG profile (before breakfast, lunch and dinner; 2 hours after a main meal [or as per investigator’s instruction] and at bedtime): at least 3 days during the week before each visit 
The SMPG before breakfast should be measured in the fasting status, ie, after the patient wakes up, before breakfast, and before injection of any insulin; preferably no food should have been taken overnight. A 
note should be made in the diary if the SMPG is not tested in fasting status (eg, if food was taken to cope with a hypoglycemic episode)  
j 
Only for patients randomized in the traditional group 
k Blood samples will be sent to and analyzed by Quest® central lab  
l 
Hematology: erythrocytes, hemoglobin, hematocrit, leukocytes and platelets. Clinical chemistry: total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), 
AST, ALT, ALP, plasma glucose, creatinine, estimated creatinine clearance, uric acid, sodium, and potassium 
m Urine analysis by dipstick: pH, glucose, ketones, leucocytes, blood/hemoglobin, protein 
n For women of child-bearing potential (WOCBP): serum pregnancy test for screening; urine pregnancy test for subsequent monitoring and it can be confirmed with a serum test if needed. For WOCBP in virtual 
group, the urine pregnancy test kit will be provided by the study.  
o For patients randomized to the virtual group, all questionnaires will be performed remotely via the mobile technology at home. For patients randomized in the traditional group, the questionnaires will be completed 
electronically (via the mobile technology) at the study site (before visiting the study site for baseline assessment on Visit 2 Step 2).  
p In a subset of patients (approximately 30) in the virtual approach group. 
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Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DDS = Diabetes Distress Scale; DTSQc = Diabetes Treatment Satisfaction 
Questionnaire change; DTSQs = Diabetes Treatment Satisfaction Questionnaire status;  e-CRF = electronic case report form; EOS = end of study; EOT = end of treatment; FPG = Fasting plasma glucose; HbA1c = 
glycated hemoglobin A1c; HFS = Hypoglycemia Fear Survey; ID = identification; IMP = investigational medicinal product; IRT = interactive response technology; MRN = medical research network; NIMP = 
noninvestigational medicinal product; OSEP = overall study experience – participation; OSES = overall study experience – sites; PC = personal computer; PRO = patient reported outcome; PTC = product technical 
complaints; RUQ = resource use questionnaire; SAE = serious adverse event; SMPG = self-monitoring of plasma glucose; US = United States; WIWI = was it worth it; WPAI-SP = work productivity and impairment  
study participation; WOCBP = women of child-bearing potential;  
 
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2 
TABLE OF CONTENTS 
 
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................17 
2.1 
LIST OF TABLES...........................................................................................................................22 
2.2 
LIST OF FIGURES.........................................................................................................................22 
3 
LIST OF ABBREVIATIONS ..........................................................................................................23 
4 
INTRODUCTION AND RATIONALE.............................................................................................25 
5 
STUDY OBJECTIVES ...................................................................................................................27 
5.1 
PRIMARY.......................................................................................................................................27 
5.2 
SECONDARY ................................................................................................................................27 
6 
STUDY DESIGN ............................................................................................................................28 
6.1 
DESCRIPTION OF THE STUDY...................................................................................................28 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................29 
6.2.1 
Duration of study participation for each patient .............................................................................29 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................29 
6.3 
INTERIM ANALYSIS......................................................................................................................29 
7 
SELECTION OF PATIENTS..........................................................................................................30 
7.1 
INCLUSION CRITERIA..................................................................................................................30 
7.2 
EXCLUSION CRITERIA ................................................................................................................30 
7.2.1 
Exclusion criteria related to study methodology ............................................................................30 
7.2.2 
Exclusion criteria related to the current knowledge of Sanofi compound......................................31 
8 
STUDY TREATMENTS .................................................................................................................32 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................32 
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8.1.1 
Formulation ....................................................................................................................................32 
8.1.2 
Injection devices and training for injection devices........................................................................32 
8.1.2.1 
Injection devices.............................................................................................................................32 
8.1.2.2 
Injection pen for Toujeo .................................................................................................................33 
8.1.2.3 
Training on injection devices..........................................................................................................33 
8.1.2.4 
Pen-related events.........................................................................................................................33 
8.1.3 
Provision of investigational medicinal product ...............................................................................34 
8.1.4 
Route and method of investigational medicinal product administration.........................................34 
8.1.5 
Starting dose of investigational medicinal product.........................................................................34 
8.1.6 
Adjustment of investigational medicinal product............................................................................35 
8.1.7 
Evaluation of patients not meeting glycemic targets......................................................................36 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................37 
8.2.1 
Adjustment of noninvestigational medicinal products....................................................................37 
8.3 
BLINDING PROCEDURES............................................................................................................38 
8.4 
METHOD OF ASSIGNING PATIENTS TO GROUP .....................................................................39 
8.5 
PACKAGING AND LABELING ......................................................................................................39 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................40 
8.7 
RESPONSIBILITIES ......................................................................................................................40 
8.7.1 
Treatment accountability and compliance......................................................................................41 
8.7.2 
Return and/or destruction of treatments ........................................................................................41 
8.7.2.1 
Investigational medicinal product (Toujeo) ....................................................................................41 
8.7.2.2 
Noninvestigational medicinal product  (mealtime insulin analogs) ................................................42 
8.8 
CONCOMITANT MEDICATION.....................................................................................................42 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................43 
9.1 
PRIMARY ENDPOINT ...................................................................................................................43 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................44 
9.2.1 
Study methodology endpoints........................................................................................................44 
9.2.1.1 
Patient satisfaction with trial experience........................................................................................44 
9.2.1.2 
Impact of trial participation patient reported outcome....................................................................44 
9.2.1.3 
Patient burden with trial participation.............................................................................................44 
9.2.1.4 
Resource use.................................................................................................................................45 
9.2.1.5 
Other study methodology endpoints ..............................................................................................45 
9.2.2 
Diabetes control endpoints ............................................................................................................45 
9.2.2.1 
Diabetes-related patient reported outcomes..................................................................................45 
9.2.2.2 
Secondary glycemic endpoints ......................................................................................................46 
9.2.2.3 
Dose of basal and mealtime insulin ...............................................................................................49 
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9.2.3 
Patient care endpoints ...................................................................................................................49 
9.2.3.1 
Investigator questionnaires ............................................................................................................49 
9.2.3.2 
Patient interviews...........................................................................................................................49 
9.2.4 
Safety endpoints ............................................................................................................................50 
9.2.4.1 
Adverse events ..............................................................................................................................50 
9.2.4.2 
Product technical complaints .........................................................................................................50 
9.2.4.3 
Laboratory safety variables............................................................................................................50 
9.2.4.4 
Hypoglycemia.................................................................................................................................50 
9.3 
FUTURE USE OF SAMPLES ........................................................................................................53 
9.4 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................53 
10 
STUDY PROCEDURES ................................................................................................................54 
10.1 
VISIT SCHEDULE..........................................................................................................................55 
10.1.1 
Screening Visit (Visit 1-Step1 and Step 2) Week -3 to Week -2....................................................55 
10.1.2 
Randomization Visit (Visit 2)..........................................................................................................57 
10.1.2.1 Visit 2-Step 1 (Week -1).................................................................................................................57 
10.1.2.2 Visit 2-Step 2 (Week 0)..................................................................................................................57 
10.1.3 
Phone call/Virtual Visits (V3-5, V7, V9 and V11)...........................................................................59 
10.1.4 
Onsite/virtual visits (V6, 8, and V10) during treatment period .......................................................59 
10.1.5 
End of Treatment (EOT) visit (Visit 12, Week 24)..........................................................................60 
10.1.6 
Follow-up Visit (Visit 13) ................................................................................................................61 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................62 
10.2.1 
Source data to be found in patient´s file ........................................................................................62 
10.2.2 
Source data verification requirements for screen failures..............................................................62 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................63 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product................................63 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product ...............................63 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................63 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................64 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................64 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................65 
10.4.1 
Definitions of adverse events.........................................................................................................65 
10.4.1.1 Adverse event ................................................................................................................................65 
10.4.1.2 Serious adverse event ...................................................................................................................65 
10.4.1.3 Adverse event of special interest...................................................................................................66 
10.4.2 
General guidelines for reporting adverse events ...........................................................................67 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................67 
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10.4.4 
Guidelines for reporting adverse events of special interest...........................................................68 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................69 
10.6 
ADVERSE EVENTS MONITORING..............................................................................................70 
11 
STATISTICAL CONSIDERATIONS..............................................................................................71 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................71 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................71 
11.3 
ANALYSIS POPULATIONS...........................................................................................................72 
11.3.1 
Intent-to-treat population................................................................................................................72 
11.3.2 
Safety population ...........................................................................................................................72 
11.3.3 
PRO population..............................................................................................................................73 
11.4 
STATISTICAL METHODS .............................................................................................................73 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................73 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................73 
11.4.1.2 Compliance ....................................................................................................................................74 
11.4.2 
Analysis of primary endpoint..........................................................................................................74 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................74 
11.4.3 
Analysis of secondary endpoints ...................................................................................................74 
11.4.3.1 Analyses of study methodology endpoints ....................................................................................74 
11.4.3.2 Analyses of diabetes control endpoints .........................................................................................76 
11.4.3.3 Analyses of patient care endpoints................................................................................................77 
11.4.3.4 Analyses of safety endpoints .........................................................................................................78 
11.5 
INTERIM ANALYSIS......................................................................................................................79 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................80 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................80 
12.2 
INFORMED CONSENT .................................................................................................................80 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................80 
13 
STUDY MONITORING...................................................................................................................82 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................82 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................82 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................83 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................83 
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13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................83 
14 
ADDITIONAL REQUIREMENTS...................................................................................................84 
14.1 
CURRICULUM VITAE....................................................................................................................84 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................84 
14.3 
CONFIDENTIALITY .......................................................................................................................84 
14.4 
PROPERTY RIGHTS.....................................................................................................................85 
14.5 
DATA PROTECTION.....................................................................................................................85 
14.6 
INSURANCE COMPENSATION....................................................................................................85 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................86 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................86 
14.8.1 
By the Sponsor...............................................................................................................................86 
14.8.2 
By the Investigator .........................................................................................................................87 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................87 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................87 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................88 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................89 
17 
APPENDICES................................................................................................................................91 
APPENDIX A 
GUIDANCE ON CONTRACEPTIVE METHODS AND COLLECTION OF 
PREGNANCY INFORMATION......................................................................................................92 
APPENDIX B 
STUDY METHODOLOGY PATIENT REPORTED OUTCOMES........................................94 
APPENDIX C DIABETES CONTROL PATIENT REPORTED OUTCOMES...........................................136 
APPENDIX D INVESTIGATOR QUESTIONNAIRES ..............................................................................231 
APPENDIX E 
BLUETOOTH DEVICES AND ASSOCIATED MATERIAL................................................243 
 
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2.1 
LIST OF TABLES 
Table 1 – Titration of investigational medicinal product dose .......................................................................36 
Table 2 - Simple titration: Titration of mealtime insulin based on a pattern of post-meal glucose (median 
<130/>180 mg/dL in the prior 3 days) ...........................................................................................................38 
Table 3 - Carbohydrate counting: Insulin-to-carbohydrate ratio group .........................................................38 
Table 4 – 24-week on-treatment period for primary and secondary endpoints (glycemic and insulin dose) 43 
Table 5 – Instruction for SMPG performed during the study.........................................................................48 
Table 6 - Summary of adverse event reporting instructions..........................................................................69 
 
2.2 
LIST OF FIGURES 
Figure 1 – Classification of hypoglycemia.....................................................................................................51 
 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine transaminase 
ANCOVA: 
analysis of covariance 
ANOVA: 
analysis of variance 
BP: 
blood pressure 
CI: 
confidence interval 
CPMP: 
Committee for Proprietary Medicinal Products 
CRF: 
case report form 
CV: 
curriculum vitae 
CVD: 
cardiovascular disease 
DDS: 
Diabetes Distress Scale 
DRF: 
discrepancy resolution form 
DTP: 
direct to patient 
DTSQ: 
diabetes treatment satisfaction questionnaire 
DTSQc: 
Diabetes Treatment Satisfaction Questionnaire change 
DTSQs: 
Diabetes Treatment Satisfaction Questionnaire status 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
FPG: 
fasting plasma glucose 
GCP: 
good clinical practice 
HbA1c: 
glycated hemoglobin A1c 
HFS-B: 
hypoglycemia fear survey-behavior 
HFS-II: 
Hypoglycemia Fear Survey-II 
HFS-W: 
hypoglycemia fear survey-worry 
HLGT: 
high level group term 
HLT: 
high level term 
ICH: 
International Conference on Harmonisation 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
IRT: 
interactive response technology 
ITT: 
intent to treat 
MedDRA: 
medical dictionary for regulatory activities 
MMRM: 
mixed effect model with repeated measures 
MRN: 
Medical Research Network 
NIMP: 
noninvestigational medicinal product 
NPH: 
neutral protamine Hagedorn 
OSEP: 
overall study experience-participation 
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OSES: 
overall study experience-sites 
PCSA: 
potentially clinically significant abnormality 
PRE: 
pen-related event 
PRO: 
patient reported outcome 
PT: 
preferred term 
PTC: 
product technical complaint 
RUQ: 
resource use questionnaire 
SAE: 
serious adverse event 
SC: 
subcutaneous 
SD: 
standard deviation 
SMBG: 
self-monitoring of blood glucose 
SMPG: 
self-monitoring of plasma glucose 
SOC: 
system organ class 
SUSAR: 
suspected unexpected serious adverse reaction 
T1DM: 
Type 1 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit normal 
US: 
United States 
USPI: 
United States package insert 
WIWI: 
was it worth it 
WOCBP: 
woman of child-bearing potential 
WPAI: 
work productivity and impairment, work productivity and impairment-study 
participation 
WPAI-SHP: 
WPAI-specific health problem 
WPAI-SP: 
Work Productivity and Impairment-study participation 
 
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4 
INTRODUCTION AND RATIONALE 
Across the clinical landscape, there are an increasing number of clinical studies with increased 
study complexity. These traditional studies typically have several factors which contribute to 
recruitment and retention challenges, as well as reduced patient engagement, study compliance, 
and, ultimately, data quality issues. Common factors include the requirement for a patient to stay 
near the clinical site, affiliation with a physician in a pharmaceutical investigator network, ability 
to schedule life events around specific study requirements, or have medical insurance. 
Traditional, complex studies increase patient burden with the often rigid study requirements. 
Additional frustration can occur when a patient does not receive their individual or study results. 
In addition, the increased study complexity and operational processes by many of the study 
sponsors place an additional burden on the clinical sites and increase the operational costs (1), 
which is a main driver of total study cost.  
The strategic use of innovative methods and mobile health technologies in clinical studies may 
provide a true patient-centric operational model, improving both patient experience and study 
compliance.  This innovative approach could facilitate patient participation beyond the established 
sponsor-investigator network, by allowing for recruitment of geographically remote patients. For 
the clinical site, this approach may provide processes equivalent with the current clinical practice, 
while allowing sites to be more efficient in the execution of clinical studies. These benefits extend 
to the sponsor: by eliminating geographical restrictions, a smaller number of sites may be needed 
per trial – thereby reducing monitoring efforts and saving costs. 
With the impact of increasing smartphone use, decreasing age and socioeconomic barriers due to 
technology (2), and the increasing number of patients seeking disease specific online communities 
(3), creating an operational approach aligned with these trends can allow for a simple, cost 
effective, and more encompassing clinical trial approach. 
The first industry sponsored virtual study was a Phase IV overactive bladder study in the United 
States (US), conducted by Pfizer in 2011. The study did not reach a successful conclusion, but 
there were many lessons learned (3). These lessons learned shared by Pfizer and the experiences 
gained from vendors who participated in the virtual study have benefited the larger pharma 
community. The integration of mobile health technology, telemedicine, and remote sensors into 
classic clinical studies has increased significantly over the past decade (4). Pfizer’s first attempt at 
the virtual study was an evolution of this continued innovative clinical activity. Sanofi eStudy will 
be a compilation of collective experience and lessons learned to provide the best chance of 
success. 
Diabetes (type 1 and type 2) affects 415 million people globally, approximately 22 million adults 
and 0.54 million children have Type 1diabetes (5). The effect of type 1 diabetes-related 
complications on patients and healthcare systems is significant, with reported incidences of 
proliferative retinopathy, nephropathy and cardiovascular disease of 47%, 17% and 14%, 
respectively, after 30 years of diabetes (6). There are a number of barriers to glycemic control in 
type 1 diabetes, including the occurrence and fear of hypoglycemia and the complexity and 
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demands of day-to-day management, in particular the need for frequent self-monitoring of blood 
glucose (SMBG) and regular adjustments in insulin dosing. These challenges have an enormous 
impact on patient quality of life and healthcare cost (7, 8). Utilizing mobile health technologies 
(eg, assisting in medication compliance, SMBG monitoring, reinforcing diabetes health, etc) 
could play an important role in reducing some of the common barriers, improving glycemic 
control, and increasing empowerment of the patients by supporting them in informed decision 
making. 
MSC15146 (eStudy) is a pilot clinical study to evaluate the methodology of a virtual clinical trial 
conduct in patients with type 1 diabetes prior to performance of full-scale studies. The effect of 
the virtual versus traditional trial conduct on multiple outcomes including study activities, 
investigational medicinal product (IMP)/noninvestigational medicinal product (NIMP) 
compliance, patient retention, etc, will be analyzed to assess the usability and appropriateness of 
the virtual methodology. The virtual study conduct on glycemic control will be evaluated by the 
changes in glycated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and self-monitoring 
of plasma glucose (SMPG) profile in the two groups that will receive the same basal plus insulin 
regimen during the study period. In addition to the glycemic parameters, the study introduced a 
number of patient reported outcomes (PROs), including the diabetes related questionnaires that 
assess glycemic control, fear of hypoglycemia, satisfaction of treatment from patients’ 
perspective, and other questionnaires that assess the operational process, physician-patient 
relationship, trial time consumption, burdens to trial patients, etc.  
For the first time in a Sanofi study, designated data (eg, SMPG, safety and central lab results, etc) 
will be available to patients in the virtual group, using a smartphone. This direct access to their 
data could support patients in diabetes management by helping them make better-informed 
decisions, which may have a positive impact on metabolic outcomes.   
With the above study design the eStudy outcomes are expected to provide useful information for 
the future use of a virtual approach about the feasibility and appropriateness in both glycemic 
control and operational process, such as IMP adherence, barriers, burden to patients and sites, 
study complexity, patient compliance, data quality etc. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to evaluate the effect of virtual approach via novel 
technologies versus traditional study conduct on glycemic control in terms of HbA1c. 
5.2 
SECONDARY 
The study secondary objective is to evaluate the appropriate utilization of virtual approach via 
novel technologies during the study and to assess the effect of the virtual versus traditional study 
conduct on multiple outcomes in terms of study methodology and diabetes control: 
• Study methodology with the two approaches: 
- 
Patient satisfaction with the trial experience via a PRO 
- 
Impact of clinical trial participation via a PRO 
- 
Patient burden with the clinical trial experience via a PRO 
- 
Resource use via a PRO 
- 
Medication and key study activity compliance 
- 
Patient retention  
• Diabetes control with the two approaches: 
- 
Diabetes related PROs 
- 
Glycemic control (HbA1c, FPG, SMPG) 
• Patient care with the two approaches: 
- 
Doctor/site-patient relationship 
- 
Site satisfaction with provisioned care 
- 
Patient experience in the clinical trial via a qualitative exit interview 
• Safety assessment managed by the two approaches including: 
- 
Hypoglycemic events 
- 
Adverse Events (AEs) 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE STUDY 
MSC15146 (eStudy) is a randomized, open label, 2 approach groups, multicenter pilot study. The 
study is a postmarketing Phase 4 trial which will recruit outpatients with Type 1 diabetes mellitus 
(T1DM) currently treated with insulin glargine 100 U/mL (eg, Lantus or Basaglar) plus rapid-
acting insulin analogs. The patients must have access to mobile technology (eg, smartphone) and 
be digital-literate. They will eSign the consent on the study website. 
The study will be conducted in the US and in Canada with at least 3 participating investigational 
centers. It is planned to recruit 150 patients. 
Eligible patients will be randomized 1:1 (virtual : traditional) into 2 study groups to follow one of 
two approaches for completion of all study procedures: 
• a remote, virtual approach (n = 75 patients); patients of this group will not visit the study 
sites during the entire study course, except for a physical examination before IMP 
initiation. All study assessments, including vital signs, weight, lab variables, etc, will be 
completed via the Bluetooth devices that instantly transfer the digital data, available for 
investigators’ view. Video chat between the patients and investigators/designees may 
occur for safety reason in addition to the planned study visits. 
• a traditional trial approach (n = 75 patients)  
Stratification factors for randomization include study site and HbA1c <7.6% or ≥7.6%. The 
rationale for stratification by study site is the small number of sites and the fact that some 
assessments for patient care are done at site level. It is therefore deemed important to ensure 
balance at site level in number of patients randomized across the virtual and traditional approach 
groups. Patients of both groups will receive the same IMP: daily subcutaneous (SC) injection of 
Toujeo as the basal insulin. Protocol-mandated background therapy consists of the existing rapid 
acting insulin analogs (Humalog, Novolog, or Apidra) that have been used before the start of the 
study and will be continued throughout the study. This background treatment will not be supplied 
by the sponsor. 
The study consists of 3 periods:  
• an up-to-3 week screening period 
• a 24-week treatment period 
• a 1-week post-treatment period (follow-up) 
The screening period includes 2 steps to complete the digital consent process via the study-
specific webpage and the eligibility assessment by the study site. Screening procedures will be 
performed by Homecare services (via the Medical Research Network [MRN]) provided medical 
professional in collaboration with the investigators. The investigators will then complete the 
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eligibility assessments at the end of screening, the randomization, and the shipment of study 
material (Step 2).  
During the 24-week treatment period, the patients in both groups will receive the same study 
treatment with Toujeo as the basal insulin plus their existing rapid-acting mealtime insulin 
analogs (Humalog, Novolog, or Apidra) to manage their diabetes. Toujeo dose will be titrated to 
target the fasting SMPG between 80 and 130 mg/dL; meal time insulin analogs will be adjusted 
following investigators’ instructions to maintain postprandial SMPG within a range of 130 to 
180 mg/dL. 
All patients will monitor their plasma glucose via the study provided glucose meter. The SMPG 
values will be used to guide the insulin dose adjustment and document the hyper- or 
hypoglycemic events. 
Any posttreatment safety information will be collected during the 1-week posttreatment period.  
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study duration consists of: 
• An up-to-3 weeks screening period. The screening starts from signed consent form 
• A 24-week treatment period 
• A 1-week (+/-2 days) posttreatment safety follow-up after treatment completion or 
premature discontinuation of study treatment. 
For an individual patient, the maximum study duration is about 28 weeks. 
6.2.2 Determination of end of clinical trial (all patients) 
End of clinical trial is defined as the last patient completes the last visit (Visit 13). 
6.3 
INTERIM ANALYSIS 
No interim analysis 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patients with T1DM diagnosed at least one year before the screening visit 
I 02. Patients who are treated with multi-dose insulin using insulin glargine 100 U/mL 
(eg, Lantus or Basaglar)  as basal insulin and rapid- acting insulin analogues as bolus 
insulin 
I 03. Patient with access to or experience with mobile technology (eg, tablet or smartphone) 
I 04. eSign the consent on the study web portal 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 2 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years at screening (Visit 1 – Step 1) 
E 02. Type 2 diabetes mellitus 
E 03. HbA1c <5.4% or ≥9.0% measured at screening (Visit 1- Step 2) 
E 04. Patients who received less than 6 months treatment with any basal plus mealtime insulin 
E 05. Use of any basal insulins other than insulin glargine 100 U/mL (eg, Lantus or Basaglar) 
within 3 months before screening 
E 06. Use of an insulin pump within 6 month before screening 
E 07. Use of meal-time insulin other than rapid-acting insulin analogs (Humalog, Novolog, or 
Apidra), eg, human regular insulin, within 30 days before screening 
E 08. Use of any noninsulin injectable or oral antidiabetic medication within the past 3 months 
before screening 
E 09. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one 
week or more within 3 months before screening 
E 10. Use of any investigational drug(s) within 3 months, or 5 half-lives, whichever is longer, 
before screening (Visit 1) 
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E 11. Patients with severe systemic disease or with short life expectancy or any medical 
condition that might interfere with the evaluation of study medication according to 
investigator's medical judgment 
E 12. Hemoglobinopathy resulting in undetectable HbA1c by the central laboratory, or hemolytic 
anemia requiring transfusion of blood or plasma products within 3 months before 
screening 
E 13. Mental disorders or any neurologic disorder that would affect patient's ability to meet the 
study requirements, or patients  deemed unlikely to safely manage insulin dosage by the 
investigator 
E 14. Patients with insufficient smartphone skills or unwilling to properly use the virtual tools 
deemed by the investigator based on the observation over the digital screening procedure 
E 15. Patients unable to speak, read, or write 
E 16. Patient is the investigator or any subinvestigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the protocol. 
7.2.2 Exclusion criteria related to the current knowledge of Sanofi compound  
E 17. Known hypersensitivity/intolerance to insulin glargine, rapid-acting insulin analogs, or any 
of their excipients 
E 18. Patients experienced with any severe hypoglycemic episode resulting in seizure, 
unconsciousness, or coma, and/or leading to hospitalization during the past 6 months 
before screening 
E 19. Documented (within 12 months) medical history of unstable proliferative diabetic 
retinopathy or  or macular edema likely to require laser, surgical treatment during the study 
period 
E 20. Pregnant or breast-feeding women or women who intend to become pregnant during the 
study period  
E 21. Woman of child-bearing potential (WOCBP) not protected by highly-effective method(s) 
of birth control and/or who are unwilling or unable to be tested for pregnancy (see 
contraceptive guidance in Appendix A).  
E 22. Any country-related specific regulation that would prevent the subject from entering the 
study 
Note: A patient should not be randomized more than once. One time re-screening is allowed at the 
Investigator’s medical judgment for any manageable reasons that cause the screening failure and 
the patient is likely to be eligible before the enrolment completion.  
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The IMP is Toujeo (insulin glargine 300 U/mL, HOE901-U300). 
Note: Dilution or mixing of Toujeo with other insulins is not allowed. 
8.1.1 Formulation 
Toujeo (HOE901-U300) is supplied for SC injection as a sterile, nonpyrogenic, clear, colorless 
solution in the Toujeo SoloSTAR® pen (a prefilled, disposable pen for insulin glargine 
300 U/mL).  
Each pen contains in total 450 units of insulin glargine (1.5 mL of 300 units/mL insulin glargine 
solution). This pen allows dose setting in the range of 1 to 80 units with a minimum of 1 unit 
increment. 
8.1.2 Injection devices and training for injection devices 
8.1.2.1 Injection devices 
Patients will be provided with needles and the pen injection devices (prefilled study drug pens) 
specifically labeled for the use in the study.  
The following commercial 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  
Handling procedures of the pen and needles and administration technique is provided in specific 
manuals. The patients will be reminded of the IMP dosage at Visit 2-Step 2 before the IMP 
administration. For the duration of the treatment, the patients will be required to use the same type 
of study drug disposable pens and needles. 
Pen device issues (malfunctions) should be reported to the sponsor by the means of a procedure 
on product technical complaint (PTC) forms (see details in Section 8.1.2.4). 
Injection pens should never be shared with others. 
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8.1.2.2 Injection pen for Toujeo  
All study patients will receive the appropriate number of disposable pens for Toujeo (insulin 
glargine 300 U/mL) and needles according to the dose range.  
Each pen contains a cartridge with a total 450 units of insulin glargine. Doses can be set in steps 
of 1 unit. If a dose of Toujeo greater than 80 units is required, it will be given as two or more 
consecutive SC injections at the same time with the daily dose split in equal or close to equal 
doses. Splitting the doses into a morning and evening injection is not allowed. 
8.1.2.3 Training on injection devices  
Instructions for use will be provided, which explain how to use the disposable pen injectors. The 
injection device for the IMP is the same as or similar to the device that they have used for insulin 
glargine 100 U/mL. Therefore, no additional training on the devices is planned. The capability of 
self-injection with the SoloSTAR pen will be checked by the site staff in-person (traditional 
group) or via video technology (virtual group). 
8.1.2.4 Pen-related events 
A Pen-Related Event (PRE) includes any suspected problem with the injection device(s) used in 
the study which has or may lead to a health hazard (eg, AE). Typical problems include pen 
performance failure, patient (or caregiver) having difficulty understanding the instructions or 
using the pen, use error, etc. 
Examples of PREs include but are not limited to: 
• Dosing problems: jamming, inability to inject, partial injection, need to repeat injection, 
dosage knob stuck 
• Needle issues: difficulty attaching the needle 
• Breakage of the pen 
• Difficulty to understand the instructions in the instructions for use 
• Use error: Incorrect use of the pen by the patient/caregiver/healthcare provider 
Pen-related events will be proactively monitored during the study by asking at each study visit 
whether the patient/caregiver experienced any PRE. If answer is yes, the specific electronic case 
report form (e-CRF) PRE Questionnaire will be completed. 
If the PRE is associated with a symptomatic hypoglycemic event, a hyperglycemic AE or another 
AE, the corresponding symptomatic hypoglycemic forms or AE forms must also be completed. 
This associated AE will be qualified as a serious adverse event (SAE) only if it fulfills seriousness 
criteria, and in this case, the SAE reporting procedure (Section 10.4.3) should be followed. 
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As needed, further instruction and troubleshooting guidance should be provided to the patient by 
the study site according to the instructional materials/troubleshooting guide provided by the 
Sponsor. 
For PREs that are not resolved by further guidance/review of instructions or troubleshooting with 
the pen during a visit, a PTC form must be completed, the pen associated with the event should be 
retrieved and both should be sent to the manufacturing site for technical investigation. 
8.1.3 Provision of investigational medicinal product 
Patients of the traditional group will be provided with the IMP by the site pharmacist or 
investigator during the on-site visits (Visit 2-Step 2, Visit 6, Visit 8, and Visit 10). 
Patients of the virtual group will receive the IMP at home using the Direct-To-Patient (DTP) 
service. Patient identification remains confidential and will not be disclosed to study sponsor. For 
this reason, the IMP delivery will be managed by the Marken company (service provider). The 
clinical site will advise the patient as appropriate as to how the DTP process operates before the 
DTP process start.  
• The clinical site investigator or pharmacist will have to inform Marken at least 72 hours 
before the pick-up time.  
• Marken will send the shipping material to the site on the day before the pick-up time at the 
latest. 
• Marken will deliver the IMP at patients’ home at Visit 2, Visit 6, Visit 8, and Visit 10. 
8.1.4 Route and method of investigational medicinal product administration 
Toujeo will be self-administered once daily by SC injection, in the left or right anterolateral or left 
or right posterolateral abdominal wall or thighs or upper arms. Within a given area, location of the 
injection site of IMP should be changed (rotated) at each time to prevent injection site skin 
reactions. 
The injection sites for IMP and NIMP should be different so that, if any, an injection site reactions 
can be attributed specifically either to IMP (Toujeo) or NIMP (mealtime insulin). 
8.1.5 Starting dose of investigational medicinal product 
After randomization, patients will follow the investigator’s instruction to start the IMP (Toujeo) 
and the daily dose of Toujeo at Visit 2-Step 2.  
Patients randomized in the virtual group will receive the IMP by DTP process (Section 8.1.3) 
while patients in the traditional group will receive their IMP at the site at Visit 2-Step 2. The IMP 
should NOT be started until the completion of all the baseline performances (see flowchart in 
Section 1.2) and discussed with the investigator at Visit 2-Step 2, which should occur 7 (± 4) days 
after the randomization interactive response technology (IRT) call. 
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The starting dose of IMP on Day 1 is the patient’s current insulin glargine 100 U/mL dose, ie, the 
same dose used on the day before. Patient should administer Toujeo at the same time of the day as 
their previous insulin glargine 100 U/mL injection, which is usually in the morning or in the 
evening around the same time daily. 
Patient should not change the injection time during the 24-week treatment period.  
The date, time, and dose of Toujeo will be documented in the e-CRF.  
8.1.6 Adjustment of investigational medicinal product 
Investigators should follow Toujeo prescribing information to adjust Toujeo (9) dose. It is 
expected that a higher dose of Toujeo is needed to maintain the same level of glycemic control, 
when patients shift the basal insulin from insulin glargine 100 U/mL (eg, Lantus or Basaglar) to 
Toujeo. During the treatment period, Toujeo will be titrated at the investigator’s discretion to 
achieve the fasting glycemic target while avoiding hypoglycemia. 
The target range for fasting (prebreakfast/preinjection) plasma glucose is between 80 and 
130 mg/dL (4.4 and 7.2 mmol/L).  
The upward dose titration should continue until the patient reaches the target fasting 
(prebreakfast/preinjection) SMPG. All efforts should be made to reach the target ranges for 
plasma glucose by 6 to 8 weeks post randomization. Thereafter, the dose will be adjusted as 
necessary to maintain the glycemic control until the end of treatment (EOT) at Week 24. 
Changes in the Toujeo dose are based on the average fasting pre-breakfast SMPG values of past 
3 days measured by the patients. If the fasting SMPG is ≥130 mg (7.2 mmol/L), the Toujeo dose 
will be increased by 10%. Table 1 provides examples for the 10% titration rule. Other preprandial 
(prelunch, predinner) SMPG measurements may also be taken into account. 
If considered helpful to achieve the fasting glycemic target by the investigator, the mealtime 
insulin (including bedtime) may be titrated before additional basal insulin titration to achieve a 
bedtime and prebreakfast glucose delta <50 mg/dL.  
A dose increase may be split into 1-2 incremental dose steps rather than implementing the entire 
dose increase at once, if it is considered by the investigators or medically qualified designee to be 
in the best interest of the patient to do so. The dose of Toujeo should be titrated no more 
frequently than every 3 to 4 days. 
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Table 1 – Titration of investigational medicinal product dose 
Toujeo daily dose   
10% increase rules  
Up to 21 u 
2 u , or split into 2 x 1 u over 3 days apart 
22 to 29 u 
2 or 3 u , split into 2 or 3 x 1 u over 3 days apart  
30 to 36 u 
3  u, split into 3 x 1 u over 3 days apart 
37 to 44 
3 or 4 u, split into 2 x 2 u over 3-4 days apart 
≥45 u 
4 u , split into 2 x 2 u over 3-4 days apart 
Good clinical judgment is to be exercised while titrating the basal insulin dose. 
Regular SMPG is very important in order to achieve the blood glucose targets. It is recommended 
to perform daily fasting/prebreakfast SMPG and 5-point profiles to support the titration process. 
More frequent SMPG at other timepoints (eg, postbreakfast and postdinner) 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 
first month of the treatment period, weekly contacts between the investigator and patient are 
scheduled to assess the response to treatment and to decide on dose adjustment. During these 
visits (phone or virtual), patients will report their SMPG data, insulin doses and hypoglycemia to 
the study site.  
It is at the discretion of the investigator to allow well-trained patients to adjust their IMP insulin 
dose between the scheduled visits without prior consultation of the site personnel. 
In cases of hypoglycemia, dose will be adjusted as follows: 
• 
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 or meal-time insulin may be reduced or modified at any time for 
hypoglycemia during the study 
• 
Patients who experience 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 
8.1.7 Evaluation of patients not meeting glycemic targets 
In case the target fasting glycemic goal cannot be achieved in spite of successive IMP dose 
titration over 4-8 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) 
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• 
IMP and mealtime insulin are properly injected 
• 
There is no intercurrent 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 any intercurrent disease (to be reported in the AE/SAE/concomitant 
medication parts of the e-CRF 
• 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 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
The noninvestigational medicinal products (NIMP) are the protocol-mandated mealtime insulins, 
ie, rapid insulin analogs (Humolog, Novolog, or Apidra), which have been used by the patient 
before the screening visit. This background treatment will not be supplied by the sponsor. 
The patients in both study groups will continue with their existing mealtime insulin throughout the 
study. The type of mealtime rapid-insulin analog for each patient cannot be changed during the 
course of study. Any other types of meal-time insulin are prohibited for this study.  
The injection sites should be different for the fast-acting mealtime insulin analogs from the IMP 
so that any injection site reactions can be attributed specifically either to the fast-acting insulin or 
to IMP. Changes in the body areas used for injection of either insulin should be avoided as far as 
possible during the study.  
8.2.1 Adjustment of noninvestigational medicinal products  
The dose of the mealtime insulin analogs (Humolog, Novolog, or Apidra) will be titrated to 
achieve a target of 2-hour postprandial plasma glucose. The dose adjustment is at the 
investigator’s discretion in accordance with the national product label. Two recommended dose 
titration algorithms are based on a pattern of postprandial plasma glucose results of SMPG 
(simple titration) 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 and 180 mg/dL 
(7.2-10.0 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. 
• While basal insulin doses are increased, mealtime insulin doses may be reduced to avoid 
daytime hypoglycemia as deemed appropriate by the investigator.  
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• Appropriate adjustment in mealtime insulin will continue throughout the entire treatment 
period (Week 0-24). 
The two recommended regimens are described in Table 2 and Table 3. 
Table 2 - Simple titration: Titration of mealtime insulin based on a pattern of post-meal glucose 
(median <130/>180 mg/dL in the prior 3 days) 
Mealtime dose of Insulin 
Pattern of postprandial BG 
values <130 mg/dLa 
Postprandial BG values  
>180 mg/dLa 
≤10 U 
Decrease dose by 1 U 
Increase dose by 1 U 
11-19 U 
Decrease dose by 2 U 
Increase dose by 2 U 
≥20 U 
Decrease dose by 3 U 
Increase dose by 3 U 
a If more than 50% of the mealtime blood glucose (2-hour PPG) values for the week were above target. 
Table 3 - Carbohydrate counting: Insulin-to-carbohydrate ratio group 
Mealtime dose of Insulin 
Pattern of postprandial BG 
values <130 mg/dLa 
Postprandial BG values  
>180 mg/dLa 
1 U/20 g 
Decrease to 1 U/25 g 
Increase to 1 U/15 g 
1 U/15 g 
Decrease to 1 U/20 g 
Increase to 1 U/10 g 
1 U/10 g 
Decrease to 1 U/15 g 
Increase to 2 U/15 g 
2 U/15 g 
Decrease to 1 U/10 g 
Increase to 3 U/15 g 
3 U/15 g 
Decrease to 2U/15 g 
Increase to 4 U/15 g 
a If more than one-half of the mealtime blood glucose values for the prior 3 days were above target. 
Starting recommendation 1 U 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.  
The injection of the mealtime insulin analogs in relation to the meal intake will be done according 
to the individual habits of the patient prior to the study while following the instructions in the 
national product label.  
Dietary modifications (eg, snacks) will be made by the Investigator, dietician, or other medically 
qualified person based on his/her best judgment. 
8.3 
BLINDING PROCEDURES 
There will be no blinding procedures during the present study. All patients will self-inject 
themselves Toujeo (open label way) during the trial. 
The study conduct approach (virtual or traditional) cannot be blinded to physicians or patients. As 
virtual and traditional approaches are distinguishable in terms of database source, it is also not 
possible to blind this information to the Data Management team. 
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Despite the open-label nature of study, assessment of outcomes will be based on objectively 
collected data, ie, assessments of HbA1c and FPG by central laboratories blinded to patients’ 
study approach group. Also, the sponsor team will be provided blinded summary tables and 
listings to follow the study before database lock. 
8.4 
METHOD OF ASSIGNING PATIENTS TO GROUP 
There is only one study medication provided in open-label boxes for all randomized patients. 
Boxes will be individually identified with treatment kit numbers. The nonrandomized sequential 
treatment kit number list will be generated centrally by Sanofi. The study medication will be 
packaged in accordance with this list. 
The Study Biostatistician will provide the randomization scheme (including stratification) to the 
centralized randomization system (IRT). Then, the IRT generates the patient randomization list 
according to which it allocates study approach to the patients.  
At screening (Visit 1 – Step 1), the investigator or designee will contact the IRT system to receive 
the patient number. The patient identification (patient number) is composed of 12-digits (3-digit 
country code, 4-digit center code, and 5-digit patient chronological number). If a patient who had 
previously failed screening is approached for rescreening, a new informed consent form must be 
signed. In such case, a new patient number will be assigned by IRT. 
Patients will be randomized in a 1:1 ratio to either virtual or traditional study conduct approach. 
Randomization will be stratified by HbA1c obtained at the screening visit (<7.6%; ≥7.6%) and 
study site (see rationale in Section 6.1).  
On Visit 2-Step 1, the IRT will be contacted for randomization and for first treatment kit(s) 
allocation. The investigator or designee will have to call the IRT to provide some information 
(such as patient number provided by IRT at screening visit, date of birth, etc). Afterwards the IRT 
will be called again each time a new treatment kit(s) allocation is necessary, ie, the visits as 
indicated in the study flowchart (Section 1.2).  
A randomized patient is a patient who has been allocated to a randomized trial approach by the 
IRT, regardless whether Toujeo treatment kit was provided and used or not. 
A patient cannot be randomized more than once in the study. 
8.5 
PACKAGING AND LABELING 
Toujeo (insulin glargine 300 U/mL solution) is supplied for SC injection as a sterile, 
nonpyrogenic, clear, colorless solution in a 1.5 mL Toujeo SoloStar disposable prefilled pen 
(450 Units/1.5 mL).  
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Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. Treatment labels will 
indicate the treatment number used for treatment allocation. 
The respective number of the study treatment will be packaged under the responsibility of sanofi 
according to good manufacturing practice and local regulatory requirement. Toujeo will be 
supplied in boxes of 5 disposable pens for insulin glargine 300 U/mL. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor. 
The expiry date is mentioned on the IMPs labels, and storage conditions are written on the IMP 
kits labels and in the instructions for use. 
As for all medications and devices, the pens should be kept out of reach of children. 
Instructions for use including storage conditions will be provided to all sites and patients for 
optimal home storage. 
8.7 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP 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 and eliminate potential hazards. 
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Under no circumstances will the Investigator supply IMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.7.1 Treatment accountability and compliance 
At each contact with the patient, either by phone, by virtual contact (eg, video chat), or during on-
site visit, the investigator or his/her delegate has to ask the patient about administered doses of 
IMP (Toujeo).  
Returned and dispensed IMP pens and kits will be documented into the Treatment Log Form. 
Investigator or delegate has to visually check the filling status of the cartridges in the pens in the 
returned treatment kits and compare to dosing records documented in the patients’ eDiaries. 
Discrepancies have to be addressed to the patient for clarification of real treatment administration.  
The investigator completes the appropriate treatment log form based on the unused, used and in-
use IMP (study drug pens) returned and records the dosing information on the appropriate page(s) 
of the e-CRF. However as type 1 diabetes patients are requiring insulin, the level of glycemia as 
reflected by SMPG and HbA1c is a sensitive marker of adherence to insulin treatment. 
The monitor will check the e-CRF data by comparing them with patient’s diary entries, treatment 
log forms and unused treatment kits. 
8.7.2 Return and/or destruction of treatments 
Patients of the traditional group will have to return all the used, in-use, and unused IMP (box[es] 
and pen[s]) at each on-site visit (or final assessment on treatment visit in case of permanent 
premature discontinuation).  
In the virtual group, the used, in-use, and unused IMP (boxes and pens) will be retrieved by 
Marken’s driver on Visit 6, Visit 8, Visit 10, and end of treatment (EOT) visit, and returned to the 
site.   
For both groups, the site will be responsible for the IMP accountability, tracking, and destruction. 
The detailed instructions for handling will be provided by the sites. 
8.7.2.1 Investigational medicinal product (Toujeo) 
All partially-used or unused treatments (inject devices with inserted cartridges; disposable 
SoloSTAR pens) will be retrieved by the Sponsor. Pens and boxes will be retrieved for destruction 
according to local regulations. The investigator will not destroy any IMP unless the Sponsor 
provides written authorization. A detailed treatment log of the returned and destroyed IMP will be 
established with the investigator (or the pharmacist) and countersigned by the investigator and the 
monitoring team.  
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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. 
8.7.2.2 Noninvestigational medicinal product  (mealtime insulin analogs) 
Since NIMPs are not provided by the sponsor, tracking and reconciliation has to be performed by 
the investigator (or pharmacist if appropriate) according to local procedures. 
Patients have to record the administration of their mealtime insulin analog in the diary. All doses 
of mealtime insulin analogs during the day as taken for all meals and all snacks must be recorded. 
The sites have also to take care of source document of the NIMP in patient source documents and 
e-CRF (NIMP name, dosage, daily total dose, injection compliance and dose-titration 
recommendation, etc, as specified in Section 8.2). 
8.8 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
The following drugs are not permitted during the study until the EOT visit (Visit 12, Week 24):  
• Any antidiabetic agents other than the study medications (IMP and NIMP) including oral 
or injectable antihyperglycemic agents, other type of basal insulin (eg, neutral protamine 
Hagedorn [NPH], Detemir, premixed insulin), and human regular insulin 
• Insulin pump therapy 
• Systemic glucocorticoid use for more than 10 days at a dose >10 mg/day of prednisone or 
the equivalent. Topical or inhaled applications are allowed. 
Note: After permanent IMP discontinuation (per protocol or premature), any treatment is 
permitted, as deemed necessary by the Investigator. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
All biological analysis (HbA1c and FPG) will be performed by a Central Laboratory. Detailed 
information on samples drawing, management and analysis will be provided in a specific manual. 
Observation period for primary and secondary endpoints (glycemic and insulin dose) 
The 24-week on-treatment period for primary and secondary endpoints (glycemic and insulin 
dose) is defined as displayed in Table 4. 
Table 4 – 24-week on-treatment period for primary and secondary endpoints (glycemic and insulin 
dose) 
Endpoint 
Start of observation period 
End of observation period 
HbA1c 
first injection of open-label IMP 
7 days after date of last IMP administration 
FPG 
first injection of open-label IMP 
1 day after date of last IMP administration 
7-point SMPG 
first injection of open-label IMP 
date of last IMP administration 
Insulin dose 
first injection of open-label IMP 
date of last IMP administration 
HbA1c:glycated hemoglobin A1c; FPG: fasting plasma glucose; SMPG: self-monitoring of plasma glucose; IMP: investigational medicinal 
product 
The randomized 24–week period for primary and secondary endpoints (glycemic and insulin 
dose) is defined from first dose of IMP up to Week 24, regardless of study treatment 
discontinuation. 
9.1 
PRIMARY ENDPOINT 
• Change in HbA1c from baseline to Week 24. 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” (NGSP) central laboratory. 
HbA1c is assayed at screening (Visit 1 – Step 2, Week -2); at Visit 10 (Week 16); Visit 12  
(Week 24; final primary endpoint assessment visit). 
 
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9.2 
SECONDARY ENDPOINTS 
9.2.1 Study methodology endpoints 
9.2.1.1 Patient satisfaction with trial experience 
Patient satisfaction with trial experience will be measured using the Was It Worth It (WIWI) 
Questionnaire (10, 11), administered at Week 24 (Visit 12). The WIWI has 5 items, each with a 3-
level categorical response scale. Each item is scored separately. The WIWI will be administered 
electronically using mobile technology. See questionnaire in Appendix B. 
9.2.1.2 Impact of trial participation patient reported outcome 
The effect of the trial on a patients’ ability to work and perform regular activities will be 
measured using an adaptation of the Work Productivity and Impairment (WPAI) Questionnaire, 
administered at Week 0 (Visit 2-Step 2) and Week 24 (Visit 12). The WPAI used in this study has 
been adapted, with permission, from the WPAI-Specific Health Problem (WPAI-SHP) V2.0 (12), 
to provide information on the impact of study participation rather than on a health condition per 
se. The WPAI-SP has 6 items, and scoring follows that of the WPAI-SHP. As such, each item is 
presented separately, expressed as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, ie, worse outcomes. In addition, the following combined 
items will be reported: 
• the percent work time missed due to study participation [Q2/(Q2 + Q4)] 
•  the percent impairment while working due to study participation [Q5/10] 
• the percent overall work impairment due to study participation [Q2/(Q2 + Q4) + (1-
(Q2/(Q2 + Q4)))x(Q5/10)] 
• the percent activity impairment due to study participation [Q6/10] 
The WPAI-SP will be administered electronically using mobile technology. 
See questionnaire in Appendix B. 
9.2.1.3 Patient burden with trial participation 
Patient burden with trial participation will be measured using a new PRO: the Overall Study 
Experience-Participation (OSEP) Questionnaire. Each item will be scored separately. The OSEP 
has 2 parts: 
• OSEP part 1 contains 4 items to examine perceptions of diabetes control; it will be 
administered at Week 0 (Visit 2-Step 2) and Week 24 (Visit 12) 
• OSEP part 2 contains 9 items to examine perceptions of study participation; it will be 
administered only at Week 24 (Visit 12) 
The OSEP will be administered electronically using mobile technology. 
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See questionnaire in Appendix B. 
9.2.1.4 Resource use 
Healthcare resource use will be measured using a new PRO: the resource use questionnaire 
(RUQ). The RUQ will be administered every 4 weeks from baseline to Week 24. The RUQ asks 
the patients to report the resources used (time and expenses) during the previous 4 weeks in terms 
of visits to healthcare professionals.  
The RUQ will be administered electronically using mobile technology. 
See questionnaire in Appendix B. 
9.2.1.5 Other study methodology endpoints 
The following additional endpoints will be considered: 
• Compliance with medication during the treatment period (from Day 1 to Week 24), 
expressed in terms of IMP exposure time and the percentage of actual dose over the 
prescribed dose 
• Compliance with key study activities during the treatment period (from Day 1 to 
Week 24), including: 
- 
Number of times the patient used the Bluetooth devices in accordance with the study 
instructions 
- 
Number of times the patient completed the blood draw visits (Visit 10 and Visit 12) in 
accordance with the study instructions 
- 
Patient withdrawal during the treatment period (from Day 1 to Week 24) 
9.2.2 Diabetes control endpoints 
9.2.2.1 Diabetes-related patient reported outcomes 
Treatment satisfaction will be measured with the Diabetes Treatment Satisfaction Questionnaire 
(DTSQ). The DTSQ is available in two versions:  
• the DTSQ status (DTSQs) version (13) evaluates absolute treatment satisfaction in the 
“past few weeks” and will be administered at Week 0 (Visit 2-Step 2) and Week 24 
(Visit 12) 
• the DTSQ change (DTSQc) version (14) measures the relative change in treatment 
satisfaction from previous therapy and will be administered (after the DTSQs) at Week 24 
(Visit 12) only 
The DTSQs and DTSQc conceptually contain the same 8 items, each scored on a 7-point scale but 
with different response options. Six items are summed to produce a measure of treatment 
satisfaction, with total scores ranging from 0 (very dissatisfied) to 36 (very satisfied) for the 
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DTSQs and −18 (much less satisfied) to +18 (much more satisfied) on the DTSQc. The remaining 
2 items, which measure perceived frequency of hyperglycemia and perceived frequency of 
hypoglycemia, are treated independently. These items are scored on a scale ranging from 0 (none 
of the time) to 6 (most of the time) on the DTSQs and −3 (much less of the time now) to +3 (much 
more of the time now) on the DTSQc.  
The DTSQs and DTSQc will be administered electronically using mobile technology. 
Fear of hypoglycemia will be measured with the Hypoglycemia Fear Survey-II (HFS-II) (15) on 
Week 0 (Visit 2-Step 2) and Week 24 (Visit 12). The HFS-II comprises 33 items: 
• 15 items explore behaviors that patients may engage in to avoid low blood sugar and its 
negative consequences (the hypoglycemia fear survey-behavior subscale [HFS-B])  
• 18 items relate to concerns that patients may have about their hypoglycemia (the 
hypoglycemia fear survey-worry subscale [HFS-W]) 
Responses are made on a 5-point Likert scale where 0 = “Never” and 4 = “Always” with a past 
3 months recall period. Subscale scores (HFS-B, HFS-W) and a total score are calculated by 
summing item responses.  
The HFS-II will be administered electronically using mobile technology. 
Diabetes-related distress will be measured using the Diabetes Distress Scale (DDS) (16) at 
Week 0 (Visit 2-Step 2) and Week 24 (Visit 12). The DDS contains 17 items related to potential 
problem areas that people with diabetes may experience. Patients are asked to consider the degree 
to which each of the items may have distressed or bothered them during the past month, and 
respond between 1 (not a problem) and 6 (a very serious problem). The DDS yields a total 
diabetes distress score and 4 subscale scores, each addressing a different kind of distress 
(emotional burden, physician distress, regimen distress, interpersonal distress). Each score (total 
and subscales) are presented as an average, by summing the patient’s responses to the appropriate 
items and divide by the number of items in that scale. In addition, total and subscale scores will be 
categorized: a mean score 2.0 – 2.9 should be considered ‘moderate distress’ and a mean score 
>3.0 should be considered ‘high distress’ (17).  
The DDS will be administered electronically using mobile technology. 
See questionnaires in Appendix C. 
9.2.2.2 Secondary glycemic endpoints 
The baseline value for glycemic endpoints is the last available value prior to the first injection of 
open-label IMP. 
List of secondary glycemic endpoints 
• Central lab HbA1c: change from baseline (Visit 1 Step 2) to Week 16 (Visit 10) 
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• Central lab FPG: change from baseline (Visit 1-Step 2) to Week 16 (Visit 10) and 
Week 24 (Visit 12) 
• Mean 7-point SMPG: change from baseline (Visit 2-Step 2) to Week 16 (Visit 10) and 
Week 24 (Visit 12) 
• 7-point SMPG at each timepoint (preprandial and 2-hour postprandial plasma glucose at 
breakfast, lunch and dinner, and bedtime): change from baseline (Visit 2-Step 2) to 
Week 16 (Visit 10) and Week 24 (Visit 12) 
9.2.2.2.1 Fasting Plasma Glucose 
Fasting plasma glucose will be measured at a central laboratory.  
Blood samples for FPG measurement will be taken at baseline (Visit 1-Step 2), at Week 16 
(Visit 10) and at Week 24 (Visit 12, EOT). 
9.2.2.2.2 Self-measured plasma glucose 
Glucose meter, patient diary and training 
Blood glucose values will be self-measured by the patients using the sponsor-provided glucose 
meter and associated accessories (lancet, control solutions, test strips etc). Note that this type of 
glucose meter does not measure glucose in plasma but in the blood of capillaries. A correction is 
applied to the result to express it as “plasma equivalent”. In the present protocol, SMPG should 
thus be understood as “self-measured plasma-equivalent glucose”. 
After the randomization IRT call, eligible patients will receive the study glucose meter and 
associated accessories by mail. Patients should not use their personal glucose meter during the 
study.  
The investigator or a member of the investigational staff will explain the importance to measure 
glucose appropriately via video chat to ensure the patient’s commitment to SMPG performances. 
Training may be repeated as deemed necessary at the study visits and the investigational staff will 
review the patient’s diary at each visit. 
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 
onsite visit and also ask the pattern of fasting and postprandial SMPG at the phone visits 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 performance of SMPG is outlined in Table 5 and also specified also in Section 1.2 flow chart.  
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Table 5 – Instruction for SMPG performed during the study 
Frequency 
SMPG 
Definition 
Recommended 
Mandatory  
5-points  
Before breakfast, lunch, and dinner, 
2 hours post a main meal (or as per 
investigator’s instruction) and at 
bedtime 
5 days per week  
3 days during the week prior to 
each visit  
7-points 
before and 2 hours after breakfast, 
lunch, and dinner, and at bedtime 
As needed  
1 day during Week -1, 15, and 
23 
SMPG: self-monitoring of plasma glucose 
5-point SMPG profiles 
Patients should measure a 5-point SMPG profile (before breakfast, lunch, and dinner [before 
insulin injection when applicable], 2 hours after the patient’s main meal [eg, lunch or dinner] or as 
per investigator’s instruction, and at bed time) for at least 3 days per week before each visit.   
Before breakfast, SMPG should be measured after the patient wakes up, before breakfast, and 
before injection of any insulin (if applicable). Preferably, no food should have been taken 
overnight.  The values will be used as fasting SMPG to guide the modification in insulin dose 
(Section 8.1.6). 
7-point SMPG profiles 
Seven-point blood glucose profiles should be measured at the following 7 time-points: before 
(preinjection after randomization) and 2 hours after breakfast; before and 2 hours after lunch; 
before and 2 hours after dinner; and at bedtime). Two hours post meal is defined as 2 hours after 
the start of the meal. 
Patients are required to have 7-point SMPG profiles performed on at least 1 day in the week 
before the baseline visit and before the visits of Week 16 and Week 24 (EOT). 
SMPG during episodes of symptomatic hypoglycemia 
Whenever the patient feels hypoglycemic symptoms, plasma glucose should be measured by the 
patient (or others, if applicable), if possible. Patients should be instructed to measure plasma 
glucose levels prior to the administration of glucose or carbohydrate intake whenever 
symptomatic hypoglycemia is suspected, unless safety considerations necessitate immediate 
glucose/carbohydrate rescue prior to confirmation with the SMPG. 
Patients have to document hypoglycemic events appropriately in their diaries and to 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 
e-CRF. This includes all symptomatic hypoglycemia events and asymptomatic hypoglycemia. 
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Hypoglycemia events fulfilling the criteria of a SAE will be documented on the SAE form in the 
e-CRF.  
9.2.2.3 Dose of basal and mealtime insulin  
Patients will record their basal insulin and mealtime insulin dosing data (time and dose), including 
corrective doses, in the eDiary daily during the following periods: 
• the randomization period after receiving of glucose meter and the eDiary device 
• the treatment period up to Visit 9 (Week 12) 
• at least over one week before each visit during the remainder of the treatment period until 
the EOT visit (Visit 12 – Week 24 or early treatment discontinuation) 
• During the week of the follow-up period  
The following endpoints will be considered: total insulin dose, basal insulin dose, mealtime/bolus 
as daily dose and u/kg. 
9.2.3 Patient care endpoints 
9.2.3.1 Investigator questionnaires 
Site investigators (one per site) will be asked to complete the Overall Study Experience-sites 
(OSES) questionnaire. The OSES has 2 parts: 
• OSES part 1 contains 1 item to examine resource requirements: “Approximately how 
much time did you spend with this participant (in person or via phone) during this 
scheduled visit/communication?”. OSES part 1 will be administered following each study 
visit. 
• OSES part 2 contains 2 items to examine relationship (“I had a good relationship with this 
patient during the study”) and satisfaction with care (“I am satisfied with the level of care I 
have provided for this participant in this study”). OSES part 2 will be administered at 
Week 24 (Visit 12) only. 
Each item is scored separately. 
See questionnaire in Appendix D. 
9.2.3.2 Patient interviews 
English-speaking patients of the virtual group who consent will be invited to participate in 
interviews following their Week 24 (Visit 12) study visit (ie, after completion of the trial). These 
qualitative exit interviews will be conducted one-on-one with up to 30 patients to: 
• Examine patients’ experiences of trial participation, in their own words 
• Explore the positive and negative aspects of trial participation 
• Provide some context to responses given in the PRO questionnaires 
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Interviews will be held by trained site staff. 
See interview guide in Appendix D. 
9.2.4 Safety endpoints 
Observation period for safety endpoints: 
The observation period of safety data will be divided into 3 segments: 
• The pre-treatment period is defined as the time between the date of the informed consent 
and the first injection of open-label IMP 
• The treatment-emergent AE (TEAE) period is defined as the time from the first injection 
of open-label IMP up to 2 days after the last injection of IMP 
• The post-treatment period is defined as the time starting 3 days after last injection of open-
label IMP (after the TEAE period) 
The baseline value for safety endpoints will be the last available value prior to the first injection 
of IMP. 
9.2.4.1 Adverse events 
Adverse events and SAEs, including injection site reactions. Refer to Section 10.4 to Section 10.6 
for details. 
9.2.4.2 Product technical complaints 
Refer to Section 8.1.2.4 for details. 
9.2.4.3 Laboratory safety variables 
For WOCBP, urine pregnancy test will be performed at Week 4, Week 8, Week 16, and Week 24. 
It can be confirmed with a serum test if needed. No other laboratory safety variables will be 
measured after baseline.  
9.2.4.4 Hypoglycemia 
9.2.4.4.1 Definition of hypoglycemia 
Hypoglycemia events will be categorized as follows (following the American Diabetes 
Association [ADA] Workgroup on Hypoglycemia) (18). Classification of hypoglycemia is 
summarized in Figure 1. 
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Figure 1 – Classification of hypoglycemia 
 
• 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 hypoglycemia includes all episodes in which neurological impairment 
was severe enough to prevent self-treatment and which were thus thought to place patients at risk 
for injury to themselves or others.  
Note that “requires assistance” means that the patient could not help himself or herself. Assisting 
a patient out of kindness, when assistance is not required, should not be considered a “requires 
assistance” incident. 
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria. All 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 of ≤70 mg/dL 
(3.9 mmol/L).  
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Clinical symptoms that are considered to result from a hypoglycemic episode can include (but are 
not necessarily limited to): increased sweating, nervousness, asthenia, tremor, dizziness, increased 
appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and coma. 
Patients will be instructed to measure finger stick plasma glucose levels prior to the administration 
of carbohydrates whenever symptomatic hypoglycemia is suspected, unless safety considerations 
necessitate immediate glucose rescue prior to confirmation, and then a glucose measurement 
should be performed as soon as safe, with appropriate diary documentation. Details on 
hypoglycemia episodes will be captured in the patient diaries, and patients will contact the sites as 
soon as possible following severe events to review the details and decide on any necessary 
measures to be taken. 
• Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration less than or equal to 70 mg/dL (3.9 mmol/L). 
• Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms typical of hypoglycemia 
are not accompanied by a plasma glucose determination, but was presumably caused by a plasma 
glucose concentration less than or equal to 70 mg/dL (3.9 mmol/L); symptoms treated with oral 
carbohydrate without a test of plasma glucose.  
• Relative hypoglycemia 
Relative hypoglycemia recently termed “pseudo-hypoglycemia” (19) is an event during which the 
person with diabetes reports any of the typical symptoms of hypoglycemia with a measured 
plasma glucose concentration >70 mg/dL (>3.9 mmol/L) but approaching that level. 
• Nocturnal hypoglycemia 
Nocturnal hypoglycemia is any hypoglycemia of the above categories that occurs: 
- 
Between 00:00 and 05:59, regardless whether patient was awake or work up because 
of the event 
- 
Sleep status: patient was asleep between bedtime and before getting up in the morning, 
ie, before the morning determination of fasting pre-breakfast SMPG and patient woke 
up due to the hypoglycemia 
9.2.4.4.2 Reporting hypoglycemia 
All hypoglycemia episodes will be documented on the dedicated hypoglycemia event page in the 
e-CRF. The information about the hypoglycemic events including onset date/time, counter- 
measurements, whether the patient needed assistance from other to treat the hypoglycemic event, 
etc. will be collected to support hypoglycemia analyses. 
Hypoglycemic events and the symptoms accompanying the events will not be reported as an AE.  
However, symptomatic hypoglycemia events fulfilling the criteria of an SAE will be documented 
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on SAE complementary forms in the e-CRF in addition to the hypoglycemic event form. All 
hypoglycemic events resulting in seizure, unconsciousness, or coma will be reported as SAEs. 
For more details on the analysis of hypoglycemia, refer to Section 11.4.3.4. 
9.3 
FUTURE USE OF SAMPLES 
Not applicable. 
9.4 
APPROPRIATENESS OF MEASUREMENTS  
The purpose of the pilot study is to evaluate the methodology of a virtual clinical trial conduct in 
management of diabetes in the patients with T1DM. The primary endpoint (HbA1c) is well 
accepted by medical society and the health agencies as a stable indication for glycemic control.  
Secondary endpoints aim at measuring the appropriate utilization of virtual approach via new 
technologies during the study; therefore, multiple endpoints are chosen to assess the effect of the 
virtual versus traditional study conduct on a number of the study activities, including diabetes 
questionnaires, IMP/NIMP compliance, patient retention, protocol deviation, etc.  
The usability and appropriateness of the virtual methodology will also be assessed by a battery of 
PRO questionnaires. The satisfaction questionnaires (WIWI) will reveal the patient experience of 
the trial participation from patient’s perspective; the WPAI-SP questionnaire will assess the 
impact of trial participation on the patients’ daily life and working hours; the OSEP questionnaire 
will measure the patient burden with trial participation; and the RUQ will evaluate the number of 
healthcare professional visits and the associated cost.  
Patients in both virtual and traditional groups will receive the exactly same insulin regimen using 
Toujeo as the basal insulin plus rapid-acting insulin analogs to treat their T1DM during the 
treatment period. With the HbA1c stratification at the randomization, the baseline HbA1c is 
expected to be similar in the two groups. The 24-week treatment is considered sufficient for the 
purpose of the study: after switching from insulin glargine 100 U/mL (eg, Lantus or Basaglar) in a 
stable dose prior to the study entry, steady state is expected to be reached within 2 weeks of 
treatment start with Toujeo and the optimal dose of Toujeo is expected to be reached within 
8 weeks following fasting SMPG-orientated dose titration regimen. 
Thus, the operational effect of the study methodology on glycemic control will be well measured 
by the change in HbA1c from baseline to Week 24, which is a widely accepted standard endpoint 
for assessing the glycemic control. Other glycemic variables (FPG, SMPG) will also be assessed. 
In addition to the laboratory variables, diabetes control will be evaluated by 3 well established 
PRO questionnaires (DTSQ, HFS-II and DDS) to assess the treatment satisfaction, the 
hypoglycemia fear, and the diabetes related stress. 
Safety will be evaluated by standard clinical measurements, including TEAE, SAE, adverse event 
of special interest (AESI), and AE leading to IMP discontinuation. Specific safety parameters of 
interest for a glucose lowering injectable peptide such as hypoglycemia and injection site 
reactions will also be assessed. 
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10 
STUDY PROCEDURES 
This is an approximately 28-week outpatient study. Screening procedures will be performed as a 
virtual visit followed by a Homecare in-person visit. Eligible and consenting patients will be 
randomized to an approach group at telephone Visit 2-Step 1, which will determine the way the 
next visits are organized: 
• Traditional group: 5 onsite visits and 7 telephone visits 
• Virtual group: 11 virtual visits and 1 mixed onsite-virtual visit (Visit 2-Step 2) 
Additional, optional virtual or telephone visits (according to the approach group) will be 
scheduled to monitor and support the progress of insulin titration whenever considered necessary 
by the investigator. For both groups, unscheduled onsite visits or Homecare physician visits 
(depending on the patient's location) may be scheduled only for safety assessment if deemed 
necessary by the investigator (ie, performance of physical examinations is critical to determine a 
diagnosis or further evaluation procedure for an AE). 
All onsite visits should take place in the morning at approximately the same time. On the day 
before each onsite visit, patients should be reminded to bring the medical devices (glucose meter), 
diaries and IMP (used, in-use or unused) to sites and to be in the fasted status if required at some 
visits.  
The fasting condition is defined as an overnight fast no less than 8 hours that consisted of no 
food or liquid intake, other than water. IMP and noninsulin antidiabetic medication should be 
administered after the fasting blood sample is drawn for all laboratory tests. 
Note: If the patient is not in fasting conditions at visits which required in fasting conditions, the 
blood sample is not collected and a new appointment should be given to the patient for the 
following day if possible, with instruction to be fasted. 
For phone-call visits and virtual visits, the patient is called by the investigator or qualified 
designee at a scheduled time.  
A visit window of ± 3 days using the day of Visit 2-Step 2 as reference is acceptable (4 days for 
Visit 6, Visit 8, and Visit 10).  
If one visit date is changed, the next visit should take place according to the original schedule, 
ie, counting from Day 1 on Visit 2-Step 2. 
Diet and lifestyle counseling including training in carbohydrate counting, if chosen to be used for 
the mealtime insulin titration, will be continued during the study. Dietary and lifestyle counseling 
should be given by a registered dietician or other medically qualified person (eg, diabetes 
educator, endocrinologist) and should be consistent with the recommendations of national or local 
guidelines (with regard to distribution of calories among carbohydrates, proteins, fats and to 
exercise) for individuals with type 1 diabetes.  
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Compliance with the diet and lifestyle recommendations will be discussed with the patients 
throughout the study, and more specifically in case of insufficient glucose control.  
For a complete list of procedures scheduled for each study visit please refer to the study flowchart 
(Section 1.2). The aim of the following sections is to provide details on how some of the 
procedures have to be performed. 
10.1 
VISIT SCHEDULE 
10.1.1 Screening Visit (Visit 1-Step1 and Step 2) Week -3 to Week -2 
The screening will be done electronically in 2 steps: 
• Step 1: electronic informed consent: patients will have been guided to the eConsent web 
portal by the sites or by multi-channel digital recruiters. The study will be presented to 
them before eConsent.  
• Step 2: eligibility assessment: verification of patient identity, vital signs measurement, and 
blood draw for central laboratory tests will be done in-person by a Homecare health 
professional visit. This visit can occur at the patient’s home, at work, or at any location 
providing the adequate space and level of privacy. Investigators will complete the 
determination of eligibility at the end of screening. 
For a complete list of procedures scheduled for each study step please refer to the study flow chart 
(Section 1.2). 
Demographic data and electronic informed consent must be obtained from the patient prior to 
any study-specific procedures. During the stepwise process on the study web portal for the e-
consent, the patient will receive information concerning the aims and methods of the study, its 
constraints and risks and the study duration and will be provided with the written information. 
This will be done virtually through the study web portal through video conferencing with the 
investigator or designee, with the support of animations or text. The informed consent will be 
counter-eSigned by the investigator. Interactive response technology will be contacted for 
notification of screening and patient number allocation (Section 8.4). Please note that it is 
important to have the IRT contact before any blood sample is drawn because the patient number is 
given by IRT and it must be reported on the laboratory requisition forms. Homecare visit will be 
scheduled with the patient. 
The following will be collected and assessed by the investigator and the site virtual team 
(designee and study coordinators): 
• Collection of diabetes history will include documentation of duration of diabetes, history 
of microvascular [eye, kidney] and of neuropathic complications and their treatments. For 
patients with a documented medical history of proliferative retinopathy or macular edema, 
if the latest ophthalmologic investigation have been performed longer than 12 months 
prior to the planned randomization, the patient has to be referred to an ophthalmologist (or 
optometrist) prior to randomization. The previous experience with hypoglycemia during 
the past 12 months will be verified with the source document.  
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• Medical/surgical history may include macrovascular complications (heart, brain, legs) as 
well as all additional comorbidities. Alcohol and smoking habits are to be recorded. 
• Check of concomitant medication refers to documentation of medication including over-
the-counter medication taken/administered within the previous 3 months prior to this visit.  
• Basal insulin analogs and mealtime insulin doses have to be recorded.   
• Further discussion about the study and answering patient questions may occur between the 
investigator and patients via e-chat. 
The following will be performed by the Homecare health professional: 
• Verification of patient identity in person 
• Determination of the reference arm for blood pressure (BP) measurements: after the 
patient has rested comfortably for at least 10 minutes, BP will be measured on both of the 
patient´s arms while the patient is in sitting position and then again on both arms after 
2 minutes . The arm with the higher diastolic BP will be determined at this visit, 
identifying the reference arm for future measurements. The reference arm will be used for 
later BP measurements by the patients themselves in the virtual group or by the site staff 
for the traditional group. The average value of the 2 measurements (2 minutes apart) will 
be recorded in the e-CRF (all BP values are to be recorded in the source data). 
• Heart rate will be measured at the time of the BP measurement.  
• Height will be measured when patient´s shoes are off, feet together, and arms by the sides. 
Heels, buttocks, and upper back should also be in contact with the wall when the 
measurement is made. 
• Body weight should be obtained with the patient wearing undergarments or very light 
clothing and no shoes, and with an empty bladder. The floor surface on which the scale 
rests must be hard and should not be carpeted or covered with other soft material. The 
same scale should be used throughout the study, and calibrated on a regular basis as 
recommended by the manufacturer. The weight is read and recorded in the e-CRF and 
source data.   
• Blood will be drawn for all central laboratory tests needed for evaluation of the eligibility 
criteria (eg, HbA1c) of the patients. Patient has to provide a urine sample.  
• In WOCBP, the contraceptive methods, if used, have to be documented. According to 
CPMP/ICH/286/95 (20), “Highly effective methods of birth control are defined as those, 
alone or in combination, that result in a low failure rate (ie, less than 1% per year) when 
used consistently and correctly.” Refer to Appendix A for details. A serum pregnancy test 
will be performed.  
• If needed, diet and lifestyle counseling should be provided. 
At Visit 1-Step 2, the investigator will complete the eligibility assessment of the patients when the 
laboratory results become available. 
As soon as a patient is found ineligible, the patient must not enter the randomized treatment phase 
and IRT has to be contacted in order to register the patient as a screening failure. 
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Patients can be rescreened one time before randomization in case of nonevaluable exclusion 
criteria (eg, not evaluable screening laboratory findings) or in case of manageable exclusion as 
deemed by the investigator. Rescreened patients will be subject to the screening visit 
procedures/assessments (see below) including new informed consent signed and allocation of a 
new patient number. 
10.1.2 Randomization Visit (Visit 2) 
10.1.2.1 Visit 2-Step 1 (Week -1) 
Visit 2-Step 1 telephone call will occur about 1 week after Visit 1-Step 2 when the investigator 
has received laboratory reports for the screened patients in order to assess exclusion criteria E 03 
and E 12 (Section 7.2). The eligible patients will be randomized to the study group through IRT. 
Appropriate study materials will be shipped to eligible patients: Bluetooth blood glucose meter 
with associated accessories (lancets, control solutions, test strips etc.), e-diaries features, and 
instructions. Bluetooth devices (pulse oximeter, BP cuff, and scale) will be shipped to patients 
allocated to the virtual group. Bluetooth devices are listed in Appendix E. 
Patients of the virtual group will record any symptoms in the eDiary so that the investigator is 
informed through the study website portal and will record the AE into the e-CRF. 
An onsite visit will be scheduled within a week (+/- 4 days) for the traditional group.   
Patient randomized in the virtual group will also be scheduled for an onsite visit, but for physical 
examination only. The virtual Visit 2-Step 2 visit will be scheduled within 1 week (+/- 4 days) of 
the Visit 2-Step 1 for the virtual group. 
Patients should be reminded to perform at least one day of 7-point SMPG prior to the 
Visit 2-Step 2 visit. Patients of the traditional group will be reminded to bring the glucose meter to 
the study visit. 
10.1.2.2 Visit 2-Step 2 (Week 0) 
This is the baseline visit (onsite visit for the traditional group and mixed onsite-virtual visit for the 
virtual group). The full list of assessments is provided in the study flow chart (Section 1.2). 
Additional details are provided below for a number of assessments. 
For the traditional group:  
• During the week prior to the scheduled site visit:  
- 
patients should perform at least one day of 7-point SMPG  
- 
The baseline questionnaires (DTSQs, DDS, HFS, WPAI-SP, OSEP part 1, RUQ, and 
OSES part 1 resource requirements) should be administered by patient via parallel 
6 portal  
• Patients will bring the glucose meter to the site and SMPG data will be collected.  
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• Any AE/SAE, including hypoglycemia, that occurred since Visit 1 will be documented. 
• A disease-focused initial physical examination will be performed by the investigators at 
the study site, including neck palpation of thyroid, screening for diabetic neuropathy 
(eg, assessment of appearance of feet and ankles, reflexes, and vibration perception at the 
great toes) and a check for injection site reactions. 
• The IMP, Toujeo basal insulin, will be dispensed. The first dose of IMP may start on the 
day of this visit (ie, evening dosing) or the second day (ie, morning dosing). Patients will 
document the dose and date/time in the eDiary.  
For the virtual group:  
• Patients will receive the Bluetooth devices by mail and IMP by DTP before Visit 2-Step 2. 
Upon receipt, they will activate the devices (Bluetooth, e-diary, digital BP and pulse 
device, etc) and confirm to the study site the successful connection with the virtual 
platform.  
• They will be scheduled within a week to visit study site in-person for the investigator to 
perform the physical examination. No other assessments will be done at this onsite visit.  
• Patients will be guided for using the device to measure BP, heart rate, and weight 
appropriately.  
• The 7-point SMPG will be performed for at least 1 day within the week prior to the first 
dose of the IMP and the data will be immediately available via the Bluetooth for 
investigator’s review. 
• Any AE/SAE, including hypoglycemia, that occurred since Visit 1 will be documented in 
the eDiary. 
• Baseline PROs should be completed electronically independently from influence of the 
investigator and the site staff.   
• After all baseline assessments have been completed, the investigator will instruct patients 
to initiate the first dose of the IMP, Toujeo basal insulin, and patients will document the 
dose and date/time in the eDiary.  
All patients in both study groups will be reminded by the study staff to refer to the instructions 
for use to properly use the Toujeo pens. IMP administration will be explained to patients 
including reminding the IMP dose, time of the once daily administration, and dose titration 
requirements (Section 8.1). 
The day of the first administration of IMP will be defined as Day 1. 
All patients are asked to self-titrate their IMP according to the algorithm provided (Section 8.1). 
The short-acting insulin analog will be continued for mealtime insulin requirements and 
correction of SMPG according to recommendation (Section 8.2.1). Investigators and their study 
staff are required to offer adequate training, thus enabling patients to successfully self-titrate their 
insulins.  
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10.1.3 Phone call/Virtual Visits (V3-5, V7, V9 and V11) 
During the study treatment period, 6 phone call/virtual visits are scheduled between the IMP 
dispensing visits. The purpose of the contact with the patients is to monitor the patients’ 
compliance with SMPG and insulin titration and to collect injection information, AE/SAE, 
including hypoglycemia, any change in concomitant medications, and OSES part 1 questionnaire 
(resource requirement). Resource use questionnaire will be administered on Visits 9 and 11. 
Patient of the traditional group will be called by the investigator or qualified designee at a 
scheduled time. If the call has been completed by site staff other than the investigator, the 
investigator has to be consulted if AE/SAE is suspected. 
Patients of the virtual group will contact the sites and communicate via virtual chat. It can also 
occur ad-hoc as needed.  
During the phone or video, the following will be checked and information collected accordingly:  
• Injection of the IMP (Toujeo) and NIMP (the mealtime insulin analogs) as instructed by 
the investigators 
• Occurrence of new medical events, diseases, or symptoms since the last visit 
• Occurrence of hypoglycemic events or symptoms, or any injection site reaction 
• Change or addition of any new medications since the last visit 
• If the patient feels comfortable in handling e-diary, glucose meter and IMP injection 
device or he/she needs help 
Further following procedures will be performed: 
• Instruct patients on further insulin dose adjustment according to their SMPG values 
• Remind the patients to measure required SMPG and complete the diary 
• Remind patients to perform the 7-point SMPG before Visit 10 and Visit 12 
• Document change of concomitant medication and actual basal and mealtime insulin doses 
in the e-CRF 
• Report AE/SAE and hypoglycemia if any 
• For patients of the traditional group, remind to be fasting prior to Visit 10 and Visit 12; 
remind and check with the patients of the virtual group to have their blood drawn at the 
local laboratory (US patients)  
• For patients of the traditional group, remind to bring the glucose meter and IMP (used, in-
use, or unused) at each onsite visit 
For a complete list of procedures scheduled for each phone-call visit please refer to the study 
flowchart (Section 1.2). 
10.1.4 Onsite/virtual visits (V6, 8, and V10) during treatment period 
Three study visits will occur onsite before the EOT for the traditional approach group. Virtual 
approach group patients will have the corresponding visit as virtual visit. 
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During these visits, study material (eg, ancillaries and glucose meter accessories) and IMP will be 
dispensed or shipped, and the patients’ progress, SMPG patterns, dose regimens and data 
collected during the study (eg, hypoglycemia, AE/SAE, average fasting and postprandial SMPGs 
over the past days) will be discussed. For patients of the traditional group, the IMP dispensation 
will be done on site by the investigator or pharmacist. For patients of the virtual group, the IMP 
will be shipped using the DTP service described in Section 8.1.3. 
Patients of the traditional group will bring their glucose meter and IMP boxes to the study site at 
each onsite visit. For patients of the virtual group, the used and unused IMP will be returned to the 
sites by Marken driver. 
Patients of the virtual group will perform all assessments via virtual device for vital signs (BP, 
HR) and weight measurements. 
The investigators and study staff will check and document in the source data if the patient has 
reached the titration goal or not at each visit. Appropriate titration will be continued until target 
fasting SMPG without hypoglycemia has been reached. 
Investigational medicinal product compliance (collecting and counting used and unused cartridges 
and syringes) will be checked and addressed with the patients. The IMP compliance will be 
checked by video chat between the patients of the virtual approach group and the site staff. 
Consultation for diet and life-style modification should be provided during the visits if needed. 
Overall Study Experience-Sites part 1 questionnaire (resource requirement) should be completed 
by the Investigator.  
Within 1 week prior to Visit 10, patients should be reminded, if needed, to perform at least one 
day of 7-point SMPG. 
Resource use questionnaire will be completed by the patients at Visits 6, 8, and 10. 
Additionally, at Visit 10, patients should be fasted and blood will be drawn for measurements of 
HbA1c and FPG at central laboratory. The patients from the virtual approach group will attend the 
local Quest laboratory with the study requisition to complete the blood sampling (for patients 
located in Canada, phlebotomy may be done by the Homecare nurses at the patients’ home or 
other suitable location). 
For a complete list of procedures scheduled for each study visit please refer to the study flowchart 
(Section 1.2). 
10.1.5 End of Treatment (EOT) visit (Visit 12, Week 24) 
The EOT visit will occur onsite for the traditional approach group. Virtual approach group 
patients will have the corresponding visit as virtual visit. 
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Before the EOT visit, the patients will be reminded to: 
• perform at least one day of 7-point SMPG during the week prior to the visit.  The visit will 
be postponed if the patient has not done or missed data point(s) of the 7-point profile 
• be fasted for about 8 hours prior to on-site visit (traditional group) or presentation to the 
local laboratory for blood draw (virtual group) 
• bring the glucose meter and used and all unused IMP to the sites (traditional group) or as 
instructed by the study sites (virtual group) 
The following will be performed at the EOT visit: 
• Vital signs including BP and HR, body weight will be assessed and collected on site 
(traditional group) or via virtual device (virtual group)  
• The questionnaires at the EOT will be performed electronically by the patients. The 
following questionnaires will be administered: DTSQs, DTSQc, DDS, HFS, WIWI, 
WPAI-SP, OSEP part 1 and 2 , and RUQ. Investigators will be asked to complete the 
OSES part 1 and 2 questionnaire. The PROs should be completed prior to any other 
procedure to ensure no impact of site-patient interaction on responses. A subset of patients 
will be interviewed (Section 9.2.3.2). 
• Blood sampling for laboratory tests will be done at study site, local Quest laboratory, or by 
Homecare nurse (virtual group patients in Canada only) 
• The last IMP must be injected no earlier than completion of all the EOT assessment. 
Patients of the traditional group will return all their used and unused IMP to the site for 
accountability and destruction at the EOT visit. For patients of the virtual group, Marken 
driver will retrieve all used and unused IMP at patients' home after the EOT visit and will 
return them to the site for accountability and destruction. 
• IRT call will be made to register the EOT for the patient 
For a complete list of procedures scheduled for this study visit please refer to the study flowchart 
(Section 1.2). 
10.1.6 Follow-up Visit (Visit 13)  
Following the last administration of IMP either as scheduled or prematurely, a post-treatment 
follow-up should be scheduled for all the patients in one week (+/- 2 days) after permanent 
discontinuation of the study treatment. This visit can be a virtual of phone call visit, or an on-site 
visit in case of ongoing or new AE during the post-treatment period, if needed. The patient is 
called by the investigator or qualified designee at scheduled time. If the call has not been 
performed by the investigator, the investigator has to be consulted if AE/SAE and hypoglycemic 
event are suspected. 
During the phone call the same set of questions as listed for other telephone/virtual visits has to be 
asked (Section 10.1.3), except IMP-related questions. 
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10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in patient´s file 
For both patient groups, all evaluations recorded in the e-CRF must be supported by appropriately 
signed source documentation related but not limited to the following: 
• Agreement and signature of informed consent form with the study identification; the 
signed electronic informed consent form will be printed from the study web portal 
• Study identification (name) 
• Patient number, confirmation of randomization, approach group, treatment batch number, 
dates and doses of study medication administration 
• Medical, surgical, diabetes history, including information on : 
- 
Demography, inclusion and exclusion criteria 
- 
Last participation in a clinical trial 
- 
Contraception method for WOCBP 
- 
Previous and concomitant medication 
• Dates and times of visits and assessments including examination results (vital signs, 
height, body weight, laboratory reports) 
• For patients of the virtual group, the data transferred directly from Bluetooth devices to the 
study web portal will be considered as source data and will not have to be recorded in the 
patient file 
• Insulin dose (both basal and mealtime) titration assessment and recommendation for 
insulin dose adjustment 
• Investigator/physician notes, nursing notes, dietician’s notes 
• AEs and AEs follow-up, 
- 
In case of SAE, the site should file in the source documents at least copies of the 
hospitalization reports and any relevant examination reports documenting the follow-
up of the SAE 
• Date of premature study discontinuation (if any) and reason. 
• Patient eDiaries 
A monitor will visit the sites to verify the accuracy of the source data listed above against 
patient’s files. 
10.2.2 Source data verification requirements for screen failures  
For screen failure patients, the following source data must be verified: patient's identification 
details, the informed consent signed by the patient, the study identification (name), dates of study 
visits, and the main reasons for screen failure. 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY 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; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product 
Temporary treatment discontinuation may be considered by the investigator because of suspected 
AEs. 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 7.1 and 
Section 7.2). 
Patients will have to document any temporary discontinuation of the IMP insulin in the diary 
(date/time of last injection of the IMP insulin; date/time of resuming IMP insulin injection). It is 
in the interest of the patient to monitor plasma glucose during the temporary discontinuation 
period, therefore SMPG or other regular determination of plasma glucose is to be performed and 
documented. 
For all temporary treatment discontinuations, duration should be recorded by the investigator in 
the appropriate pages of the e-CRF.  
Temporary treatment discontinuation decided by the investigator corresponds to more than 1 dose 
not administered to the patient. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. 
10.3.3 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 
e-CRF. 
Criteria for permanent treatment continuation include: 
• At the patient’s own request, eg, withdrawal of consent for treatment  
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• If, in the investigator's opinion, continuation with the administration of the study treatment 
would be detrimental to the patient's well-being, (eg, requiring treatment with insulin 
pump)  
• Pregnancy 
• Specific request of the sponsor. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients 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. 
As far as possible, and after the permanent discontinuation of treatment, the patients will have a 
week-24 visit (on-site for traditional, remote for virtual approach group) with all assessments, 
except those related to IMP, performed as planned 24 weeks after randomization. 
After permanent discontinuation of the IMP, patients will return to standard of care for T1DM 
management based on investigator and patient healthcare providers’ clinical recommendation.  
Since the IMP, insulin Toujeo is approved basal insulin available in the market. It can be 
prescribed by the physician if deemed by the Investigator as the best option to manage the 
diabetes. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients requesting withdrawal should be informed 
that withdrawal of consent for follow-up may jeopardize the public health value of the study. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals should be recorded by the investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
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For patients who fail to attend the EOT visit, unless the patient withdraws consent for follow-up, 
the Investigator should make the best effort to recontact the patient (eg, contact patient’s family or 
private physician, review available registries or health care databases), and to determine his/her 
health status, including at least his/her vital status. Attempts to contact such patients must be 
documented in the patient’s records (eg, times and dates of attempted telephone contact, receipt 
for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events  
10.4.1.1 Adverse event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
10.4.1.2 Serious adverse event 
A SAE is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
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 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered a medically important event. The list is not 
intended to be exhaustive: 
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- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
Alanine transaminase (ALT) >3 x upper limit normal (ULN) + total bilirubin 
>2 x ULN or asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
10.4.1.3 Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. AEs of special interest may be added, modified or removed 
during a study by protocol amendment. 
• Pregnancy occurring in a female participant entered in the clinical trial.  
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant is mandatory until the outcome has 
been determined (see Appendix A). 
• Symptomatic overdose (serious or nonserious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic IMP 
count) and resulting in clinical symptoms and/or signs and considered a “significant 
overdose” by the Investigator. 
• Reportable by Canadian sites – not applicable to other countries: unusual lack of efficacy 
for IMP (serious or nonserious) 
- 
An unusual lack of efficacy is when a health product fails to produce the expected 
pharmacological or therapeutic benefit and there may be an adverse outcome for the 
patient, including an exacerbation of the condition for which the medication is being 
taken. Since no health product can be expected to be effective in 100% of the patients, 
clinical judgment should be exercised by a qualified health care professional to 
determine if the problem reported is related to the product itself, rather than one of 
treatment selection or disease progression. One example of unusual failure in efficacy 
is a previously well-stabilized condition that deteriorates when the patient changes to a 
different brand or receives a new prescription. 
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10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF (or the pre-screening log for the patients who will have consented to the study 
but will not be assigned a patient number, eg, because they are ineligible). 
• For patients of the virtual group, any symptom will be entered by the patients in the 
eDiary. The investigator will be informed through the study web portal and will document 
the corresponding AEs in the e-CRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms; 
if not possible, then each symptom must be reported separately as an AE (eg, nausea, 
headache). The Investigator should specify the date of onset, intensity, action taken with 
respect to IMP, corrective treatment/therapy given, additional investigations performed, 
outcome, and his/her opinion as to whether there is a reasonable possibility that the AE 
was caused by the IMP or by the study procedure(s). 
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs or electrocardiogram abnormalities are to be recorded as AEs only 
if:  
- 
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 
Instructions for AE reporting are summarized in Table 6. 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
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identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
medications, patient status, etc) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life-threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper case report form [CRF] process) is available and should be 
used when the e-CRF system does not work. 
Any SAE brought to the attention of the investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest  
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF.  
For reporting unusual lack of efficacy for Canadian patients: 
To be in line with Canadian Regulations, any AE that can be related to an unusual lack of efficacy 
(definition in Section 10.4.1.3) in the Investigator’s judgment must be reported to the Sponsor in 
an expedited report even if a seriousness criterion hasn’t been met. Consequently, as soon as the 
Investigator is informed by the patient of the occurrence of an AE that can be related to unusual 
lack of efficacy, he/she must immediately report this event on the AE page of the e-CRF. Even if 
the seriousness criterion has not been met, a paper copy of the SAE Complementary form and the 
Follow-up Information form (if needed) must still be completed: 
• ENTER (within 1 working day) the information related to the unusual lack of efficacy in 
the appropriate screens of the e-CRF (AE screen); 
• SEND (by fax) a printed copy of the AE form and a paper copy of the completed SAE 
Complimentary form to the representative of the Monitoring Team whose fax number 
appear on the Clinical Trial Protocol.  Send also any photocopy of all examinations carried 
out and the dates on which these examinations were performed. Care should be taken to 
ensure that the patient’s identity is protected and the patient’s identifiers in the Clinical 
Trial are properly mentioned on any copy of source document provided to the Sponsor. 
For laboratory results, include the laboratory normal ranges. 
Instructions for AE reporting are summarized in Table 6. 
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Table 6 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event 
category 
Reporting 
timeframe 
Specific events in this category 
AE form 
Safety  
Complementary 
Form 
Other 
specific 
forms 
Adverse Event 
(non-SAE, non-
AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI 
or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
 
 
 
 
 
 
Adverse Event of 
Special Interest  
Expedited 
(within 24 hours) 
Pregnancy 
No 
No 
Yes 
 
 
Symptomatic overdose 
Yes 
No 
Yes 
Adverse Event of 
Special Interest 
(Canada only) 
 
Unusual lack of efficacy of IMP, Canada 
only 
Yes 
Yes 
No 
 
 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (suspected 
unexpected serious adverse reaction [SUSAR]), to the regulatory authorities, independent 
ethics committees (IECs)/institutional review boards (IRBs) as appropriate and to the 
Investigators.   
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
• For Canada, Phase IV studies will follow post-marketing regulatory requirements.  
Reports of unusual lack of efficacy (serious or not), originating from Canada, will be 
submitted to the Canadian regulatory authority, according to local regulations. 
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected (please refer to the “Adverse Reaction section” in the US Package Insert 
(USPI) for Toujeo (9). Any other AE not listed in the “Adverse Reaction” in the USPI will be 
considered as unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
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10.6 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
Adverse events will be monitored until final outcome or return to patient’s baseline as applicable. 
Follow-up information on SAEs ongoing after study completion and for which an outcome is 
unavailable must be reported to the Sponsor’s Global Pharmacovigilance and Epidemiology 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of 150 patients (75 in virtual approach and 75 in traditional approach) will be 
randomized using a 1:1 ratio (virtual:traditional); this sample size was not powered for 
confirmatory testing, only descriptive statistics will be provided.  
As this is a pilot study, no formal sample size calculation was performed.  
Nevertheless, a precision calculation of the primary endpoint based on the 2-sided 95% 
confidence interval (CI) shows that the change in HbA1c from baseline in virtual approach, the 
change in HbA1c from baseline in traditional approach and the difference in HbA1c change 
between the two approaches will be estimated with a precision of approximately 0.37%, using a 
standard deviation (SD) of 1.1 and taking into account an up to 10% rate of non-evaluable patients 
for HbA1c. These calculations were made using nQuery Advisor 7.0. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all screened patients with a trial approach group allocated and 
recorded in the IRT database, regardless of whether the treatment kit was used or not. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
The total number of patients for each of the following categories will be presented. 
• Screened patients  
• Screen failure patients and reason for screen failure 
• Randomized patients 
• Safety population (Section 11.3.2) presented as treated 
• The intent-to-treat (ITT) population (Section 11.3.1) analyzed as randomized 
• The randomization strata (sites and screening HbA1c categories [<7.6%, ≥7.6%] assigned 
by IRT); the discrepancy between the strata assigned by IRT  and the information reported 
on e-CRF will be listed for all randomized patients 
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• Patients who permanently discontinued the IMP, and the reasons for permanent treatment 
discontinuation 
• Patients who completed the 24-week treatment period (patients who have attended 
Visit 12, who did not permanently discontinue treatment, and who did not take any rescue 
medication) 
• Patients who did not complete the 24-week treatment period 
• Patients who discontinued 24-week treatment by main reason for permanent treatment 
discontinuation 
• Patients who completed the study (patients who have attended Visit 12, whichever the 
treatment duration) 
• Patients who did not complete the study (patients who have not attended Visit 12) 
• Patients who discontinued the study by main reason for study discontinuation 
For all categories of patients except screened and screen failure patients, percentages will be 
calculated using the number of randomized patients as denominator for each approach group. 
Patients with the following deviations will be identified and described in separate listings: 
• Treated but not randomized 
• Randomized but not treated 
• Randomized but not treated as randomized 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Intent-to-treat population 
The ITT population will be used to analyze all non-safety endpoints. It consists of all randomized 
patients, irrespective of the trial approach group actually being used, analyzed according to the 
approach group allocated by randomization.  
11.3.2 Safety population 
The safety population is defined as all randomized patients who did actually receive at least one 
dose of IMP, regardless of the amount of IMP administered. 
In the event of patients having followed a trial approach that differed from the one assigned 
according to the randomization schedule, the safety analyses will be conducted according to the 
trial approach group assigned by randomization. 
Patients will not be considered exposed if there is documented evidence that patients have not 
taken the study drug: 
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• If a patient is dispensed IMP and is lost to follow-up without any documented evidence, 
the patient will be considered exposed and included in the safety population 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
In addition: 
• Non randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately 
11.3.3 PRO population  
The analysis of PROs will be conducted on the ITT population. 
11.4 
STATISTICAL METHODS 
No multiplicity adjustment will be made on endpoints; 95% CIs presented for these endpoints will 
be calculated for descriptive purpose only. 
Except if defined below, the baseline value will be the last available value prior to the first 
injection of IMP. 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
randomized trial approach group within the safety population. 
11.4.1.1 Extent of investigational medicinal product exposure 
The duration of exposure during the study will be the total number of days of administration of 
IMP, regardless of unplanned intermittent discontinuations. 
The duration of exposure to the open-label IMP during the study is defined as: 
(Date of the last IMP administration – date of the first IMP administration) + 1 day. 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum). In addition, duration of treatment exposure will 
also be summarized categorically by numbers and percentages for each of the following 
categories and cumulatively according to these categories: 
• up to 4 weeks 
• >4 to 8 weeks 
• >8 to 12 weeks 
• >12 to 16 weeks 
• >16 to 20 weeks 
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• >20 to 22 weeks 
• >22 to 23 weeks 
• >23 to 24 weeks 
• >24 weeks 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance percentage will be summarized descriptively (N, Mean, SD, Median, Min, 
and Max). The percentage of patients with compliance is <80% will be summarized. 
11.4.2 Analysis of primary endpoint 
Primary endpoint is described in Section 9.1. 
11.4.2.1 Analysis of primary efficacy endpoint 
11.4.2.1.1 Primary analysis 
The change in HbA1c from baseline to Week 24 will be analyzed using available data during the 
24-week randomized period. A mixed effect model with repeated measures (MMRM) approach 
will be used, under the missing at random framework carried out via SAS PROC MIXED using 
an adequate contrast at Visit 12 (Week 24). 
This model will be run with an unstructured correlation matrix to model the within-patient errors. 
Parameters will be estimated using restricted maximum likelihood method with the Newton 
Raphson algorithm. Denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation. This model will provide baseline adjusted least squares means estimates at 
Week 24 for both approach groups, as well as the differences of these estimates, with their 
corresponding standard errors and 95% CIs. 
The model will include fixed categorical effects of trial approach group, visit, trial approach-by-
visit interaction, randomization stratum of sites; and the continuous fixed covariates of baseline 
HbA1c value and baseline HbA1c value-by-visit interaction. 
11.4.3 Analysis of secondary endpoints  
11.4.3.1 Analyses of study methodology endpoints 
The analysis of study methodology endpoints will be conducted on the ITT population, on the 
24-week randomized period, ie, using all available post-baseline data, regardless of IMP 
discontinuation. 
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Study methodology endpoints are described in Section 9.2.1. 
11.4.3.1.1 Analysis of study methodology questionnaires 
For WIWI, WPAI-SP, and OSEP questionnaires a descriptive summary will be provided for each 
approach group at each applicable visit (baseline and/or Week 24) and, if applicable, change from 
baseline to Week 24, including:  
• WIWI scores for each item  
• WPAI-SP: item scores, and combined scores (Section 9.2.1.2) 
• OSEP: each item score 
For RUQ, descriptive summary will be provided for each approach group at baseline and for each 
applicable on-treatment visit on the following items: 
• Total number of visits (overall and per healthcare professional type) 
• Total money spent 
• Total time spent 
In addition, the total and average resource utilization per patient will be calculated on all on-
treatment questionnaires. The change between baseline and this on-treatment average will be 
calculated. 
The change in WPAI-SP and OSEP part 1 (perceptions of diabetes control) scores from baseline 
to Week 24 will be analyzed using an ANCOVA. This model will include fixed categorical effects 
of approach group, on randomization strata of screening HbA1c (<7.6%, ≥7.6%) and 
randomization strata of sites as well as continuous fixed covariates of corresponding baseline 
score. WIWI and OSEP part 2 scores (measured only at Week 24) will be compared between 
approach groups using an ANOVA. This model will include fixed categorical effects of approach 
group, on randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of 
sites. 
11.4.3.1.2 Analysis of compliance with IMP 
See Section 11.4.1.1. 
11.4.3.1.3 Analysis of compliance with key study activities 
For the number of times the patient used the Bluetooth devices and the number of times the 
patient completed blood draw visit in accordance with the study instructions from baseline to 
Week 24, only descriptive statistics will be calculated including the number of available data, 
mean, SD, median, minimum, and maximum. These endpoints will be calculated only for the 
virtual group. 
For patient withdrawal from baseline to Week 24, Kaplan-Meier plots/estimates of the 
cumulative incidence of study discontinuation due to any reason will be provided. Time to study 
discontinuation is defined as the number of days from Day 1 until the day of study 
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discontinuation. All completers are considered as censored observations. The censoring time is the 
number of days from the randomization date until the last visit date. 
11.4.3.2 Analyses of diabetes control endpoints 
The analysis of diabetes control endpoints will be conducted on the ITT population on the 24-
week randomized period, ie, using all available post-baseline data, regardless of IMP 
discontinuation. 
Diabetes control endpoints are described in Section 9.2.2. 
11.4.3.2.1 Analysis of diabetes control PROs 
For each questionnaire a descriptive summary at each applicable visit (baseline and/or Week 24) 
and change from baseline to Week 24 will be provided, including:  
• DTSQs and DTSQc subscale scores (total treatment satisfaction, perceived frequency of 
hyperglycemia, and perceived frequency of hypoglycemia, see Section 9.2.2.1) 
• HFS-II total score and subscale scores (HFS-B and HFS-W) 
• DDS: total score, subscales scores, distress category for total and subscales 
(Section 9.2.2.1) 
The change in DTSQs, HFS-II, and DDS scores from baseline to Week 24 will be analyzed using 
an ANCOVA. This model will include fixed categorical effects of approach group, on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as 
well as continuous fixed covariates of corresponding baseline score. 
Average scores at Week 24 in total treatment satisfaction score, hyperglycemia perception, and 
hypoglycemia perception score from DTSQc will be analyzed using an ANCOVA model. This 
model will include fixed categorical effects of approach group, on randomization strata of 
screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as well as continuous fixed 
covariates of corresponding baseline score from DTSQs. 
11.4.3.2.2 Analysis of glycemic endpoints 
The following endpoints will be analyzed using available data during the 24-week treatment 
period. A mixed effect model with repeated measures (MMRM) approach will be used, under the 
missing at random framework carried out via SAS PROC MIXED using an adequate contrast at 
Visit 12 (Week 24). 
This model will be run with an unstructured correlation matrix to model the within-patient errors. 
Parameters will be estimated using restricted maximum likelihood method with the Newton 
Raphson algorithm. Denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation. This model will provide baseline adjusted least squares means estimates at 
Week 24 for both approach groups, as well as the differences of these estimates, with their 
corresponding standard errors and 95% CIs. 
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• HbA1c (%): change from baseline to Week 16 
• FPG: change from baseline to Week 16 and Week 24 
• Change in 7-point SMPG profiles per time-point from baseline to Week 16 and Week 24 
For HbA1c endpoint, the model will include fixed categorical effects of trial approach group, 
visit, trial approach-by-visit interaction, randomization stratum of sites, as well as, the continuous 
fixed covariates of baseline HbA1c value and baseline HbA1c value-by-visit interaction. 
For FPG and 7-Point SMPG endpoints, the model will include fixed categorical effects of trial 
approach group, visit, trial approach-by-visit interaction, randomization stratum of sites, 
randomization stratum of HbA1c (7.6 % and ≥7.6%), the continuous fixed covariates of the 
corresponding baseline value, and baseline value-by-visit interaction. 
11.4.3.3 Analyses of patient care endpoints 
The analysis of patient care endpoints will be conducted on the ITT population on the 24-week 
randomized period, ie, using all available post-baseline data, regardless of IMP discontinuation  
Patient care endpoints are described in Section 9.2.3. 
11.4.3.3.1 Analysis of investigator questionnaires 
For OSES (Section 9.2.3.1) a descriptive summary will be provided for each approach group at 
each applicable visit.  
For OSES part 1 (study-specific resource requirements), a descriptive summary will be provided 
for each approach group at each applicable visit, and a total time will be calculated for each 
patient and averaged within each approach group. Overall Study Experience-Sites part 1 scores 
will be compared between approach groups using an ANCOVA. This model will include fixed 
categorical effects of approach group, on randomization strata of screening HbA1c (<7.6%, 
≥7.6%) and randomization strata of sites as well as continuous fixed covariates of corresponding 
baseline score. 
For OSES part 2 (relationship and satisfaction), a descriptive summary will be provided for each 
item for each approach group at Week 24. Item scores will be compared between approach groups 
using an ANOVA. This model will include fixed categorical effects of approach group, on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites. 
11.4.3.3.2 Analysis of patient interviews 
Exit interviews with a subset of patient from the virtual group is described in Section 9.2.3.2. Data 
will be analyzed via an expert qualitative research analysis group using standardized qualitative 
methods (eg, thematic analysis, grounded theory). A specific Statistical Analysis Plan and report 
will be developed for the exit interviews. 
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11.4.3.4 Analyses of safety endpoints 
Safety endpoints are described in Section 9.2.4. 
The summary of safety results will be presented by approach group.  
All safety analyses will be performed on the safety population, on the on-treatment period, 
defined as the time from first IMP injection up to 2 days after the last IMP injection. 
The baseline value for safety endpoints will be the last available value prior to the first injection 
of IMP. 
11.4.3.4.1 Hypoglycemia 
The number and incidence of patients experiencing at least 1 hypoglycemic event will be 
presented per trial approach group and type of hypoglycemic event (Section 9.2.4.4) according to 
time of occurrence (nocturnal [ie, 00:00 to 05:59, by sleep status], any time of the day) during the 
treatment period. The Odds Ratio and its corresponding 95% CI of virtual group over traditional 
group for each hypoglycemic event will be estimated by a logistic regression model adjusted on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites. This 
model will also estimate the Odds Ratio of virtual group and traditional group and its 
corresponding 95% CI. 
The number and rate of hypoglycemic events (in patient-year of exposure) will be determined per 
trial approach group and type of hypoglycemic event (Section 9.2.4.4), according to time of 
occurrence (nocturnal [ie, 00:00 to 05:59, by sleep status], any time of the day) during the on 
treatment period. For each hypoglycemic event, the rate ratio, and its corresponding 95% CI, of 
virtual group over traditional group will be estimated using an over-dispersed Poisson regression 
model adjusted on randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization 
strata of site. 
11.4.3.4.2 Adverse events 
All AEs will be coded to a preferred term (PT), high level group term (HLGT), high level term 
(HLT), and associated primary system organ class (SOC) using the version of medical dictionary 
for regulatory activities (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 approach 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 approach group. 
Adverse event incidence table will be provided by study conduct approach group for all types of 
TEAEs: all TEAEs, all treatment emergent SAEs, all TEAEs leading to permanent treatment 
discontinuation and all TEAEs related to local tolerability at injection site and hypersensitivity. 
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Death 
The following deaths summaries will be generated on the safety population: 
• Number (%) of patients who died by study period (TEAE, on-study, poststudy) and 
reasons for death summarized by allocated approach group 
• Death in nonrandomized patients or randomized and not treated patients 
• TEAE leading to death by primary SOC, HLGT, HLT and PT showing number (%) of 
patients sorted by internationally agreed order of SOC and alphabetic order of HLGT, 
HLT, and PT 
Post-study deaths, if presented, will follow safety guideline instruction. 
Injection site reaction and hypersensitivity reaction 
Number (%) of patients with events related to injection site reactions or hypersensitivity reaction 
will be provided separately. 
Adverse event of special interest 
A listing of patients with symptomatic overdose with IMP/NIMP will be provided separately. 
Patients with an SAE or AESI should be followed until resolution, stabilization, or death as 
appropriate. 
Product technical complain 
Information regarding PTC will be described. 
11.4.3.4.3 Vital signs and physical examination 
The potentially clinically significant abnormality (PCSA) values are defined as abnormal values 
considered medically important by the Sponsor according to predefined criteria/thresholds based 
on literature review and defined by the Sponsor for vital signs 
Potentially clinically significant abnormality criteria will determine which patients had at least 
one PCSA during the TEAE period, taking into account all evaluations performed during the on-
treatment TEAE period, including unscheduled or repeated evaluations. The number of all such 
patients will be the numerator for the PCSA percentage during the TEAE on-treatment period 
The incidence of PCSAs at any time during the TEAE period will be summarized by approach 
group whatever the baseline level and according to baseline status. 
11.5 
INTERIM ANALYSIS 
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by the Sponsor, the Investigator, and delegated Investigator 
staff and Subinvestigator, in accordance with consensus ethics principles derived from 
international ethics guidelines, including the Declaration of Helsinki, and the ICH guidelines for 
good clinical practice (GCP), all applicable laws, rules and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
Before accessing to the study web portal, potential participants to the study will have to agree 
with the General Terms of Use of the portal. 
Electronic consent is described in Section 10.1.1.  
The patients will be fully informed of all pertinent aspects of the clinical trial including the written 
information giving approval/favorable opinion by the ethics committee (IRB/IEC). All 
participants should be informed to the fullest extent possible about the study, in language and 
terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
electronically signed, name filled in and dated by the patient or by the patient’s legally acceptable 
representative. A paper version of the signed electronic consent form will be printed twice for 
giving a copy to the patient and filing in the investigator study file. The informed consent form 
used by the Investigator for obtaining the patient's informed consent must be reviewed and 
approved by the Sponsor prior to submission to the appropriate ethics committee (IRB/IEC) for 
approval/favorable opinion. 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)  
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party a 
copy of the written and dated approval/favorable opinion signed by the chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, labeling documents [summary of product 
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characteristics, package insert], Investigator’s curriculum vitae [CV], etc) and the date of the 
review should be clearly stated on the written (IRB/IEC) approval/favorable opinion. 
The IMP will not be released at the study site and the Investigator will not start the study before 
the written and dated approval/favorable opinion is received by the Investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. They should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
labeling information will be sent to the IRB/IEC and to health authorities (competent regulatory 
authority), as required by local regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Subinvestigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Subinvestigators shall be appointed and listed in a timely manner. The 
Subinvestigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. Source document requirements 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
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secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF. The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the ethics committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient's medical file, 
appointment books, original laboratory records, etc). These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the CV describing the experience, qualification and training of each 
Investigator and Subinvestigator will be signed, dated and provided to the Sponsor prior to the 
beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure, and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Subinvestigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Subinvestigators of the confidential nature of the clinical trial. 
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The Investigator and the Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Subinvestigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database and the study web 
portal database, shall be treated in compliance with all applicable laws and regulations 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship. This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP, and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio 
• Patient enrollment is unsatisfactory 
• The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• Noncompliance of the Investigator or Subinvestigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP 
• The total number of patients are included earlier than expected 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway, 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication. In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes to the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of health authorities (competent regulatory 
authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the health authorities 
(competent regulatory authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be recollected if 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 
Smith A. Pew Research Center's Internet & American Life Project. [Mobile Access]. 2010 
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2. 
Wicks P, Vaughan TE, Massagli MP, Heywood J. Accelerated clinical discovery using 
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3. 
Orri M, Lipset CH, Jacobs BP, Costello AJ, Cummings SR. Web-based trial to evaluate 
the efficacy and safety of tolterodine ER 4 mg in participants with overactive bladder:REMOTE 
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4. 
Patel S, Park H, Bonato P, Chan L, Rodgers M. A review of wearable sensors and systems 
with application in rehabilitation. J Neuroeng Rehabil. 2012;9:21 
5. 
International Diabetes Federation. IDF Diabetes Atlas. 7th ed. [Online]. Brussels, Belgium: 
International Diabetes Federation; 2015. Available from: URL:http://www.diabetesatlas.org. 
6. 
DCCT/EDIC Research Group, Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, 
Miller R, et al. Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the 
Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and 
Complications and Pittsburgh Epidemiology of Diabetes Complications experience (1983-2005). 
Arch Intern Med. 2009;169(14):1307–16. 
7. 
American Diabetes Association. Economic costs of diabetes in the U.S. In 2007. Diabetes 
Care. 2008;31(3):596–615. 
8. 
Aschner P, Horton E, Leiter LA, Munro N, Skyler JS. Practical steps to improving the 
management of type 1 diabetes: recommendations from the Global Partnership for Effective 
Diabetes Management. Int J Clin Pract. 2010;64(3):305-15. 
9. 
TOUJEO (insulin glargine injection) –U300, for subcutaneous use – initial U.S. Approval: 
2015. 
10. 
Sloan JA, Mahoney MR, Sargent DJ, Hubbard JM, Liu H, Basch EM, et al. Was it worth it 
(WIWI)?Patient satisfaction with clinical trial participation: Results from North Central Cancer 
Treatment Group (NCCTG) phase III trial N0147. J Clin Oncol. 2011;29 suppl:abstr 6122. 
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Mallory MJ, Croghan KA, Sandhu NP, Lemaine V, Degnim AC, Bauer BA, et al. 
Acunpuncture in the postoperative setting for breast cancer patients: a feasibility study. Am J 
Chin Med. 2015;43(1):45-56. 
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Reilly MC, Zbrozek AS, Dukes EM. The validity and reproducibility of a work 
productivity and activity impairment instrument. PharmacoEconomics. 1993;4(5):353-65. 
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13. 
Bradley C. The Diabetes Treatment Satisfaction Questionnaire: DTSQ. In: Bradley C, 
editor. Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes 
research and practice. Chur, Switzerland: Harwood Academic Publishers; 1994. p. 111–32. 
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Bradley C. Diabetes Treatment Satisfaction Questionnaire: Change version for use 
alongside status version provides appropriate solution where ceiling effects occur. Diabetes Care. 
1999;22(3):530–2. 
15. 
Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J. Fear of hypoglycemia: 
quantification, validation, and utilization. Diabetes Care. 1987;10(5):617–21. 
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Polonsky WH, Fisher L, Earles J, Dudl RJ, Lees J, Mullan J, et al. Assessing Psychosocial 
Distress in Diabetes: development of the diabetes distress scale. Diabetes Care. 2005;28(3):626-
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Fisher L, Hessler DM, Polonsky WH, Mullan J. When is diabetes distress clinically 
meaningful?: establishing cut points for the Diabetes Distress Scale. Diabetes Care. 
2012;35(2):259-64. 
18. 
Defining and Reporting Hypoglycemia in Diabetes: A Report from American diabetes 
Association Workgroup on hypoglycemia. Diabetes Care. 2005;28(5):1245-9. 
19. 
Seaquist E, 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. 
20. 
ICH Topic M 3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical 
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17 
APPENDICES 
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Appendix A 
Guidance on contraceptive methods and collection of pregnancy 
information 
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
2. Postmenopausal 
- 
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, a single FSH measurement is insufficient.  
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use 1 of the 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 enrolment. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Since glycemic control may be unstable and insulin doses may be variable during the study, 
female patients must not be breast feeding or pregnant (as confirmed by serum pregnancy test) at 
the time of study entry and must agree to undergo urine pregnancy testing at onsite visits as 
indicated in the study flow chart (Section 1.2). All WOCBP must be fully informed about the 
requirement to prevent pregnancy while in this study. Sexually active WOCBP must agree to use 
a reliable medically accepted contraceptive method throughout the study.  
Reliable contraception regimens are defined for this protocol as: 
• True abstinence: when this is in line with the preferred and usual lifestyle of the patient 
(periodic abstinence [eg, calendar, ovulation, symptothermal, post ovulation methods] and 
withdrawal are not acceptable methods of contraception). Non-sexually active WOCBP 
participating to this study before becoming sexually active must also agree that they will 
use acceptable contraception method. 
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• Highly effective oral contraceptives, such as biphasic and triphasic oral contraceptives are 
considered adequate. Progestogen only pills or “mini pills” which have demonstrated high 
efficacy will be acceptable. 
• Injectable hormones (ie, Depo-Provera), hormonal implants, transdermal patches, 
intrauterine devices, intrauterine systems, or an intravaginal ring (NuvaRing) which have 
demonstrated efficacy comparable to high efficacy oral contraceptives are adequate. 
• Female patients having a sterilized permanent partner; before becoming sexually active 
with another partner, such patients must also agree to use an acceptable contraceptive 
method. 
Local additional requirements must be followed. 
If during the study, a female patient becomes pregnant (Section 10.4.1.3) or decides to attempt to 
become pregnant, then she must contact the Investigator immediately and the IMP will be 
withdrawn and exchanged by an approved basal insulin. The study IMP will also be withdrawn 
and exchanged by an approved basal insulin if a female patient undertakes behavior deemed by 
the investigator to be at risk of getting pregnant. 
COLLECTION OF PREGNANCY INFORMATION 
Female subjects who become pregnant  
• The Investigator will collect pregnancy information on any female subject, 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.  
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which 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 procedure.  
• Pregnancy is considered to be an AESI. 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 SAE occurring as a result of a post-study pregnancy which is considered reasonably 
related to the study treatment by the Investigator, will be reported to the Sponsor as 
described in Section 10.4.4. While the Investigator is not obligated to actively seek this 
information in former study subjects, he or she may learn of an SAE through spontaneous 
reporting.  
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Appendix E 
Bluetooth devices and associated material 
The following devices and associated material will be used during the study. Detailed instructions 
for use will be provided to the patients and included in the study operational manual. 
GLUCOMETER AND ANCILLARY SUPPLIES 
Class 3 Devices/Products 
• MyGlucoHealth Wireless Blood Glucose Monitoring System model MGH-BT1 
(manufacturer: Infopia)  
• MyGlucoHealth test strips model MGH-TS50 (manufacturer: Infopia)   
• MyGlucoHealth Control Solution model MGH-CS3 (manufacturer: Infopia) 
Class 2 Device 
• Lancets (manufacturer: Taidoc)   
PULSE OXIMETER 
• Finger pulse oximeter model 9560 ONYX II (manufacturer: Nonin)  
BLOOD PRESSURE CUFF 
• Blood pressure cuff model, HEM 9200T (manufacturer: OMRON)  
WEIGHT SCALE 
Per Entra “For the weight scale, there is no requirement for a license in Canada, unless the scale 
calculates BMI or Fat Analysis.  The scale is branded with Entra Health’s name. 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MSC15146 16.1.1 Protocol
Clinical Approval
13-Mar-2017 12:08 GMT+0100
Clinical Approval
15-Mar-2017 09:24 GMT+0100
Regulatory Approval
16-Mar-2017 22:02 GMT+0100

SAP_001.pdf: 
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According to template: QSD-002643 VERSION 6.0 (06-JUL-2016) 
Page 1
STATISTICAL ANALYSIS PLAN 
Evaluation of virtual versus traditional study conduct in a 6-month, multicenter, 
randomized, open-label, 2-parallel group pilot study in adult patients with Type 1 
diabetes mellitus  
HOE901-MSC15146-eSTUDY 
STATISTICIAN: 
  
Statistical Project Leader: 
 
DATE OF ISSUE: 08-Jul-2019 
Total number of pages: 
107 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 7 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 7 
1.2 
OBJECTIVES ................................................................................................................................... 7 
1.2.1 
Primary objectives ............................................................................................................................ 7 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
STUDY PLAN ................................................................................................................................... 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 10 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 11 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 11 
2.1.1 
Demographic and baseline characteristics .................................................................................... 11 
2.1.2 
Prior or concomitant medications ................................................................................................... 13 
2.1.3 
Efficacy endpoints .......................................................................................................................... 14 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 15 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 15 
2.1.3.3 
Secondary endpoints related to compliance .................................................................................. 15 
2.1.3.4 
Exploratory efficacy endpoints ....................................................................................................... 15 
2.1.4 
Safety endpoints ............................................................................................................................ 15 
2.1.4.1 
Hypoglycemia events ..................................................................................................................... 16 
2.1.4.2 
Adverse events variables ............................................................................................................... 17 
2.1.4.3 
Deaths ............................................................................................................................................ 18 
2.1.4.4 
Laboratory safety variables ............................................................................................................ 18 
2.1.4.5 
Vital signs variables ....................................................................................................................... 19 
2.1.4.6 
Electrocardiogram variables .......................................................................................................... 19 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 19 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................ 19 
2.1.7 
Patient reported outcome endpoints .............................................................................................. 19 
2.1.7.1 
Study methodology endpoints: Patient satisfaction with trial experience (WIWI) .......................... 19 
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2.1.7.2 
Study methodology endpoints: Impact of trial participation (WPAI) ............................................... 19 
2.1.7.3 
Study methodology endpoints: Patient burden with trial participation (OSEP) .............................. 20 
2.1.7.4 
Study methodology endpoints: Resource use (RUQ) .................................................................... 20 
2.1.7.5 
Diabetes control endpoints: Diabetes-related patient reported outcomes (DTSQs, DTSQc, 
HFS-II, DDS) .................................................................................................................................. 20 
2.1.8 
Investigator (clinician) reported outcome (ClinRO) endpoints ....................................................... 22 
2.1.9 
Health economic endpoints ............................................................................................................ 22 
2.1.10 
Patient interviews ........................................................................................................................... 22 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 23 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 24 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 25 
2.3.1 
Efficacy populations ....................................................................................................................... 25 
2.3.1.1 
Intent–to-treat population ............................................................................................................... 25 
2.3.2 
Safety population ........................................................................................................................... 26 
2.3.3 
PRO and ClinRO populations ........................................................................................................ 26 
2.4 
STATISTICAL METHODS ............................................................................................................. 26 
2.4.1 
Demographics and baseline characteristics .................................................................................. 27 
2.4.2 
Prior or concomitant medications ................................................................................................... 27 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 27 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 28 
2.4.3.2 
Daily insulin doses ......................................................................................................................... 28 
2.4.3.3 
Compliance .................................................................................................................................... 29 
2.4.3.4 
Compliance with key study activities.............................................................................................. 29 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 29 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 29 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 31 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 32 
2.4.4.4 
Additional efficacy analyses ........................................................................................................... 32 
2.4.5 
Analyses of safety data .................................................................................................................. 32 
2.4.5.1 
Analyses of hypoglycemia ............................................................................................................. 33 
2.4.5.2 
Analyses of adverse events ........................................................................................................... 34 
2.4.5.3 
Deaths ............................................................................................................................................ 36 
2.4.5.4 
Analyses of laboratory variables .................................................................................................... 37 
2.4.5.5 
Analyses of vital sign variables ...................................................................................................... 37 
2.4.5.6 
Analyses of electrocardiogram variables ....................................................................................... 37 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 37 
2.4.7 
Analyses of PRO and ClinRO variables......................................................................................... 37 
2.4.7.1 
Study methodology endpoints: Patient satisfaction with trial experience (WIWI) .......................... 38 
2.4.7.2 
Study methodology endpoints: Impact of trial participation patient reported outcome 
(WPAI-SP) ...................................................................................................................................... 38 
2.4.7.3 
Study methodology endpoints: Patient burden with trial participation (OSEP) .............................. 38 
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2.4.7.4 
Study methodology endpoints: Resource use (RUQ) .................................................................... 38 
2.4.7.5 
Diabetes control endpoints: Diabetes-related patient reported outcomes (DTSQs, DTSQc, 
HFS-II, DDS) .................................................................................................................................. 39 
2.4.7.6 
Investigator (clinician) reported outcome (ClinRO) endpoints ....................................................... 41 
2.4.8 
Patient interviews ........................................................................................................................... 41 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 41 
2.5.1 
General conventions ...................................................................................................................... 41 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 43 
2.5.3 
Missing data ................................................................................................................................... 46 
2.5.4 
Windows for time points ................................................................................................................. 47 
2.5.5 
Unscheduled visits ......................................................................................................................... 50 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 50 
2.5.7 
Statistical technical issues ............................................................................................................. 50 
3 
INTERIM ANALYSIS ..................................................................................................................... 51 
4 
DATABASE LOCK ........................................................................................................................ 52 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 53 
6 
REFERENCES ............................................................................................................................... 54 
7 
LIST OF APPENDICES ................................................................................................................. 55 
APPENDIX A 
POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA ...................... 56 
APPENDIX B 
STUDY FLOWCHART ......................................................................................................... 62 
APPENDIX C 
PRO: WAS IT WORTH IT (WIWI) ....................................................................................... 67 
APPENDIX D 
PRO: WORK PRODUCTIVITY AND IMPAIRMENT (WPAI) ............................................... 69 
APPENDIX E 
PRO: OVERALL STUDY EVALUATION – PARTICIPATION (OSEP) ................................ 75 
APPENDIX F 
PRO: RESSOURCES USE QUESTIONNAIRE (RUQ) ....................................................... 78 
APPENDIX G 
PRO: DIABETES TREATMENT SATISFACTION QUESTIONNAIRE  STATUS 
(DTSQS) ........................................................................................................................................ 80 
APPENDIX H 
PRO: DIABETES TREATMENT SATISFACTION QUESTIONNAIRE CHANGE 
(DTSQC) ........................................................................................................................................ 85 
APPENDIX I 
PRO: HYPOGLYCEMIA FEAR SURVEY-II (HFS-II) ............................................................ 89 
APPENDIX J 
PRO: DIABETES DISTRESS SCALE (DDS) ..................................................................... 100 
APPENDIX K 
CLINRO : OVERALL STUDY EVALUATION – SITE (OSES) ........................................... 106 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ADA: 
american diabetes association 
ADaM: 
analysis data model 
AEs: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
BMI: 
body mass index 
CI: 
confidence interval 
CLcr: 
creatinine clearance 
ClinRO: 
investigator (CLInician) reported outcome 
DDS: 
diabetes distress scale 
DTSQ: 
diabetes treatment satisfaction questionnaire 
DTSQc: 
diabetes treatment satisfaction questionnaire change 
e-CRF: 
electronic case report form 
FPG: 
fasting plasma glucose 
GFR: 
glomerular filtration rate 
HbA1c: 
glycosylated hemoglobin A1c 
HFS-B: 
hypoglycemia fear survey-behavior 
HFS-W: 
hypoglycemia fear survey-worry 
HLGT: 
high-level group term 
HLT: 
high-level term  
IMP: 
investigational medicinal product 
ITT: 
intent to treat 
KM: 
Kaplan-Meier 
LLT: 
lower-level term 
LS: 
least square 
MDRD: 
modification of diet in renal disease 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
mixed-effect model with repeated measures 
MRN: 
Medical Research Network 
NIMP: 
non-investigational medical product 
OSEP: 
overall study experience-participation 
OSES: 
overall study experience-sites 
PRO: 
Patient Reported Outcome 
PT: 
preferred term , preferred term 
RBC: 
red blood cell 
RUQ: 
ressource use questionnaire 
SAE(s): 
serious adverse event(s)  
SAS: 
statistical analysis system 
SEs: 
standard error 
SMPG: 
self-monitoring plasma glucose 
SOC: 
system organ class  
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T1DM: 
Type I Diabetes Mellitus 
TEAE: 
treatment-emergent adverse event 
US: 
United States 
WHO-DD: 
world health organization-drug dictionary 
WIWI: 
was it worth it 
WPAI: 
work productivity and impairment 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is an open label, 1:1 randomized, 2 groups approach, multicenter pilot study. The study is a 
post-marketing Phase 4 trial which will recruit outpatients with Type 1 diabetes mellitus (T1DM) 
currently treated with insulin glargine 100 U/mL (eg, Lantus or Basaglar) plus rapid-acting insulin 
analogs. The patients must have access to mobile technology (eg, smartphone) and be digital-
literate. They will eSign the consent on the study website or on the “Subject application”. The 
patients will be switched at randomization to insulin glargine 300 U/mL (eg, Toujeo) plus rapid-
acting insulin analogs. 
The study will be conducted in the US and in Canada with approximatively 6 participating 
investigational centers. It is planned to randomize 150 patients (250 patients will be recruited). 
Eligible patients will be randomized 1:1 (virtual: traditional) into 2 study groups to follow one of 
two approaches for completion of all study procedures: 
 A remote, virtual approach (n = 75 patients); patients of this group will not visit the study 
sites during the entire study course, except for a physical examination before IMP 
initiation. All study assessments, including vital signs, weight, lab variables, etc, will be 
completed via the Bluetooth devices that instantly transfer the digital data, available for 
investigators’ view. Video chat between the patients and investigators/designees may 
occur for safety reason in addition to the planned study visits. 
 A traditional approach (n = 75 patients).  
Stratification factors for randomization include study site and HbA1c <7.6% or ≥7.6%. The 
rationale for stratification by study site is the small number of sites and the fact that some 
assessments for patient care are done at site level. It is therefore deemed important to ensure 
balance at site level in number of patients randomized across the virtual and traditional approach 
groups. Patients of both groups will receive the same IMP: daily subcutaneous (SC) injection of 
Toujeo as the basal insulin. Protocol-mandated background therapy consists of the existing rapid 
acting insulin analogs (Humalog, Novolog, or Apidra) that have been used before the start of the 
study and will be continued throughout the study. This background treatment will not be supplied 
by the sponsor. 
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to evaluate the effect of virtual approach via novel 
technologies versus traditional study conduct on glycemic control in terms of HbA1c. 
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1.2.2 Secondary objectives  
The study secondary objective is to evaluate the appropriate utilization of virtual approach via 
novel technologies during the study and to assess the effect of the virtual versus traditional study 
conduct on multiple outcomes in terms of study methodology and diabetes control: 
 Study methodology with the two approaches: 
- 
Patient satisfaction with the trial experience via a PRO 
- 
Impact of clinical trial participation via a PRO 
- 
Patient burden with the clinical trial experience via a PRO 
- 
Resource use via a PRO 
- 
Medication and key study activity compliance 
- 
Patient retention  
 Diabetes control with the two approaches: 
- 
Diabetes related PROs 
- 
Glycemic control (HbA1c, FPG, SMPG) 
 Patient care with the two approaches: 
- 
Doctor/site-patient relationship 
- 
Site satisfaction with provisioned care 
- 
Patient experience in the clinical trial via a qualitative exit interview 
 Safety assessment managed by the two approaches including: 
- 
Hypoglycemic events 
- 
Adverse Events (AEs) 
1.3 
DETERMINATION OF SAMPLE SIZE  
A sample size of 150 patients (75 in virtual approach and 75 in traditional approach) will be 
randomized using a 1:1 ratio (virtual: traditional); this sample size was not powered for 
confirmatory testing, only descriptive statistics will be provided.  
As this is a pilot study, no formal sample size calculation was performed.  
Nevertheless, a precision calculation of the primary endpoint based on the 2-sided 95% 
confidence interval (CI) shows that the change in HbA1c from baseline in virtual approach, the 
change in HbA1c from baseline in traditional approach and the difference in HbA1c change 
between the two approaches will be estimated with a precision of approximately 0.37%, using a 
standard deviation (SD) of 1.1 and taking into account an up to 10% rate of non-evaluable patients 
for HbA1c.  
These calculations were made using nQuery Advisor 7.0. 
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1.4 
STUDY PLAN  
The following figure describes the design of the study: 
Figure 1 - Study design  
 
The study consists of 3 periods:  
 An up-to-3 week screening period. 
 A 24-week treatment period. 
 A 1-week post-treatment period (follow-up). 
The screening period includes 2 steps to complete the digital consent process via the study-
specific webpage and the eligibility assessment by the study site. Screening procedures will be 
performed by Homecare services (via the Medical Research Network [MRN]) provided medical 
professional in collaboration with the investigators. The investigators will then complete the 
eligibility assessments at the end of screening, the randomization, and the shipment of study 
material (Step 2).  
During the 24-week treatment period, the patients in both groups will receive the same study 
treatment with Toujeo as the basal insulin plus their existing rapid-acting mealtime insulin 
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analogs (Humalog, Novolog, or Apidra) to manage their diabetes. Toujeo dose will be titrated to 
target the fasting SMPG between 80 and 130 mg/dL; meal time insulin analogs will be adjusted 
following investigators’ instructions to maintain postprandial SMPG within a range of 130 to 
180 mg/dL. 
All patients will monitor their plasma glucose via the study provided glucose meter. The SMPG 
values will be used to guide the insulin dose adjustment and document the hyper- or 
hypoglycemic events. 
Any post-treatment safety information will be collected during the 1-week post-treatment period. 
In total the study duration per patient will be approximately 28 weeks (3 weeks of screening +  
24 weeks on treatment + 1 week post-treatment follow-up). 
See the study flowchart with details of all assessments in Appendix B. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Not applicable 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
Not applicable 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
 
The study was early terminated by the Sponsor on November 2018 due to prolonged low patient 
recruitment. At this date 15 patients were randomized instead of 150 as expected. Therefore the 
primary and secondary objectives will not be analyzed as initially planned as detailed below in 
this Statistical analysis Plan. Consequently only basics descriptive statistics will be provided using 
tables or listings according to the availability of assessments for each endpoints and parameters. 
 
Any technical details related to computation, dates and imputation for missing dates are described 
in Section 2.5. 
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline value is defined as the last available value prior to the first injection of open-label 
IMP and up to randomization for patients randomized not treated. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the on-treatment summary statistics in the safety and efficacy sections (Section 2.4.5 and 
Section 2.4.4). 
Demographic characteristics 
 Age (years). 
 Age qualitative categories: <65, [65-75[ and ≥75 years. 
 Gender (Male, Female). 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Not reported, Unknown). 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown /Not Reported). 
Vital signs 
 Baseline body weight (kg), 
 Baseline body weight categories (kg) : <50, ≥50 and <100, ≥100 kg. 
 Baseline Body Mass Index (kg/m2). 
 Baseline body mass index (BMI) categories (kg/m2): <25, [25-30[, [30-40[ and ≥40 kg/m². 
Renal function 
 Baseline Creatinine (μmol/L). 
 Baseline Creatinine Clearance (CLcr): CLcr (mL/min) estimated using Cockcroft-Gault   
formula (Section 2.5.1). 
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 Creatinine clearance category (mL/min): ≥90, [60-90[, [30-60[, <30 
 Baseline estimated glomerular filtration rate ([GFR], using modification of diet in renal 
disease [MDRD] formula, mL/min/1.73m2), (Section 2.5.1). 
 Baseline estimated glomerular filtration rate (GFR, using MDRD formula, 
mL/min/1.73m2) categories : <15 End stage, [15-30[ Severe decrease, [30-60[ Medium 
decrease, [60 -90[ Mild decrease, ≥ 90 Normal. 
Medical or surgical history 
All medical/surgical history information (including allergies, diabetic complications, history of 
seizure/coma and/or hospitalization due to severe hypoglycemia), will be coded to a “lower level 
term (LLT), “preferred term (PT), “high level term (HLT)”, “high level group term (HLGT)” and 
associated primary “system organ class (SOC) using the version of Medical Dictionary for 
Regulatory Activities (MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics at baseline   
Specific disease history includes:  
 Duration of diabetes (years). 
 Category of duration of diabetes (<10, ≥10 years). 
 Age (years) at onset of diabetes. 
 Previous basal insulin treatment: 
- 
Daily dose (U and U/kg) = median of previous basal insulin daily doses during the last 
3 days prior to the first IMP, 
- 
Product, for last 3 months before Visit 1 only, (insulin glargine, insulin detemir, NPH, 
other); daily dose and daily injection number will be provided by product too (in U and 
U/kg). 
 Previous mealtime insulin treatment: 
- 
Daily dose (U and U/kg) = median of previous mealtime insulin daily doses during the 
last 3 days prior to the first IMP, 
- 
Product; daily dose will be provided by product too (in U and U/kg). 
 Previous total insulin treatment: 
- 
Daily dose (U and U/kg): sum of previous basal plus mealtime, during the last 3 days 
prior to the first IMP (or prior to randomization for not treated patients). 
 Diabetic complications at baseline: 
- 
Diabetic retinopathy (Yes, No, Unknown), including type (proliferative/non-
proliferative), 
- 
Diabetic neuropathy (Yes, No, Unknown), 
- 
Diabetic nephropathy (Yes, No, Unknown), 
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Other baseline characteristics 
 Randomization strata of screening HbA1c categories (<7.6; ≥7.6%). 
 Randomization strata of site. 
Baseline efficacy data  
The following baseline efficacy data will be provided: 
 HbA1c (% and mmol/mol). 
 FPG (mmol/L and mg/dL). 
 Mean of SMPG (mmol/L and mg/dL) from 7-point profiles measured on a 24-hour period. 
 Average pre-breakfast SMPG (mmol/L and mg/dL) = Mean of pre-breakfast (fasting) 
SMPG values in the last 7 days prior the 1st IMP (see Section 2.5.2 for handling missing 
data).  
Other baseline efficacy endpoints are presented along with the summary statistics. 
Insulin dose at baseline 
 Basal insulin daily dose at baseline (U and U/kg) = planned and actual dose reported in the 
e-CRF. 
 Mealtime insulin daily dose at baseline (U and U/kg) = median of mealtime insulin daily 
doses of the 3 first days from the first IMP. The first mealtime insulin daily dose is 
identified by the start date reported on the Visit 1 form for the IMP exposure in the e-CRF. 
 Total insulin daily dose at baseline (U and U/kg) = planned and actual dose of basal 
insulin plus median of mealtime insulin daily dose. 
Smoking/alcohol habits 
 Tobacco habits (never, current, former, including the average number of cigarettes per 
day). 
 Alcohol habits (never, occasional, at least monthly, at least weekly, at least daily) 
including the number of daily standard drink (1 or 2, >2). 
Any technical details related to computation, dates and imputation for missing dates are described 
in Section 2.5.  
Other baseline characteristics (such as quality of life/health economic endpoints) are presented 
along with the summary statistics. 
2.1.2 Prior or concomitant medications  
All medications taken within the past 3 months before screening and until the end of the study are 
to be reported in the eCRF form pages. 
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All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
 Prior medications are those the patient used within 3 months before screening and from 
screening to first investigational medicinal product (IMP) intake.  Prior medications can be 
discontinued before first administration or can be ongoing during treatment phase.   
 Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from first injection of IMP to the last injection of IMP+2 days (0 day for antidiabetic 
therapy).  A given medication can be classified both as a prior medication and as a 
concomitant medication.  Concomitant medications do not include medications started 
during the post-treatment period (as defined in the observation period in Section 2.1.4).  
 Post-treatment medications are those the patient continued or started on or after 3 days 
(1 day for antidiabetic therapy) after the last dose of open-label IMP. 
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
Anti-diabetic medications will be identified by a pre-defined list of ATC codes provided in the 
ADaM metadata. 
2.1.3 Efficacy endpoints  
The baseline value for efficacy endpoints is the last available value prior to the first injection of 
open-label IMP and up to randomization for patients randomized not treated. 
HbA1c and FPG are measured at a central laboratory, for scheduled and unscheduled time points. 
In case of premature permanent IMP discontinuation, the process described in Section 2.5.4 will 
be applied to retrieve efficacy assessments performed at the end of treatment visit. 
 
Observation period for efficacy endpoints 
 The 24-week randomized period (ITT estimand) for efficacy variables is defined as the 
time from randomization up to Week 24 (Visit 12) for randomized patients, regardless of 
study treatment discontinuation. 
 The 24-week on-treatment period for efficacy variables is defined as the time from the first 
dose of IMP up to Week 24 (Visit 12) or, in case of premature treatment discontinuation 
before Week 24, up to: 
- 
7 days after the last dose of IMP for HbA1c, 
- 
1 day after the last dose of IMP for FPG, 
- 
0 day after the last dose of IMP for SMPG value and insulin dose. 
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2.1.3.1 Primary efficacy endpoint(s)  
The primary efficacy variable is the change in HbA1c from baseline to Week 24 which is defined 
as: HbA1c value at Week 24 – HbA1c value at baseline (%) in the ITT population, using all 
HbA1c values regardless of adherence to treatment (ITT estimand). Results for primary efficacy 
endpoint will also be presented in mmol/mol. 
2.1.3.2 Secondary efficacy endpoint(s)  
All secondary endpoints are calculated on the 24-week randomized period using the ITT 
population (ITT estimand). 
 HbA1c: change from baseline to Week 16 (Visit 10) 
 FPG: change from baseline to Week 16 (Visit 10) and Week 24 (Visit 12) 
 Mean 7-point SMPG: change from baseline to Week 16 (Visit 10) and Week 24 (Visit 12) 
 7-point SMPG at each timepoint (preprandial and 2-hour postprandial plasma glucose at 
breakfast, lunch and dinner, and bedtime): change from baseline to Week 16 (Visit 10) and 
Week 24 (Visit 12) 
2.1.3.3 Secondary endpoints related to compliance  
The following additional endpoints will be considered: 
 Compliance with medication during the treatment period (from Day 1 to Week 24), 
expressed in terms of IMP exposure time and the percentage of actual dose over the 
prescribed dose 
 Compliance with key study activities during the treatment period (from Day 1 to 
Week 24), including: 
- 
Number of times the patient used the Bluetooth devices in accordance with the study 
instructions 
- 
Number of times the patient completed the blood draw visits (Visit 10 and Visit 12) in 
accordance with the study instructions  
- 
Patient withdrawal during the treatment period (from Day 1 to Week 24)  
2.1.3.4 Exploratory efficacy endpoints  
 Mean of fasting pre-breakfast SMPG (mean over the last 7 days before each on-site visit). 
2.1.4 Safety endpoints  
The safety analysis will be based on: 
 All hypoglycemia events (according to American Diabetes Association [ADA] Workgroup 
on Hypoglycemia).  
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 Local tolerability at injection site.  
  Hypersensitivity reactions. 
 Adverse events with special interest (AESI): 
- 
Pregnancy; 
- 
Symptomatic overdose with IMP/NIMP; 
- 
Unusual lack of efficacy of IMR (Canada only) 
 Other adverse events (AE) or serious adverse events (SAEs), 
 Vital signs including body weight. 
In case of premature permanent IMP discontinuation, the process described in Section 2.5.4 will 
be applied to retrieve safety assessments performed at the end of treatment visit. 
Observation period for safety endpoints 
The observation period of safety data will be divided into 3 segments: 
 The pre-treatment period is defined as the time between the date of the informed consent 
and the first injection of open-label IMP. 
 The treatment-emergent AE (TEAE) period is defined as the time from the first 
injection of open-label IMP up to 2 days after the last injection of IMP. 
 The post-treatment period is defined as the time starting 3 days after last injection of 
open-label IMP (after the TEAE period). 
The on-study observation period is defined as the time from start of treatment until the end of 
the study (defined as last protocol planned visit or the resolution/stabilization of all serious 
adverse events and adverse events with pre-specified monitoring). 
The baseline value for safety endpoints will be the last available value prior to the first injection 
of open-label IMP. 
2.1.4.1 Hypoglycemia events  
All hypoglycemia will be categorized according to the ADA definitions (1) as described below: 
 Severe hypoglycemia: Severe hypoglycemia will be derived as an event requiring 
assistance of another person to actively administer carbohydrate, glucagon, or other 
resuscitative actions.  
 Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia will 
be derived as an event with symptoms of hypoglycemia and with a measured plasma 
glucose concentration less than or equal to 3.9 mmol/L (70 mg/dL). 
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 Asymptomatic hypoglycemia: Asymptomatic hypoglycemia will be derived as an event 
without symptoms of hypoglycemia but with a measured plasma glucose concentration 
less than or equal to 3.9 mmol/L (70 mg/dL). 
 Probable symptomatic hypoglycemia: Probable symptomatic hypoglycemia will be 
derived as an event with symptoms of hypoglycemia and missing plasma glucose 
concentration. 
 Relative hypoglycemia: Relative hypoglycemia (recently termed “pseudo-
hypoglycemia”) will be derived as an event with symptoms of hypoglycemia but with a 
measured plasma glucose concentration greater than 3.9 mmol/L (70 mg/dL).  
Hypoglycemia episodes will be analyzed regardless of the time of onset and in the following time 
periods defined by time of the day: 
 Nocturnal hypoglycemia (defined by time of the day): any hypoglycemia that occurs 
between 00:00 and 05:59 a.m. hours, regardless whether patient was awake or woke up 
because of the event. 
 Daytime hypoglycemia (defined by time of the day): any hypoglycemia that occurs 
between 6:00 a.m. to 23:59. 
 Nocturnal hypoglycemia (defined by sleep status): any hypoglycemia waking the patient 
up from sleep after having gone to bed in the evening and before getting up in the morning 
(ie, before the morning determination of fasting pre-breakfast SMPG and before 
administration of insulin (IMP or NIMP). 
Some analyses will be also performed by distribution by hour of the day (0:00-23:59). 
Hypoglycemia episodes will be analyzed only during the following period: 
 24-weeks TEAE period, 
2.1.4.2 Adverse events variables  
Adverse event observation period  
 Pretreatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of IMP. 
 Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period. 
 Posttreatment adverse events are adverse events that developed or worsened or became 
serious during the posttreatment period. 
All adverse events (including serious adverse events and adverse events with special interest) will 
be coded to a lower-level term (LLT), preferred term (PT), high-level term (HLT), high-level 
group term (HLGT), and associated primary system organ class (SOC) using the version of 
Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time 
of database lock. 
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The occurrence of adverse events (including serious adverse events and adverse events with 
special interest) is recorded from the time of signed informed consent until the end of the study. 
Injection site reaction adverse events and hypersensitivity reactions adverse events will be 
identified using MedDRA searches listed in the ADaM metadata.  
 
Adverse events of special interest include: 
 Pregnancy occurring in a female patient entered in the clinical trial.  
 Symptomatic overdose (serious or non-serious) with IMP/NIMP (event suspected by the 
investigator or spontaneously notified by the patient/parent [not based on systematic drug 
accountability]). 
 Unusual lack of efficacy of IMR (Canada only). 
2.1.4.3 Deaths  
The deaths observation period are per the observation periods defined above.  
 Death on-study: deaths occurring during the on-study observation period (defined as the 
time from the signed informed consent date up to the end of the study, ie, last protocol 
planned visit or the resolution/stabilization of all SAEs). 
 Death pretreatment: deaths occurring before the on-study observation period. 
 Death on-treatment: deaths occurring during the on-treatment period. 
 Death post study: death occurring after the end of study. 
2.1.4.4 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis.  Clinical laboratory values after conversion will be describe into standard international 
units and international units will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken at screening visit (Visit 1 – Week -2) for 
identifying patients with exclusion criteria or safety consideration and will be test at screening 
visit. The laboratory parameters will be classified as follows:   
 Hematology,  
- 
Erythrocytes, hemoglobin, hematocrit, leukocytes and platelets;  
 Clinical chemistry, 
- 
Sodium, potassium, uric acid, creatinine, estimated creatinine clearance, eGFR 
(derived), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), total and conjugated bilirubin; 
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 Urine samples will be collected as follows:  
- 
Urinalysis - quantitative analyses: pH, glucose, ketones, leucocytes, 
blood/hemoglobin, protein.  
Technical formulas are described in Section 2.5.1. 
2.1.4.5 Vital signs variables  
Vital signs include: heart rate (bpm), sitting systolic and diastolic blood pressure (mmHg) as well 
as body weight (kg). 
2.1.4.6 Electrocardiogram variables  
Not applicable. 
2.1.5 Pharmacokinetic variables  
Not applicable 
2.1.6 Pharmacodynamic/genomics endpoints  
Not applicable 
2.1.7 Patient reported outcome endpoints  
All the following endpoints are considered as secondary endpoints. 
All PROs will be administered electronically using mobile technology. 
2.1.7.1 Study methodology endpoints: Patient satisfaction with trial experience (WIWI)  
Patient satisfaction with trial experience will be measured using the Was It Worth It (WIWI) 
Questionnaire, completed at Week 24 (Visit 12). The WIWI has 5 items, each with a 3-level 
categorical response scale. Each item is scored separately.  
See questionnaire in Appendix C. 
2.1.7.2 Study methodology endpoints: Impact of trial participation (WPAI)  
The effect of the trial on a patients’ ability to work and perform regular activities will be measured 
using an adaptation of the Work Productivity and Impairment (WPAI) Questionnaire, 
administered at baseline and Week 24 (Visit 12).  
The WPAI-SP has 6 items, and scoring follows that of the WPAI-SHP. As such, each item is 
presented separately, expressed as impairment percentages, with higher numbers indicating 
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greater impairment and less productivity, ie, worse outcomes. In addition, the following combined 
items will be reported: 
 the percent work time missed due to study participation [Q2/(Q2 + Q4)]. 
  the percent impairment while working due to study participation [Q5/10]. 
 the percent overall work impairment due to study participation [Q2/(Q2 + Q4) + (1-
(Q2/(Q2 + Q4)))x(Q5/10)]. 
 the percent activity impairment due to study participation [Q6/10]. 
See questionnaire in Appendix D. 
2.1.7.3 Study methodology endpoints: Patient burden with trial participation (OSEP)  
Patient burden with trial participation will be measured using a new PRO: the Overall Study 
Experience-Participation (OSEP) Questionnaire. Each item will be scored separately. The OSEP 
has 2 parts: 
 OSEP Part 1 contains 4 items to examine perceptions of diabetes control; it will be 
administered at baseline and Week 24 (Visit 12). 
 OSEP Part 2 contains 9 items to examine perceptions of study participation; it will be 
administered only at Week 24 (Visit 12). 
See questionnaire in Appendix E. 
2.1.7.4 Study methodology endpoints: Resource use (RUQ)  
Healthcare resource use will be measured using a new PRO: the resource use questionnaire 
(RUQ). The RUQ will be administered every 4 weeks from baseline to Week 24. The RUQ asks 
the patients to report the resources used (time and expenses) during the previous 4 weeks in terms 
of visits to healthcare professionals.  
See questionnaire in Appendix F. 
2.1.7.5 Diabetes control endpoints: Diabetes-related patient reported outcomes (DTSQs, 
DTSQc, HFS-II, DDS)  
Diabetes Treatment Satisfaction Questionnaire (DTSQ) 
Treatment satisfaction will be measured with the Diabetes Treatment Satisfaction Questionnaire 
(DTSQ). The DTSQ is available in two versions:  
 The DTSQ status (DTSQs) version evaluates absolute treatment satisfaction in the “past 
few weeks” and will be administered at baseline and Week 24 (Visit 12). 
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 The DTSQ change (DTSQc) version measures the relative change in treatment satisfaction 
from previous therapy and will be administered (after the DTSQs) at Week 24 (Visit 12) 
only. 
The DTSQs and DTSQc conceptually contain the same 8 items, each scored on a 7-point scale but 
with different response options. Six items are summed to produce a measure of treatment 
satisfaction, with total scores ranging from 0 (very dissatisfied) to 36 (very satisfied) for the 
DTSQs and −18 (much less satisfied) to +18 (much more satisfied) on the DTSQc. The remaining 
2 items, which measure perceived frequency of hyperglycemia and perceived frequency of 
hypoglycemia, are treated independently. These items are scored on a scale ranging from 0 (none 
of the time) to 6 (most of the time) on the DTSQs and −3 (much less of the time now) to +3 (much 
more of the time now) on the DTSQc.  
See questionnaire in Appendix G and Appendix H. 
Hypoglycemia Fear Survey-II (HFS-II) 
Fear of hypoglycemia will be measured with the Hypoglycemia Fear Survey-II (HFS-II) at 
baseline and Week 24 (Visit 12). The HFS-II comprises 33 items: 
 The hypoglycemia fear survey-behavior subscale [HFS-B]: 15 items explore behaviors 
that patients may engage in to avoid low blood sugar and its negative consequences.  
 The hypoglycemia fear survey-worry subscale [HFS-W]:18 items relate to concerns that 
patients may have about their hypoglycemia. 
 HFS-total score : all 33 items. 
Responses are made on a 5-point Likert scale where 0 = “Never” and 4 = “Always” with a past 
3 months recall period.  
Higher total score reflects greater fear of hypoglycemia. A higher Behavior score reflects greater 
tendency to avoid hypoglycemia and/or its negative consequences. A higher Worry score reflects 
higher worry concerning episodes of hypoglycemia and its consequences. 
See questionnaire in Appendix I. 
Diabetes Distress Scale (DDS)  
Diabetes-related distress will be measured using the Diabetes Distress Scale (DDS) at baseline 
and Week 24 (Visit 12).  
The DDS contains 17 items related to potential problem areas that people with diabetes may 
experience. Patients are asked to consider the degree to which each of the items may have 
distressed or bothered them during the past month, and respond between 1 (not a problem) and 6 
(a very serious problem).  
The DDS yields a total diabetes distress score and 4 subscale scores, each addressing a different 
kind of distress (emotional burden, physician distress, regimen distress, interpersonal distress). 
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Each score (total and subscales) are presented as an average, by summing the patient’s responses 
to the appropriate items and divide by the number of items in that scale.  
In addition, total and subscale scores will be categorized: a mean score 2.0 – 2.9 should be 
considered ‘moderate distress’ and a mean score >3.0 should be considered ‘high distress’.  
See questionnaire in Appendix J. 
2.1.8 Investigator (clinician) reported outcome (ClinRO) endpoints  
Overall Study Experience-sites (OSES) questionnaire  
Site investigators (one per site) will be asked to complete the Overall Study Experience-sites 
(OSES) questionnaire. The OSES has 2 parts: 
 OSES Part 1 contains 1 item to examine resource requirements: “Approximately how 
much time did you spend with this participant (in person or via phone) during this 
scheduled visit/communication?”. OSES Part 1 will be administered following each study 
visit. 
 OSES Part 2 contains 2 items to examine relationship (“I had a good relationship with this 
patient during the study”) and satisfaction with care (“I am satisfied with the level of care I 
have provided for this participant in this study”). OSES Part 2 will be administered at 
Week 24 (Visit 12) only. 
Each item is scored separately. 
See questionnaire in Appendix K. 
2.1.9 Health economic endpoints  
Not applicable 
2.1.10 Patient interviews  
English-speaking patients of the virtual group who consent will be invited to participate in 
interviews following their Week 24 (Visit 12) study visit (ie, after completion of the trial). These 
qualitative exit interviews will be conducted one-on-one with up to 30 patients to: 
 Examine patients’ experiences of trial participation, in their own words. 
 Explore the positive and negative aspects of trial participation. 
 Provide some context to responses given in the PRO questionnaires. 
Analysis plan and analysis report will be performed and details by an external vendor in specific 
separate documents. 
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2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patients who met the inclusion criteria and signed the 
informed consent.  
Randomized patients consist of all patients with a signed informed consent form who have had a 
treatment kit number allocated and recorded in the IRT database, regardless of whether the 
treatment kit was used. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
 Screened patients. 
 Screen failure patients and reasons for screen failure. 
 Non randomized but treated patients. 
 Randomized patients. 
 Randomized but not treated patients. 
 Randomized and treated patients. 
 The intent-to-treat (ITT) population Section 2.3.1.1) analyzed as randomized. 
 The randomization strata (sites and screening HbA1c categories [<7.6%, ≥7.6%] assigned 
by IRT); the discrepancy between the strata assigned by IRT  and the information reported 
on e-CRF will be listed for all randomized patients. 
 Patients who completed the 24-week treatment period (patients who have attended Visit 12 
[Week 24] and who did not permanently discontinue treatment). 
 Patients who permanently discontinued the IMP during the 24-week treatment period, and 
the reasons for permanent treatment discontinuation. 
 Patients who completed the 24-week study period (patients who have performed Visit 12 
[Week 24], whichever the treatment duration). 
 Patients who discontinued the study during the 24-week period, and the reason for study 
discontinuation. 
 Patient's decision for treatment discontinuation decision for treatment discontinuation 
during the 24-week period. 
 Status at last study contact. 
For all categories of patients (except for the screened and nonrandomized categories) percentages 
will be calculated using the number of randomized patients as denominator for different study 
conduct approach groups.  Reasons for treatment discontinuation will be supplied in tables giving 
numbers and percentages by study conduct approach group.   
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Reasons for treatment discontinuation will be supplied in tables giving numbers and percentages 
by study conduct approach group. A listing of patients who prematurely discontinued study 
treatment with further reason (“other reason”) provided in free text will be provided. 
 
Patients with the following deviations will be identified and described in separate listings: 
 Treated but not randomized. 
 Randomized but not treated. 
 Randomized but allocated to one approach (virtual or traditional) by randomization, and 
actually switched of study conduct approach. 
A list of patients who prematurely discontinued the treatment, along with reasons for 
discontinuation, will be provided. 
Kaplan-Meier (KM) plots/estimates of the cumulative incidence of IMP discontinuation due to 
any reason, or due to AE, will be provided for the 24-week on-treatment period separately. Time 
to treatment discontinuation will be defined as the number of days from the first dose of IMP until 
the day of treatment discontinuation. All completers will be considered as censored observations. 
The censoring time will be the number of days from the first dose of IMP until the last dosing 
date.  
 
All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by study conduct approach group. 
Additionally, the analysis populations for safety, efficacy will be summarized in a table by 
number of patients on the randomized population.  
 Efficacy population: intent-to-treat (ITT) population.  
 Safety population. 
2.2.1 Randomization and drug dispensing irregularities  
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error.  
 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
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Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report.  If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages).  Nonrandomized, treated patients will be described separately.  
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to:  
 Kit dispensation without IRT transaction. 
 Erroneous kit dispensation. 
 Kit not available. 
 Randomization by error. 
 Patient randomized twice. 
 Forced randomization. 
 Stratification error. 
 Patient switched to another site. 
2.3 
ANALYSIS POPULATIONS  
Patients treated without or before being randomized will not be considered randomized and will 
not be included in any efficacy population.   
The randomized population includes any patient who has been allocated to a study conduct 
approach group regardless of whether the study conduct approach group is followed. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population.  The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
2.3.1 Efficacy populations  
The primary efficacy analysis population will be the intent-to-treat (ITT) population, as defined in 
the protocol. 
2.3.1.1 Intent–to-treat population  
The intent-to-treat population is all randomized patients, irrespective of the trial approach group 
actually being used, analyzed according to the approach group allocated by randomization. 
The ITT population will be used to analyze all non-safety endpoints. 
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2.3.2 Safety population  
The safety population is defined as all randomized patients who did actually receive at least one 
dose of IMP, regardless of the amount of IMP administered. 
In the event of patients having followed a trial approach that differed from the one assigned 
according to the randomization schedule, the safety analyses will be conducted according to the 
trial approach group assigned by randomization. 
Patients will not be considered exposed if there is documented evidence that patients have not 
taken the study drug: 
 If a patient is dispensed IMP and is lost to follow-up without any documented evidence, 
the patient will be considered exposed and included in the safety population. 
 Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
In addition:  
 Nonrandomized but treated patients (or treated before being randomization (if any)) will 
not be part of the safety population; however, their safety data will be presented 
separately. 
 For patients following more than one study approach (virtual and traditional), the patient 
will be analyzed in the study conduct approach group as randomized. 
2.3.3 PRO and ClinRO populations  
The analysis of PROs and ClinROs will be conducted on the ITT population. 
2.4 
STATISTICAL METHODS  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum and maximum for each study conduct approach group. For 
insulin dose and PROs and ClinROs, summary statistics will include quartiles Q1, Q3 and 
medians.  
Categorical and ordinal data will be summarized using the number and percentage of patients in 
each study conduct approach group. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from baseline) by scheduled post-baseline visits will be provided on observed cases, ie, the 
inclusion of only patients having non-missing assessments at a specific visit. All statistical 
analyses (descriptive statistics, plots, and statistical models) will be performed on visits defined 
using the time windows provided in Section 2.5.4. 
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2.4.1 Demographics and baseline characteristics  
Parameters described in Section 2.1.1 will be summarized by study conduct approach group and 
overall using descriptive statistics.  
Parameters will be summarized on the randomized population analyzed in the study conduct 
approach group to which patients were randomized.   
Medical/surgical history will be classified into primary system organ class (SOCs) and HLTs 
using MedDRA and will be summarized by study conduct approach groups. Events will be sorted 
by SOC internationally agreed order and decreasing frequency of HLT based on incidence in the 
overall population. 
P-values on demographic and baseline characteristic data will not be calculated.  
2.4.2 Prior or concomitant medications  
The prior, concomitant and post-treatment medications will be presented on the randomized 
population, separately for anti-diabetic medications and non-anti-diabetic medications. 
Anti-diabetic medications will be identified by a pre-defined list of ATC codes. 
Medications will be summarized by treatment group and overall (only for prior medications) 
according to the WHO-DD dictionary. Non-anti-diabetic medications will be summarized 
considering the first digit of the ATC class (anatomic category) and the first 3 digits of the ATC 
class (therapeutic category).  All ATC codes corresponding to a medication will be summarized, 
and patients will be counted once in each ATC category (anatomic or therapeutic) linked to the 
medication. Therefore patients may be counted several times for the same medication. Anti-
diabetic medications will be presented by pharmacological class (ATC3), chemical class (ATC4), 
and standardized medication name. 
The tables for prior medications will be sorted by decreasing frequency within the ATC categories 
presented based on the overall incidence across treatment groups. In case of equal frequency, 
alphabetical order will be used. 
The tables for concomitant and post-treatment medications will be sorted by decreasing frequency 
within the ATC categories presented based on the incidence in the Virtual group. In case of equal 
frequency, alphabetical order will be used.  
Frequency statistics including number of patients and percentage will be provided. No statistical 
test for the between-group difference will be performed. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by study conduct 
approach actual group within the safety population (Section 2.3.2). 
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2.4.3.1 Extent of investigational medicinal product exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
The duration of exposure to the IMP during the study will be the total number of days of 
administration of IMP, ignoring temporary drug discontinuation (see Section 2.5.3 for calculation 
in case of missing or incomplete data) and is defined as: 
(Date of the last IMP administration – date of the first IMP administration) + 1 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum). In addition, duration of treatment exposure will 
also be summarized categorically by numbers and percentages for each of the following categories 
and cumulatively according to these categories: 
 up to 4 weeks. 
 >4 to 8 weeks. 
 >8 to 12 weeks. 
 >12 to 16 weeks. 
 >16 to 20 weeks. 
 >20 to 22 weeks. 
 >22 to 23 weeks. 
 >23 to 24 weeks. 
 >24 weeks. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
2.4.3.2 Daily insulin doses  
The process described in Section 2.5.4 will be applied to assign visits to the insulin doses 
transferred from the e-diary into the clinical database, and to retrieve doses in case of premature 
treatment discontinuation. 
At each visit, the average daily basal, mealtime, and total (basal plus mealtime) insulin doses  
(U and U/kg body weight) will be calculated as the mean of daily insulin doses collected in the 
week before the visit. No minimum number of available doses will be required. Technical details 
related to the computation and handling of missing data are described in Section 2.5.3. 
The daily insulin doses (basal, mealtime, total) will be described at each visit, as well as the 
changes from baseline, relative change from baseline and change from previous visit. 
The calculation of daily insulin doses at baseline is defined in Section 2.1.1. 
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2.4.3.3 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Percentage of compliance for a patient will be defined as the exposure duration of study minus 
number of days with a dose equal to 0 divided by the duration of the IMP exposure. 
Treatment compliance will be summarized descriptively as quantitative variables (number, mean, 
SD, median, minimum, and maximum). The percentage of patients whose compliance is <80% 
will be summarized. 
2.4.3.4 Compliance with key study activities  
For the following endpoints, descriptive statistics will be calculated including the number of 
available data, mean, SD, median, minimum, and maximum by study conduct approach group.  
 The number of times the patient used the Bluetooth devices in accordance with the study 
instructions from baseline to Week 24.  Qualitative deviations will be used to collect this 
information. 
 Number of times the patient completed the blood draw visits (Visit 10 and Visit 12) in 
accordance with the study instructions will be based on the protocol deviations.  
Number of patient withdrawal during the treatment period (from Day 1 to Week 24) will be 
described in patient disposition Section 2.2. 
2.4.4 Analyses of efficacy endpoints  
For statistics where international and conventional units do not impact the results (eg, means and 
least square (LS) means for percent changes from baseline, p-values for both percent and absolute 
changes from baseline, rates of patients below a threshold), derivations will be done and statistical 
models will be run using conventional units. For other statistics (eg, descriptive statistics at 
baseline and over time, absolute changes from baseline), derivations will be done with both 
international and conventional units. 
Figures will be provided with 2 different axes by parameter when applicable. For example, for 
HbA1c, figures will be presented by % and mmol/mol. 
2.4.4.1 Analysis of primary efficacy endpoint(s)  
2.4.4.1.1 Primary efficacy analysis  
The primary efficacy variable, change in HbA1c from baseline to Week 24 in % as defined in 
Section 2.1.3.1 will be analyzed in the ITT population using available data during the 24-week 
randomized period (defined in Section 2.1.3, used to assess the ITT estimand). A mixed-effect 
model with repeated measures (MMRM) approach will be used, under the missing at random 
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framework carried out via SAS PROC MIXED using an adequate contrast at Week 16 and  
Week 24). 
The model will include fixed categorical effects of study conduct approach group (Virtual, 
Traditional), visit (Week 16, Week 24), study conduct approach-by-visit interaction, visit-by- 
study conduct approach-by-baseline HbA1c interaction, randomization stratum of site as well as, 
the continuous fixed covariates of baseline HbA1c value and baseline HbA1c value-by-visit 
interaction. 
This model will be run with an unstructured correlation matrix to model the within-patient errors. 
Parameters will be estimated using restricted maximum likelihood method with the Newton-
Raphson algorithm. Denominator degrees of freedom will be estimated using Satterthwaite’s 
approximation.  
This model will provide baseline adjusted least squares (LS) means estimates at Week 24 for both 
study conduct approach groups, as well as, the differences of these estimates, with their 
corresponding standard error (SEs) and 95% CIs. 
This analysis will be performed using the randomization strata as per IVRS. 
No formal comparison and no p-value will be provided. 
Model assumption checks 
As no formal comparison the analysis of the residuals of MMRM based on studentized residuals 
will be not performed. 
2.4.4.1.2 Subgroup analyses  
Where appropriate for the size of a subgroup, exploratory analyses will be performed on the 
primary endpoint to summarize the treatment effects across subgroups.  
For each subgroup, the primary efficacy variable will be analyzed in the ITT population using 
post-baseline HbA1c data available on the 24-week randomized period, (to assess the ITT 
estimand). A similar MMRM approach as described for primary analysis will be applied adding 
the corresponding subgroup factor, subgroup factor-by-study conduct approach arm interaction, 
subgroup factor-by-visit interaction and subgroup factor-by-visit-by study conduct approach arm 
interaction. 
 The subgroups will be defined by the following baseline and screening factors: 
 Age group (<65, [65-75[ and ≥75 years). 
 Gender (male, female). 
 Baseline BMI (<25, [25-30[, [30-40[ and ≥40 kg/m²). 
 Randomization stratum of screening HbA1c (<7.6%, ≥7.6%). 
 Randomization stratum of site, (“only if the size of the subgroup will be relevant,” 
 Duration of diabetes (<10, ≥10 years). 
 Baseline estimated GFR categories (mL/min/1.73m²): (<60; ≥60). 
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If the subgroup factor is a randomization stratification factor, then the strata as per IVRS will be 
used.  
The randomization strata of screening HbA1c and site will not be included in the model. 
Least Square Means Difference Virtual versus Traditional approach at Week 24 will be provided, 
as well as the corresponding SEs and 95% CI, within each subgroup. The significance level of the 
study conduct approach-by-subgroup factor interaction term at Week 24 will be not provided for 
each factor as no formal comparison. Forest plots will be provided. 
Subgroups analyses using randomization strata derived as per electronic case report form  
(e-CRF), should be performed only if necessary (in case of high number of discrepancies between 
stratum as per IRT and stratum as per e-CRF) and should be considered as sensitivity analysis.  
Further subgroup analyses may be performed if deemed necessary for interpretation of results. 
2.4.4.2 Analyses of secondary efficacy endpoints  
Secondary efficacy endpoints are described in Section 2.1.4. 
All secondary efficacy endpoints will be analyzed or summarized on the 24-week randomized 
period (to assess the ITT estimand) using the ITT population. 
The following secondary efficacy endpoints will be analyzed using the same model (same 
analysis) as the one used for primary endpoint (MMRM model) as described in Section 2.4.4.1.1. 
 HbA1c (%): change from baseline to Week 16; 
The following secondary efficacy endpoints will be analyzed using the same approach as the one  
used for primary endpoint (MMRM model) as described in Section 2.4.4.1.1.The model will 
include fixed categorical effects of study conduct approach group, visit, study conduct approach-
by-visit interaction, randomization stratum of site, randomization stratum of HbA1c (<7.6 % and 
≥ 7.6%), the continuous fixed covariates of the corresponding baseline value, and baseline value-
by-visit interaction. 
 FPG: change from baseline to Week 16 and Week 24; 
 Change in mean 24-hour plasma glucose based on 7-point SMPG from baseline to 
Week 16 and Week 24; 
For the model on change in FPG and on the mean 24-hour plasma glucose based on 7-point 
SMPG, the visit term has 2 levels (Week 16 and Week 24).   
No formal comparison and no p-value will be provided. 
The following secondary endpoints will be analyzed using descriptive measures: 
 Change in 7-point SMPG profiles per time-point from baseline to Week 16 and Week 24; 
For all continuous endpoints, observed values and change from baseline will be also described for 
all visits with mean, median, SD, minimum and maximum. A figure representing the mean  
(+/- SE) change from baseline at each visit will be produced by study conduct approach group. 
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2.4.4.3 Multiplicity issues  
No formal comparison and no p-value will be provided; 95% CIs presented for these endpoints 
will be calculated for descriptive purpose only. 
2.4.4.4 Additional efficacy analyses  
Not applicable. 
2.4.5 Analyses of safety data  
The summary of safety results will be presented by study conduct approach group.  
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
 Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately 
 The baseline value is defined as the last available value prior to the first injection of IMP. 
 When the time of assessment is not available, the value is considered as baseline if 
assessment date is the date of 1st IMP intake. 
 For clinical vital signs only, the potentially clinically significant abnormality (PCSA) 
values are defined as abnormal values considered medically important by the Sponsor 
according to predefined criteria/thresholds based on literature review and defined by the 
Sponsor (PCSA criteria will be provided in the ADaM metadata). 
 For clinical vital signs only, PCSA criteria will determine which patients had at least 1 
PCSA during the TEAE period, taking into account all evaluations performed during the 
TEAE period, including nonscheduled or repeated evaluations. The number of all such 
patients will be the numerator for the on-treatment PCSA percentage. 
 For clinical vital signs only, the treatment-emergent PCSA denominator by group for a 
given parameter will be based on the number of patients assessed for that given parameter 
in the treatment-emergent adverse event period by study conduct approach group on the 
safety population. 
 For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results. 
 The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned.   
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2.4.5.1 Analyses of hypoglycemia  
All analyses of hypoglycemia events will be performed on the safety population, separately on 
events occurring during the 24-Weeks TEAE period (as defined in Section 2.1.4). The analyses 
planned to be done during the 24-Weeks TEAE period only (as defined in Section 2.1.4.1). 
Patients with at least one hypoglycemia event 
 Number and incidence of patients with at least one hypoglycemia event will be presented 
for any hypoglycemia and for each hypoglycemia ADA category, overall and by time of 
the day (as described in Section 2.1.4.1). 
 For any hypoglycemia and for each hypoglycemia ADA category (except probable, 
pseudo), incidence of patients with at least one hypoglycemia will be compared, overall 
and by time of the day. Odds Ratio and its corresponding 95% CI of Virtual group over 
Traditional group for each hypoglycemic event will be estimated by a logistic regression 
model adjusted on randomization strata of screening HbA1c (<7.6%, ≥7.6%) and 
randomization strata of sites. 
 Percentage (%) of patients with at least one severe hypoglycemia event will be 
summarized by symptom during 24 weeks TEAE period, 
Number and rate of hypoglycemia event 
 Number and rate of hypoglycemia event per patient-year will be summarized for any 
hypoglycemia and for each hypoglycemia ADA category (as described in Section 2.1.4.1), 
overall and by time of the day (as described in Section 2.1.4.1). Non classified 
hypoglycemia will be displayed. 
 For any hypoglycemia and for each hypoglycemia ADA category (except probable, 
pseudo), the number of hypoglycemia events per patient-year will be compared, overall 
and by time of the day. For each hypoglycemic event ,the rate ratio, and its corresponding 
95% CI, of Virtual group over Traditional group will be estimated using an over-dispersed 
Poisson regression model adjusted on randomization strata of screening HbA1c (<7.6%, 
≥7.6%) and randomization strata of sites. 
For Hypoglycemic ADA categories, only the threshold hypoglycemia episodes with 
plasma glucose ≤70 mg/dL (3.9 mmol/L) will be analyzed. 
Subgroups analyses  
 The incidence of patients with at least one any hypoglycemia during the 24-week TEAE 
period, will also be presented by the following subgroups (defined below) and analyzed 
using a similar logistic regression model approach as presented previously, but adding the 
corresponding subgroup factor and study conduct approach arm-by-subgroup interaction 
factor. Odds ratio estimates and 95% CI will be provided in each subgroup category. The 
interaction study conduct approach arm-by-subgroup p-value will be provided for 
descriptive propose. When the subgroup considered is equal to one of the randomization 
strata or is part of one of the adjustment factor, this randomization stratum/adjustment 
factor is removed from the model. If the logistic regression model does not converge (eg, 
due to sparse data) some of the randomization strata may be removed. Forest plots will be 
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provided. Further subgroup analyses may be performed if deemed necessary for 
interpretation of results. 
- 
Age group (<65, [65-75[ and ≥75 years), 
- 
Gender (male, female), 
- 
Baseline BMI (<25, [25-30[, [30-40[ and ≥40 kg/m²), 
- 
Randomization stratum of screening HbA1c (<7.6%, ≥7.6%), 
- 
Randomization stratum of site. (only if the size of subgroup is relevant) 
- 
Duration of diabetes (<10, ≥10 years), 
- 
Baseline estimated GFR categories (mL/min/1.73m²): (<60[; ≥60), 
2.4.5.2 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events.   
Pre-treatment and post-treatment adverse events will be described separately.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
an imputation algorithm will be used to classify the adverse event as pretreatment, treatment-
emergent, or post-treatment.  The algorithm for imputing date/time of onset will be conservative 
and will classify an adverse event as treatment emergent unless there is definitive information to 
determine it is pretreatment or post-treatment.  Details on classification of adverse events with 
missing or partial onset dates are provided in Section 2.5.3.  
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each study conduct approach group, the number (n) and percentage (%) of patients 
experiencing an adverse event.  Multiple occurrences of the same event in the same patient will be 
counted only once in the tables within a treatment phase.  The denominator for computation of 
percentages is the safety population within each study conduct approach group.  
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pretreatment, treatment-emergent, and post-treatment).  For that purpose, the 
table of all treatment-emergent adverse events presented by SOC and PT sorted by the 
internationally agreed SOC order and decreasing frequency of PTs within SOCs will define the 
presentation order for all other tables unless otherwise specified.  Sorting will be based on results 
for the Virtual arm.   
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
 Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any 
- 
Treatment-emergent adverse event 
- 
Serious treatment-emergent adverse event 
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- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
 All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
 All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC.  This sorting 
order will be applied to all other tables, unless otherwise specified. 
 All common treatment-emergent adverse event (HLT incidence ≥ 2% in any study conduct 
approach group) by primary SOC, HLT, and PT, showing number (%) of patients with at 
least 1 common treatment-emergent adverse event sorted by the SOC internationally 
agreed order. The other levels (HLT, PT) will be presented in alphabetical order. 
 All treatment-emergent adverse events regardless of relationship and related to IMP by 
primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least 
1 treatment-emergent adverse event, sorted by the internationally agreed SOC order. The 
other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
 All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above. 
Analysis of all treatment emergent serious adverse event(s) 
 All treatment-emergent serious adverse events by primary SOC, HLGT, HLT, and PT, 
showing the number (%) of patients with at least 1 serious treatment-emergent adverse 
event, sorted by the internationally agreed SOC order.  The other levels (HLGT, HLT, PT) 
will be presented in alphabetical order, 
 All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC, HLGT, HLT, and PT, showing the number (%) of patients with at 
least 1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order.  The other levels (HLGT, HLT, PT) will be presented in alphabetical order. 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
 All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order.  The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
Analysis of injection site reactions and hypersensitivity reaction TEAE(s)  
 All treatment-emergent adverse events related to injection site reactions or hypersensitivity 
reactions, by PT, showing the number (%) of patients sorted by decreasing incidence of 
PTs in Virtual arm. 
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Analysis of adverse events of special interest 
 A listing of patients with symptomatic overdose with IMP/NIMP, pregnancy and unsual 
lack of efficacy of IMR (Canada only) will be provided separately. 
Analysis of pretreatment and post-treatment adverse events  
 All pre-treatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 pre-treatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs in Virtual arm within each SOC. (If more 
relevant a listing will be performed instead of table). 
 All pre-treatment adverse events leading to study discontinuation by primary SOC and PT, 
showing the number (%) of patients, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs Virtual arm within each SOC. (If more relevant a listing will 
be performed instead of table). 
 All post-treatment adverse events by primary SOC and PT, showing the number (%) of 
patients with at least 1 post-treatment adverse event, sorted by the internationally agreed 
SOC order and decreasing incidence of PTs Virtual arm within each SOC. 
 All post-treatment serious adverse events by primary SOC and PT, showing the number 
(%) of patients with at least 1 posttreatment serious adverse event, sorted by the 
internationally agreed SOC order and decreasing incidence of PTs Virtual arm within each 
SOC. 
 Listing of SAE. 
 Listing of AEs leading to permanent treatment discontinuation. 
2.4.5.3 Deaths  
The following summaries of deaths will be generated for the safety population. 
 Number (%) of patients who died by study period (on-study, pre-study, on-treatment, post-
study). 
 Deaths in non-randomized patients or randomized but not treated patients. 
 Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC , HLGT, 
HLT, and PT showing number (%) of patients sorted by internationally agreed SOC order, 
with HLGT, HLT, and PT presented in alphabetical order within each SOC. 
 All pre-treatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC, 
 All post-treatment adverse events leading to death by primary SOC and PT, showing the 
number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC, 
 Listing of deaths. 
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2.4.5.4 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values) will be calculated at baseline by 
study conduct approach group.  This section will be organized by biological function as specified 
in Section 2.1.4.4. 
2.4.5.5 Analyses of vital sign variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables blood pressure, heart rate and body weight (and changes 
from baseline) will be calculated for each visit or study assessment (baseline, each post baseline 
time point, last on-treatment) by study conduct approach group.    
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized by study conduct approach group irrespective of the baseline level and/or according 
to the following baseline status categories:  
 Normal/missing. 
 Abnormal according to PCSA criterion or criteria. 
The change in body weight from baseline to Week 24 will be analyzed in the safety population 
using a similar MMRM model as described in Section 2.4.4.1.1.  
2.4.5.6 Analyses of electrocardiogram variables  
Not applicable 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables  
Not applicable 
2.4.7 Analyses of PRO and ClinRO variables  
The analysis of the following endpoints will be conducted on the ITT population, on the 24-week 
randomized period, ie, using all available post-baseline data, regardless of IMP discontinuation. 
No p-value will be provided. 
For interpretation of results, Effect Sizes (ES) using Cohen’s definition will be calculated in order 
to interpret changes from baseline to Week 24 in PRO scores. 
 Within ES: calculated at the study conduct approach group level, when focusing on 
changes from baseline 
 Between ES: Calculated when comparing study conduct approach groups 
The calculation and interpretation of ES is described on Section 2.5.1. 
To help the interpretation of PROs and ClinRO, plots will be provided if relevant. 
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2.4.7.1 Study methodology endpoints: Patient satisfaction with trial experience (WIWI)  
Descriptive statistics (mean, median, SD, minimum and maximum) for each score will be 
presented by study conduct approach group at Week 24.  
WIWI scores (1 score for each item) will be compared between approach groups using an 
ANOVA. This model will include fixed categorical effects of study conduct approach group, of 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites. 
2.4.7.2 Study methodology endpoints: Impact of trial participation patient reported 
outcome (WPAI-SP)  
Descriptive statistics (mean, median, SD, minimum and maximum) for each score and combined 
scores will be presented by study conduct approach group at baseline and Week 24.  
The change in WPAI-SP scores from baseline to Week 24 will be analyzed using an ANCOVA. 
This model will include fixed categorical effects of study conduct approach group, on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as 
well as continuous fixed covariates of corresponding baseline score. 
2.4.7.3 Study methodology endpoints: Patient burden with trial participation (OSEP)  
Descriptive statistics (mean, median, SD, minimum and maximum) for each score and combined 
scores will be presented by study conduct approach group at baseline (OSEP (Part 1)) and  
Week 24 (OSEP (Part 1), OSEP (Part 2)).  
The change in OSEP (Part 1) score from baseline to Week 24 will be analyzed using an 
ANCOVA. This model will include fixed categorical effects of study conduct approach group, on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as 
well as continuous fixed covariates of corresponding baseline score. 
OSEP (Part 2) score will be compared between study conduct approach groups using an ANOVA. 
This model will include fixed categorical effects of study conduct approach group, on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites. 
2.4.7.4 Study methodology endpoints: Resource use (RUQ)  
Descriptive summary (mean, median, SD, minimum and maximum) will be provided for each 
study conduct approach group at baseline and for each applicable on-treatment visit on the 
following items: 
 Total number of visits (overall and per healthcare professional type) 
 Total money spent 
 Total time spent 
In addition, the total and average resource utilization per patient will be calculated on all on-
treatment questionnaires. The change between baseline and this on-treatment average will be 
calculated. 
A plot will be provided for each 3 above items. 
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2.4.7.5 Diabetes control endpoints: Diabetes-related patient reported outcomes (DTSQs, 
DTSQc, HFS-II, DDS)  
For each PRO questionnaire total and domain scores: 
A graphical presentation will be used to illustrate trends over time per study conduct approach 
group, by visit on mean scores ±√2 SE and on change from baseline values ±√2 SE.  
Cumulative distribution functions of PRO changes from baseline to Week 24 will be plotted by 
study conduct approach group. 
The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs)  
 Descriptive summary (mean, median, SD, minimum and maximum) at each visit (baseline and 
Week 24) and change from baseline to Week 24 will be provided including: 
 “total treatment satisfaction” score (sum of items 1, 4, 5, 6, 7 and 8), score ranging is from 
0 (no satisfaction) to 36 (high satisfaction with treatment). 
  “perceived frequency of hyperglycemia” score (Item 2), score ranging is from 0 (none of 
the time) to 6 (most of the time). 
  “perceived frequency of hypoglycemia” score (Item 3), score ranging is from 0 (none of 
the time) to 6 (most of the time). 
The change for each DTSQs scores from baseline to Week 24 will be analyzed using an 
ANCOVA. This model will include fixed categorical effects of study conduct approach group, 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as 
well as continuous fixed covariates of corresponding baseline score. 
The change for each DTSQs scores from baseline to Week 24 will be analyzed using cumulative 
distribution functions of scores. Changes from baseline will be displayed by study conduct 
approach group, for each the 3 DTSQs scores and a graphical presentation will be used to 
illustrate trends over time per study conduct approach group by visit on mean scores ± 2 SE and 
on change from baseline values ± 2 SE. 
The Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) 
 Descriptive summary (mean, median, SD, minimum and maximum) at Week 24 will be provided 
including: 
 “total treatment satisfaction” score (sum of items 1, 4, 5, 6, 7 and 8), score ranging is from 
-18 to 18. Positive scores are indicative of improvement in treatment satisfaction, 
whereas negative scores are indicative of deterioration in treatment satisfaction. A score of
 0 represents no change. 
 “perceived frequency of hyperglycemia” score (Item 2), score ranging is from -3 (‘much 
less of the time now’) to +3 (‘much more of the time now’), meaning negative scores 
indicate fewer problems with blood glucose levels and positive scores indicate more 
problems than before. A score of 0 represents no change. 
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  “perceived frequency of hypoglycemia” score (Item 3), score ranging is from -3 (‘much 
less of the time now’) to +3 (‘much more of the time now’), meaning negative scores 
indicate fewer problems with blood glucose levels and positive scores indicate more 
problems than before. A score of 0 represents no change. 
Average scores at Week 24 in total treatment satisfaction score, hyperglycemia perception and 
hypoglycemia perception score from DTSQc will be analyzed using an ANCOVA model. This 
model will include fixed categorical effects of study conduct approach group, randomization strata 
of screening HbA1c (<7.6%, ≥7.6%), randomization strata of site, as well as continuous fixed 
covariates of corresponding baseline score from DTSQs. 
Hypoglycemia Fear Survey-II (HFS-II) 
Fear of hypoglycemia will be measured with the Hypoglycemia Fear Survey-II (HFS-II) at 
baseline and Week 24 (Visit 12). The HFS-II comprises 33 items: 
 The hypoglycemia fear survey-behavior subscale [HFS-B] determined by computing the 
mean of the 15 items measuring behavior (score from 0 to 4). 
 The hypoglycemia fear survey-worry subscale [HFS-W] determined by computing the 
mean of the 18 items measuring worry (score from 0 to 4). 
 The total score determined by computing the mean of all 33 items (score from 0 to 4) 
The change in HFS-II scores from baseline to Week 24 will be analyzed using an ANCOVA. This 
model will include fixed categorical effects of study conduct approach group, on randomization 
strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as well as continuous 
fixed covariates of corresponding baseline score. 
Diabetes Distress Scale (DDS)  
Descriptive summary (mean, median, SD, minimum and maximum) at each visit (baseline and 
Week 24) and change from baseline to Week 24 will be provided including the total score and the 
4 domains scores determined by computing the mean of item responses: 
 Emotional burden score: mean of items 2, 4, 7, 10 and 14 (score from 0 to 6). 
 Physician distress score: mean of items 1, 5, 11 and 15 (score from 0 to 6). 
 Regimen distress score: mean of items 6, 8, 3, 12 and 16 (score from 0 to 6). 
 Interpersonal distress score: mean of items 9, 13 and 17 (score from 0 to 6). 
 Total DDS score: mean of the 17 items (score from 0 to 6).  
The change in DDS scores from baseline to Week 24 will be analyzed using an ANCOVA. This 
model will include fixed categorical effects of study conduct approach group, on randomization 
strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites as well as continuous 
fixed covariates of corresponding baseline score. 
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The incidence of patients experiencing a score ≥3 (in DDS total score and domain scores) as well 
as responder patients (in DDS total score and domain scores) will be determined, during the 24-
week randomized period. 
2.4.7.6 Investigator (clinician) reported outcome (ClinRO) endpoints  
Overall Study Experience-sites (OSES) questionnaire  
For OSES Part 1 (study-specific resource requirements), a descriptive summary will be provided 
for each approach group at each applicable visit, and a total time will be calculated for each 
patient and averaged within each approach group. Overall Study Experience-Sites Part 1 scores 
will be compared between approach groups using the same approach as the one used for primary 
endpoint (MMRM model) as described in Section 2.4.4.1.1. This model will include fixed 
categorical effects of approach group, on randomization strata of screening HbA1c (<7.6%, 
≥7.6%) and randomization strata of sites as well as continuous fixed covariates of corresponding 
baseline score. 
For OSES Part 2 (relationship and satisfaction), a descriptive summary will be provided for each 
item for each approach group at Week 24. Item scores will be compared between approach groups 
using an ANOVA. This model will include fixed categorical effects of approach group, on 
randomization strata of screening HbA1c (<7.6%, ≥7.6%) and randomization strata of sites. 
2.4.8 Patient interviews  
Exit interviews with a subset of patient from the virtual group is described in Section 2.1.10. Data 
will be analyzed via an expert qualitative research analysis group using standardized qualitative 
methods (eg, thematic analysis, grounded theory). No details of analysis will be provided in this 
SAP, but will be developed by expert. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
Reference day 
The reference day for the calculation of extent of exposure, time to onset and relative days is the 
day of the first administration of IMP, denoted as Day 1. 
Demographic formulas 
Body Mass Index (kg/m2) = (Weight in kg)/(Height in meters)2. 
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Disease characteristics formulas 
Duration of diabetes (years) = (Date of informed consent – date of diagnosis of diabetes 
+1)/365.25. 
Age at onset of diabetes (years) = (Date [DD-MM-YYYY] of diagnosis of diabetes – date 
[DD-MM-YYYY] of birth +1) /365.25. In case of unavailable date of birth, only the year of the 
date of diabetes diagnosis and the year of the date of birth (retrieve using the age recorded at 
screening) will be considered in the age at onset calculation. 
Duration of previous mealtime insulin treatment (years) = Duration of mealtime insulin treatment 
in patient life (years) = (Date of informed consent – Date of first intake of mealtime Anti-
hyperglycemic therapy in patient life +1)/365.25. 
Duration of basal insulin treatment (years) = (Date of informed consent – Date of first intake of 
Basal Anti-hyperglycemic therapy +1)/365.25 
 
HbA1c transformation 
To transform HbA1c in % to mmol/mol, the following formula is used: 
IFCC = (10.93*NGSP) - 23.50 
NGSP (National Glycohemoglobin Standardization Program network) corresponds to HbA1c (%) 
and IFCC (International Federation of Clinical Chemistry network) to HbA1c (mmol/mol) 
FPG and SMPG conversion 
From mg/dL to mmol/L: x 0.0555 
From mmol/L to mg/dL: x 18.0148 
Renal function formulas  
Conversion for serum creatinine:  
From mg/dL to µmol/L: x 88.402 
Conversion for total bilirubin:  
From mg/dL to µmol/L: x 17.104 
Creatinine clearance (CLcr) value will be derived using the equation of Cockroft and Gault (2), 
using weight assessed at the same visit: 
 For Male:  
CLcr (mL/min) = 
 
 For Female: result above multiplied by 0.85. 
mol/L)]
( 
creatinine
 
serum
 x 
[0.814
kg)]
 x weight(
)
age(years)
 - 
[(140

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eGFR will be derived using MDRD formula (3): 
eGFR (mL/min/1.73m2) = 
 
2.5.2 Data handling conventions for secondary efficacy variables  
Fasting condition 
FPG measurement not collecting in fasting condition will not be used in the analyses. 
Invalid laboratory data 
HbA1c or FPG measurements flagged as invalid by the laboratory will not be used in the 
analyses.  
Handling of missing data in the calculation of SMPG variables 
At least 4 measurements from the 7 points profile are required for analyzing the profile by 
timepoint, the 24-hour mean SMPG and the corresponding variability. 
At least 3 measurements from the 5 points profile are required for analyzing the profile by 
timepoint. 
At least 3 fasting (prebreakfast) SMPG values in the last 7 days are required for calculating the 
mean of the fasting SMPG. 
Patient Reported Outcomes and Clinician Reported Outcomes 
Was It Worth It (WIWI) 
No total score is calculated. Each item will be analysed separately with all available data ie. with 
no imputation 
Work Productivity and Impairment (WPAI) Questionnaire 
See Appendix D 
Overall Study Experience-Participation (OSEP) Questionnaire 
For OSEP (Part 1), no total score is calculated. Each item will be analysed separately with all 
available data ie. with no imputation. For participants with data at one timepoint only – for example, 
Visit 2-Step 2 but not Visit 12 - they will be excluded from the analysis. 
For OSEP (Part 2), no total score is calculated. Each item will be analysed separately with all 
available data ie. with no imputation.  






female)
 
(if
 
0.742
 x 
black)
 
(if
 
1.212
 x 
Age
 x 
 
(mg/dL)
 
Creatinine
 
Serum
175x 
-0.203
-1.154
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Resource Use Questionnaire (RUQ) 
No total score is calculated. For analysis of average on-treatment RUQ score, all available data will be 
used and no imputation will be completed. For a participant with only 3 post-baseline RUQ 
completions, the average for each item will be taken of these 3 scores. For a participant with 10 post-
baseline RUQ completions, the average for each item will be taken of these 10 scores.   
Overall Study Experience-sites (OSES) Questionnaire 
For OSES (Part 1), no total score is calculated. For analysis of average on-treatment OSES (Part 1) 
time score, all available data will be used and no imputation will be completed. For a participant with 
only 3 post-baseline OSES-Part 1 completions, the average will be taken of these 3 scores. For a 
participant with 10 post-baseline OSES-Part 1 completions, the average will be taken of these  
10 scores.   
For OSES (Part 2), no total score is calculated. Each item will be analysed separately with all 
available data ie. with no imputation.  
Diabetes Treatment Satisfaction Questionnaire DTSQs and DTSQc) 
The total treatment satisfaction score is the sum of items 1, 4, 5, 6, 7 and 8. 
If  no more than 2 out of the 6 questions comprising the total treatment satisfaction score are 
missing, the total treatment satisfaction score is imputed by calculating the average of the scores 
from the answered questions, dividing this sum by the number of answered questions and 
multiplying the average by six.  
If items 2 or 3 are not answered, frequency of hypoglycemia or hyperglycemia scores is 
considered as missing. 
Hypoglycemia Fear Survey (HFS-II) 
Using an item mean score also makes handling missing data more sensible. Instead of dividing by 
the entire scale or subscale to compute the item mean, only divide by the number of questions 
answered. This allows a more reasonable comparison between respondents. However, it is 
recommended that this technique be used only if more than 75% of the items have responses. This 
equates to having responses for 25 items if scoring the whole HFS-II, for 12 items if scoring the 
HFS-B, and for 14 items if scoring the HFS-W. If less than 75% of the data is available, the score 
for that scale or subscale should be counted as missing as it may not be a true reflection of the 
participants’ behaviors and/or worries. 
The Diabetes Distress Scale (DDS) 
Minimum number of items required for score calculation (at least 2/3). 
 
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Table 1 - PROs: Diabetes related - Missing Data Handling  
PRO scales 
Score 
Number of items 
included in score 
derivation 
Minimum number of 
items required for 
score calculation 
DTSQs 
Total treatment satisfaction score 
6 
4 
 
Perceived frequency of hyperglycemia score 
1 
1 
 
Perceived frequency of hypoglycemia score 
1 
1 
DTSQc 
Total treatment satisfaction score 
6 
4 
 
Perceived frequency of hyperglycemia score 
1 
1 
 
Perceived frequency of hypoglycemia score 
1 
1 
HFS-II 
total score 
33 
25 
 
HFS-B score 
15 
12 
 
HFS-W score 
18 
14 
DDS 
Emotional Burden score 
5 
4 
 
Physician distress score 
4 
3 
 
Regimen distress score 
5 
4 
 
Interpersonal distress score 
3 
2 
 
Total DDS score 
17 
12 
Effect Size 
The effect size is defined as: ES= difference/SD where SD is the standard deviation.  
Note that there are two main types of effect size: 
 Within ES: Calculated at the group level, when focusing on change from baseline. 
 Between ES: Calculated when comparing treatments groups. 
The within-group ES (WES) indicates if the changes from baseline to the end of treatment are 
clinically meaningful for each group. 
WES = 
𝐿𝑆 𝑚𝑒𝑎𝑛 𝑐ℎ𝑎𝑛𝑔𝑒 𝑓𝑟𝑜𝑚 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑎𝑡 𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑡
𝑝𝑜𝑜𝑙𝑒𝑑 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑑𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛
 
The between-group ES (BES) indicates if the mean changes from baseline to the end of treatment 
are clinically meaningful between groups. 
BES = 
𝑑𝑖𝑓𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑖𝑛 𝐿𝑆 𝑚𝑒𝑎𝑛𝑠 𝑏𝑒𝑡𝑤𝑒𝑒𝑛 𝑔𝑟𝑜𝑢𝑝𝑠 𝑎𝑡 𝑡𝑖𝑚𝑒𝑝𝑜𝑖𝑛𝑡 𝑡
𝑝𝑜𝑜𝑙𝑒𝑑 𝑏𝑎𝑠𝑒𝑙𝑖𝑛𝑒 𝑠𝑡𝑎𝑛𝑑𝑎𝑟𝑑 𝑑𝑒𝑣𝑖𝑎𝑡𝑖𝑜𝑛
 
Cohen’s rules for Effect Size (ES) and interpretation 
ES <0.2 : Negligeable 
0.2 ≤ ES <0.5 : Small 
0.5 ≤ ES <0.8 : Moderate 
ES ≥0.8 : Important 
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2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
For example, if either a baseline assessment or an endpoint assessment is missing for a particular 
patient, then the change from baseline at endpoint is missing. Depending upon the assessment, 
analyses may not include all patients in the analysis population, because certain patients in the 
intended population may have missing data. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date 
of last administration reported on the end-of-treatment e-case report form page. If this date is 
missing, the exposure duration should be left as missing. 
The last dose intake should be clearly identified in the e-case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
No imputation of adverse event/hypoglycemia dates/times will be performed. 
By default all adverse events/hypoglycemia are emergent except if additional information allows 
to classify otherwise. 
Handling of adverse events/hypoglycemia, laboratory data, vital signs when date and time of 
first investigational medicinal product administration is missing 
When the date and time of the first IMP administration is missing, all adverse 
events/hypoglycemia that occurred on or after the day of randomization should be considered as 
treatment-emergent adverse events/hypoglycemia. The exposure duration should be kept as 
missing. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
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Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values.   
Handling of hypoglycemia event classification when some classification items are missing 
Rule for handling missing data in classification items for hypoglycemia event will be provided in 
ADaM metadata. 
Handling of missing data in the calculation of 7-point SMPG variables 
For a given 7-point SMPG profile, at least 4 available measurements in the last 7 days are 
required to be taken into account in the statistical analyses (including the descriptive analyses at 
each time-point). 
Handling of missing data in the calculation of average pre-breakfast SMPG, 
At least 3 pre-breakfast (fasting) SMPG values in the last 7 days are required to be taken into 
account in the statistical analyses (including descriptive analyses at each time-point).  
Handling of missing data in the calculation of insulin doses 
At each visit, the average daily insulin doses (basal, mealtime, and total) will be calculated as the 
average of the daily insulin doses available in the week (7 days) before the visit. 
No minimum number of available doses will be required. 
For insulin doses in U/kg, if the body weight measurement is missing at a given visit, the last 
available measurement from previous visit will be used. 
2.5.4 Windows for time points  
The following process will be applied for visit re-allocation. Re-allocated visits will be used in all 
statistical analyses (descriptive statistics, plots, and statistical models). 
No re-allocation will be performed for nominal visits already provided in the clinical database 
(Visit 1 to Visit 20). 
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SMPG 
In the clinical database, SMPG profiles transferred from the e-diary will not be assigned to a 
protocol visit. For the analysis, they will be assigned to the next visit actually performed by the 
patient after the date/time of data collection (Visit 3 to Visit 12, or Visit 700). 
In the clinical database, SMPG assessments which do not correspond to a 7-point profile 
transferred from the e-diary will not be assigned to a protocol visit. For the analysis, they will be 
assigned to the next visit after the date/time of data collection. 
Insulin doses 
In the clinical database, insulin doses transferred from the e-diary will not be assigned to a 
protocol visit. For the analysis, they will be assigned to the next on-site visit actually performed 
by the patient after the date/time of data collection. 
PROs and ClinRO 
In the clinical database, PROs and ClinRO transferred from the e-diary will not be assigned to a 
protocol visit. For the analysis, they will be assigned to the video chat/phone call/ on-site visit 
using the date/time of data collection and the  date of first IMP taken (or Randomization date if no 
IMP taken) as reference for derivation of the Study day . 
Table 2 - Reallocation time windows definition  
Scheduled visit post 
baseline 
Targeted study day 
Analysis window in study days 
 
DTSQs, DDS, HFS-II, WPAI-SP, OSES Part 1 
Day 1 (Visit 2 Step 2) 
1 
-28 to 1 
Week 24 (Visit 12) 
169 
141 to 196 
DTSQc, WIWI, OSES Part 2, OSEP Part 2 
Week 24 (Visit 12) 
169 
141 to 196 
OSES Part 1 
Day 1 (Visit 2 Step 2) 
1 
-28 to 1 
Week 1 (Visit 3) 
8 
5 to 11 
Week 2 (Visit 4) 
15 
12 to 18 
Week 3 (Visit 5) 
22 
19 to 25 
Week 4 (Visit 6) 
29 
26 to 32 
Week 6 (Visit 7) 
43 
36 to 49 
Week 8 (Visit 8) 
57 
50 to 63 
Week 12 (Visit 9) 
85 
71 to 98 
Week 16 (Visit 10) 
113 
99 to 126 
Week 20 (Visit 11) 
141 
127 to 154 
Week 24 (Visit 12) 
169 
155 to 196 
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Scheduled visit post 
baseline 
Targeted study day 
Analysis window in study days 
 
RUQ 
Day 1 (Visit 2 Step 2) 
1 
-28 to 1 
Week 4 (Visit 6) 
29 
15 to 42 
Week 8 (Visit 8) 
57 
43 to 70 
Week 12 (Visit 9) 
85 
71 to 98 
Week 16 (Visit 10) 
113 
99 to 126 
Week 20 (Visit 11) 
141 
127 to 154 
Week 24 (Visit 12) 
169 
155 to 196 
Study days are calculated from the day of first IMP, the day of first IMP injection being Day 1. For randomized but not treated patients, Day 1 is 
the day of randomization. 
End of treatment visit 
The following analysis windows will be applicable to re-allocate the premature end of treatment 
assessments (premature EOT visit) for HbA1c and FPG assessments. 
Table 3 - Reallocation time windows definition  
Scheduled visit post 
baseline 
Targeted study day 
Analysis window in study days 
 
HbA1c and FPG 
Week 16 (Visit 10) 
113 
85 to 140 
Week 24 (Visit 12) 
169 
141 to 196 
Study days are calculated from the day of first IMP, the day of first IMP injection being Day 1. For randomized but not treated patients, Day 1 is 
the day of randomization. 
Study days are calculated form the day of first IMP injection; the day of first IMP injection being 
Day1. 
To retrieve all safety and other assessments performed at the end of treatment visit, the following 
process will be followed: if a patient discontinues the treatment prematurely, end of treatment 
assessments will be re-allocated to the next scheduled visit for the patient. The next scheduled 
visit for each patient will be determined as the next visit that should be performed as per protocol, 
following the last visit actually performed by the patient before end of treatment visit. 
For a given parameter, the value will not be re-allocated in the following cases: 
 If the parameter is not planned to be collected at the re-allocation visit. 
 If a value is already available for the parameter at the re-allocation visit. 
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2.5.5 Unscheduled visits  
The analysis windows mentioned in Section 2.5.4 will be applicable to re-allocate the 
unscheduled assessments (measurements from the central laboratory only) for HbA1c and FPG 
assessments. 
After applying the time windows as mentioned in Section 2.5.4, if two assessments are associated 
to the same time point, the closest from the targeted study day is used. In case of equality, the 
earliest measurement is used. 
The determination of baseline for HbA1c and FPG variables is based on all measurements from 
both scheduled and unscheduled visits (measurements from the central laboratory only). The 
determination of baseline for safety parameters is based on all assessments from both scheduled 
and unscheduled visits too. The determination of the last on-treatment value for safety parameters 
is also based on all assessments from both scheduled and unscheduled visits. Measurements from 
the unscheduled visits (including results from local laboratory when no corresponding central 
laboratory results are available) are also considered for PCSA summary of safety parameters. 
Unscheduled visit measurements are not included in the by-visit summaries. 
2.5.6 Pooling of centers for statistical analyses  
No pooling of centers is planned for statistical analyses. 
2.5.7 Statistical technical issues  
None. 
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3 
INTERIM ANALYSIS  
No interim analysis will be performed during the study. 
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4 
DATABASE LOCK  
The database is planned to be locked at approximatively between 5 and 7 weeks after last patient 
last visit. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS Enterprise Guide version 5.1 
or higher. 
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6 
REFERENCES  
 
1. 
American Diabetes Association Workgroup on Hypoglycemia. Defining and Reporting 
Hypoglycemia in Diabetes: a report from the American Diabetes Association Workgroup on 
Hypoglycemia. Diabetes Care. 2005;28(5):1245-9. 
2. 
Cockcroft DW, Gault MH. Prediction of CLcr from serum creatinine. 
Nephron.1976;16(1):31-41. 
3. 
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A More Accurate Method 
To Estimate Glomerular Filtration Rate from Serum Creatinine: A New Prediction Equation. 
American College of Physicians–American Society of Internal Medicine-Annals of Internal 
Medicine.1999;130(6):461-70. 
 
 
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7 
LIST OF APPENDICES  
 
Appendix A: 
Potentially clinically significant abnormalities criteria  
Appendix B: 
Study flochart  
Appendix C: 
PRO: Was It Worth It (WIWI)  
Appendix D: 
PRO: Work Productivity And Impairment (WPAI)  
Appendix E: 
PRO: Overall Study Evaluation – Participation (OSEP)  
Appendix F:  
PRO: Ressources Use Questionnaire (RUQ)  
Appendix G: 
PRO: Diabetes Treatment Satisfaction Questionnaire  status (DTSQs)  
Appendix H: 
PRO: Diabetes Treatment Satisfaction Questionnaire change (DTSQc) 
Appendix I: 
PRO: Hypoglycemia Fear Survey-II (HFS-II)  
Appendix J: 
PRO: Diabetes Distress Scale (DDS) 
Appendix K: 
ClinRO : Overall Study Evaluation – Site (OSES)  
 
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Appendix A 
Potentially clinically significant abnormalities criteria  
 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Clinical Chemistry 
ALT 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed 
in ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
AST 
By distribution analysis : 
>3 ULN 
>5 ULN 
>10 ULN 
>20 ULN 
Enzymes activities must be expressed 
in ULN, not in IU/L.  
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
Alkaline Phosphatase 
>1.5 ULN 
Enzymes activities must be expressed 
in ULN, not in IU/L. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Total Bilirubin 
>1.5 ULN 
>2 ULN 
Must be expressed in ULN, not in 
µmol/L or mg/L. Categories are 
cumulative. 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
Conjugated Bilirubin 
>35% Total Bilirubin and TBILI>1.5 ULN 
Conjugated bilirubin dosed on a case-
by-case basis. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
ALT and Total Bilirubin 
ALT>3 ULN and TBILI>2 ULN 
Concept paper on DILI – FDA draft 
Guidance Oct 2007. 
Internal DILI WG Oct 2008. 
To be counted within a same treatment 
phase, whatever the interval between 
measurements. 
CPK 
>3 ULN 
>10 ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
First row is mandatory. Rows following 
one mentioning zero can be deleted. 
CLcr (mL/min) 
(Estimated creatinine clearance based on 
the Cokcroft-Gault equation)  
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, data 
analysis, and impact on dosing and 
labeling 
eGFR (mL/min/1.73m2) 
(Estimate of GFR based on an MDRD 
equation)  
 
<15 (end stage renal disease) 
≥15 - <30 (severe decrease in GFR) 
≥30 - <60 (moderate decrease in GFR) 
≥60 - <90 (mild decrease in GFR) 
≥ 90 (normal GFR) 
FDA draft Guidance 2010 
Pharmacokinetics in patients with 
impaired renal function-study design, data 
analysis, and impact on dosing and 
labeling 
Creatinine 
≥150 μmol/L (Adults) 
≥30% change from baseline 
≥100% change from baseline 
Benichou C., 1994. 
 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L 
<120 μmol/L  
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Blood Urea Nitrogen 
≥17 mmol/L 
 
Chloride 
<80 mmol/L 
>115 mmol/L 
 
Sodium 
≤129 mmol/L 
≥160 mmol/L 
 
Potassium 
<3 mmol/L 
≥5.5 mmol/L 
FDA Feb 2005. 
Total Cholesterol 
≥7.74 mmol/L  
Threshold for therapeutic intervention. 
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CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Triglycerides 
≥4.6 mmol/L 
Threshold for therapeutic intervention. 
Lipasemia 
≥3 ULN 
 
Amylasemia 
≥3 ULN 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
≤3.9 mmol/L and <LLN 
≥11.1 mmol/L (unfasted); ≥7 mmol/L 
(fasted) 
 
ADA May 2005. 
ADA Jan 2008. 
HbA1c 
>8% 
 
Albumin 
≤25 g/L 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) 
 FDA Sept 2005. 
Hematology 
WBC 
<3.0 Giga/L (Non-Black); <2.0 Giga/L 
(Black) 
≥16.0 Giga/L 
Increase in WBC: not relevant. 
To be interpreted only if no differential 
count available. 
Lymphocytes 
>4.0 Giga/L 
 
Neutrophils 
<1.5 Giga/L (Non-Black);<1.0 Giga/L (Black) International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
FDA criteria. 
Monocytes 
>0.7 Giga/L 
 
Basophils 
>0.1 Giga/L 
 
Eosinophils 
>0.5 Giga/L or >ULN (if ULN≥0.5 Giga/L) 
Harrison- Principles of internal Medicine 
17th Ed., 2008. 
Hemoglobin 
≤115 g/L (Male); ≤95 g/L (Female) 
≥185 g/L (Male); ≥165 g/L (Female) 
 
Decrease from Baseline ≥20 g/L 
Criteria based upon decrease from 
baseline are more relevant than based 
on absolute value. Other categories for 
decrease from baseline can be used 
(≥30 g/L, ≥40 g/L, ≥50 g/L). 
Hematocrit 
≤0.37 v/v (Male) ; ≤0.32 v/v (Female) 
≥0.55 v/v (Male) ; ≥0.5 v/v (Female) 
 
RBC 
≥6 Tera/L 
Unless specifically required for 
particular drug development, the 
analysis is redundant with that of Hb. 
Otherwise, consider FDA criteria. 
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Page 59 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
Platelets 
<100 Giga/L 
≥700 Giga/L 
International Consensus meeting on 
drug-induced blood cytopenias, 1991. 
Urinalysis 
pH 
≤4.6 
≥8 
 
Vital signs 
HR 
≤50 bpm and decrease from baseline ≥20 
bpm 
≥120 bpm and increase from baseline≥20 
bpm 
To be applied for all positions (including 
missing) except STANDING. 
SBP 
≤95 mmHg and decrease from baseline 
≥20mmHg 
≥160 mmHg and increase from baseline 
≥20 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline 
≥10 mmHg 
To be applied for all positions (including 
missing) except STANDING. 
Orthostatic Hypotension 
Orthostatic SDB 
Orthostatic DBP 
 
 
≤-20 mmHg 
≤-10 mmHg 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
FDA Feb 2007. 
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HOE901-MSC15146 
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Page 60 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
ECG 
Ref.: ICH E14 guidance (2005) and E14 
Q&A (2012), and Cardiac Safety 
Research Consortium White Paper on 
PR and QRS (Nada et al. Am Heart J. 
2013; 165(4) : 489-500) 
HR 
<50 bpm 
<50 bpm and decrease from baseline ≥20 
bpm 
<40 bpm 
<40 bpm and decrease from baseline ≥20 
bpm 
<30 bpm 
<30 bpm and decrease from baseline ≥20 
bpm 
 
>90 bpm 
>90 bpm and increase from baseline 
≥20bpm 
>100 bpm  
>100 bpm and increase from baseline 
≥20bpm 
>120 bpm  
>120 bpm and increase from baseline ≥20 
bpm 
Categories are cumulative 
 
 
 
 
 
 
Categories are cumulative 
 
PR 
>200 ms 
>200 ms and increase from baseline ≥25% 
>220 ms 
>220 ms and increase from baseline ≥25% 
>240 ms 
>240 ms and increase from baseline ≥25% 
Categories are cumulative 
 
QRS 
>110 ms 
>110 msec and increase from baseline 
≥25% 
>120 ms 
>120 ms and increase from baseline ≥25% 
Categories are cumulative 
QT 
>500 ms 
 
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Page 61 
CRITERIA for POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES 
for phase 2/3 studies (oncology excepted) 
 
Parameter 
PCSA 
Comments 
QTc 
 
Absolute values (ms) 
 
 
>450 ms 
>480 ms 
>500 ms 
 
Increase from baseline 
Increase from baseline ]30-60] ms 
Increase from baseline >60 ms 
To be applied to any kind of QT 
correction formula.  
Absolute values categories are 
cumulative 
 
QTc >480 ms and QTc>60 ms are the 
2 PCSA categories to be identified in 
individual subjects/patients listings. 
 
 
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Screening  
Randomization  
Treatment period 
Follow-up 
Visits  
1 
Step-1a
1 
Step-2b
2 
Step-1c
2
Step-2d
3

 
4
 
 
5
 
 
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8 
 
 
9 
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EOTg
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Traditional group  
 
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P 
 
 
 
P 
 
P 
 
P 
 
P 
 
Virtual group  
 
P &
 
 
 
 
 
 
 
 
 
 
 
 
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

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0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
1 week 
Window (day) 
 
 
-/+ 4 
 
-/+ 3 
-/+ 3 
-/+ 3 
-/+ 4 
-/+3 
-/+ 4 
-/+ 3 
-/+ 4 
-/+ 3 
-/+ 3 
+/-2 
Informed Consent (eConsent) 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
Schedule Homecare visit  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interactive response technology (IRT) calls 
X 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
Inclusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Video chat with Investigator and site staff 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history; diabetes 
history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication(s) 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationd
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Vital signsh and body weight
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Height
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Virtual material/device shipment 
(Bluetooth devices)e
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation/collection of e-diary 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
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Screening  
Randomization  
Treatment period 
Follow-up 
Visits  
1 
Step-1a
1 
Step-2b
2 
Step-1c
2
Step-2d
3

 
4
 
 
5
 
 
6 
 
 
7 
8 
 
 
9 
10 
 
 
11 
 
 
12 
EOTg
13 
EOS 
 
Traditional group  
 
(Digital screening)
 
P 
 
 
 
P 
 
P 
 
P 
 
P 
 
Virtual group  
 
P &
 
 
 
 
 
 
 
 
 
 
 
 
Weeks  


-1 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
1 week 
Window (day) 
 
 
-/+ 4 
 
-/+ 3 
-/+ 3 
-/+ 3 
-/+ 4 
-/+3 
-/+ 4 
-/+ 3 
-/+ 4 
-/+ 3 
-/+ 3 
+/-2 
Randomization via IRT call  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Video chat with investigator and site staff 
via the virtual devicee
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Allocation of study medication (IMP) 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
First IMP (Toujeo) injectione
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation and review of IMP and 
NIMPdosesf
 
 

X
X
X
X
X
X
X
X
X
X
X

IMP compliance check; collecting & 
counting used & unused pens 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 

Diet and lifestyle counselling 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Glucose meter shipmentc
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
7-Point SMPGi
 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
 
5-point SMPGi 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Upload SMPG to PCj
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
AE/SAE 
 
To be assessed and reported (if any) since consent throughout the study (report SAE to the sponsor within 24 hours) 
Hypoglycemia recording 
 
 
To be assessed and reported (if any) since randomization throughout the study 
Injection site reactions, PTCs 
 
 
To be assessed and reported (if any) since randomization throughout the study
Central Laboratoryk,e
 
HbA1c, FPG 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
Hematology, clinical biochemistryl

X 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening  
Randomization  
Treatment period 
Follow-up 
Visits  
1 
Step-1a
1 
Step-2b
2 
Step-1c
2
Step-2d
3

 
4
 
 
5
 
 
6 
 
 
7 
8 
 
 
9 
10 
 
 
11 
 
 
12 
EOTg
13 
EOS 
 
Traditional group  
 
(Digital screening)
 
P 
 
 
 
P 
 
P 
 
P 
 
P 
 
Virtual group  
 
P &
 
 
 
 
 
 
 
 
 
 
 
 
Weeks  


-1 
0 
1 
2 
3 
4 
6 
8 
12 
16 
20 
24 
1 week 
Window (day) 
 
 
-/+ 4 
 
-/+ 3 
-/+ 3 
-/+ 3 
-/+ 4 
-/+3 
-/+ 4 
-/+ 3 
-/+ 4 
-/+ 3 
-/+ 3 
+/-2 
Urine analysism

X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP only)n

X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
PROs and other questionnaireso
 
Diabetes related PROs: DTSQs, DDS, 
HFS-II 

 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Diabetes related PRO: DTSQc 

 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Was it Worth It (WIWI) Questionnaire 

 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Work Productivity and Impairment Study 
Participation (WPAI-SP) 

 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Overall Study Experience - Participation 
(OSEP) Part 1 

 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Overall Study Experience - Participation 
(OSEP) Part 2 

 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Resource Use Questionnaire (RUQ) 

 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
 
Overall Study Experience - Sites (OSES) 
– Part 1 (resource requirements) 

 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Overall Study Experience – Sites (OSES) 
– Part 2 (relationship, satisfaction) 

 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Qualitative exit interviewp

 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a Prior to Visit 1, patients will be contacted by the sites or guided by the multi-channel digital recruiters to the eConsent web portal (Parallel 6 Website). Informed consent process will be completed electronically by 
the candidate trial patients.  During the eConsent process, the study purpose, virtual tools for participation, and other protocol requirements will be introduced and discussed with the patients in the text or 
audio/video manner.  After eSigning and counter-eSigning by the patient and the investigator, the enrolment IRT call will be made and the patient ID assigned.  
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b Assessments at Visit 1- Step 2 will be performed in-person by Homecare health professional (The MRN) in corporation with the study investigators and designees. This visit can occur at the patient’s home, at 
work, or at any location providing the adequate space and level of privacy. Patient identification will be further verified and confirmed.   
c At the end of screening, investigators will determine the eligibility of the screened patients for participation. The randomization IRT call will be made at the Visit 2- Step 1. Patients will be informed by the study sites 
of their randomization group and Visit 2- Step 2 will be scheduled for the baseline assessments within 1 week (+/- 4 days). 
Glucose meters with Bluetooth access and associated accessories (lancet, control solutions, test strips, etc), e-diaries features, and instructions will be shipped to all eligible patients. Patients will use the study 
provided glucose meters throughout the study.  
d Physical examination will be performed at the in-person visit in the traditional group. In the virtual group, physical examination will be performed on-site, in-person, between randomization IRT call and the first IMP 
administration. All other assessments will occur remotely on the day of the first IMP administration (Day 1). 
e Only for patients randomized in virtual group: 
• 
They will receive the Bluetooth devices for their remote participation and the IMP (Toujeo®) before Visit 2-Step 2. 
• 
Shortly after randomization (IRT call), they will be scheduled for an in-person visit to allow for the initiation physical examination performed by the investigator. 
• 
They will be further trained on the Bluetooth devices utilization. 
• 
The IMP starting date and dose will be instructed by the investigator at the time of Visit 2-Step 2. The first IMP (Day 1) data will be documented with the dose in the e-CRF. 
• 
All study assessments, including vital signs and weight, will be done via the Bluetooth devices by the patients at home.   
• 
Patients located in the United States (US) will receive a laboratory requisition and have their blood drawn at any local Quest®. For patients located in Canada, blood draw will be performed by the Homecare 
via The MRN.  
• 
Unscheduled on-site visits or Homecare physician visits (depending on the patient’s location) only for safety assessment could be scheduled as deemed necessary by the investigator (ie, performance of 
physical examinations is critical to determine a diagnosis or further evaluation procedure for an AE). 
f 
IMP dose will be titrated at the investigator’s discretion to achieve the fasting glycemic target while avoiding hypoglycemia 
g EOT assessments will also be performed for any patients who prematurely discontinue the study treatment.  Patients should continue the study procedure as planned up to the EOS after IMP discontinuation.  
h Heart rate and blood pressure (sitting position)  
i 
7-point SMPG profile (before [preinjection after randomization] and 2 hours after breakfast, lunch and dinner, and at bedtime): at least ONE day during the weeks before Visit 2-Step 2 (Week 0), Visit 10 (Week 16), 
and Visit 12 ( Week 24) 
5-point SMPG profile (before breakfast, lunch and dinner; 2 hours after a main meal [or as per investigator’s instruction] and at bedtime): at least 3 days during the week before each visit 
The SMPG before breakfast should be measured in the fasting status, ie, after the patient wakes up, before breakfast, and before injection of any insulin; preferably no food should have been taken overnight. A 
note should be made in the diary if the SMPG is not tested in fasting status (eg, if food was taken to cope with a hypoglycemic episode)  
j 
Only for patients randomized in the traditional group 
k Blood samples will be sent to and analyzed by Quest® central lab  
l 
Hematology: erythrocytes, hemoglobin, hematocrit, leukocytes and platelets. Clinical chemistry: total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), 
AST, ALT, ALP, plasma glucose, creatinine, estimated creatinine clearance, uric acid, sodium, and potassium 
m Urine analysis by dipstick: pH, glucose, ketones, leucocytes, blood/hemoglobin, protein 
n For women of child-bearing potential (WOCBP): serum pregnancy test for screening; urine pregnancy test for subsequent monitoring and it can be confirmed with a serum test if needed. For WOCBP in virtual 
group, the urine pregnancy test kit will be provided by the study.  
o For patients randomized to the virtual group, all questionnaires will be performed remotely via the mobile technology at home. For patients randomized in the traditional group, the questionnaires will be completed 
electronically (via the mobile technology) at the study site (before visiting the study site for baseline assessment on Visit 2 Step 2).  
p In a subset of patients (approximately 30) in the virtual approach group. 
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Abbreviations: AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; DDS = Diabetes Distress Scale; DTSQc = Diabetes Treatment Satisfaction 
Questionnaire change; DTSQs = Diabetes Treatment Satisfaction Questionnaire status;  e-CRF = electronic case report form; EOS = end of study; EOT = end of treatment; FPG = Fasting plasma glucose; HbA1c = 
glycated hemoglobin A1c; HFS = Hypoglycemia Fear Survey; ID = identification; IMP = investigational medicinal product; IRT = interactive response technology; MRN = medical research network; NIMP = 
noninvestigational medicinal product; OSEP = overall study experience – participation; OSES = overall study experience – sites; PC = personal computer; PRO = patient reported outcome; PTC = product technical 
complaints; RUQ = resource use questionnaire; SAE = serious adverse event; SMPG = self-monitoring of plasma glucose; US = United States; WIWI = was it worth it; WPAI-SP = work productivity and impairment  
study participation; WOCBP = women of child-bearing potential;  
 
 
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Appendix C 
  
 
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Appendix D 
  
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1.  General Guidelines 
In the general health version (WPAI:GH), respondents are asked questions about work and 
activity impairment due to health problems.  In the specific health problem version (WPAI:SHP), 
respondents are asked questions concerning impairment due to the target health problem (eg, 
arthritis).   In the combination version, WPAI:GH/SHP respondents are asked about impairment 
due to a specified health problem and impairment due to other health reasons.  The sum of 
impairment due to the specified problem and other health reasons is considered impairment due to 
all health problems.  The WPAI:GH/SHP, therefore, measures impairment due to the specified 
problem and all health problems. 
The WPAI elicits hours worked (all versions), hours missed due to the target condition 
(WPAI:GH/SHP, WPAI:SHP, WPAI:AS), hours missed due to other health problems 
(WPAI:GH/SHP) and hours missed for any other reasons (WPAI:SHP, WPAI:GH, 
WPAI:GH/SHP).  Hours missed for "other reasons" is not used in the scoring, but only as a 
prompt to the respondent to exclude those hours from the count of actual hours worked.  In the 
WPAI:AS, respondents are asked about usual hours worked, not actual hours worked.    
2.  Coding Rules for Interviewers 
The coding rules below apply to the WPAI:GH, WPAI:SHP, WPAI:GH/SHP and the WPAI:AS, 
as noted. 
Are you currently employed? (All versions) 
   Yes: works part-time or full-time; self-employed; works in family business; on vacation from 
paid employment, eg, schoolteachers on leave for the summer.  No: does not work for pay; only 
does volunteer work; usually works, but has been laid-off or unemployed during past seven days; 
seasonal workers not currently working.  
Work time missed due to specified health problem (WPAI:SHP, WPAI:GH/SHP and WPAI:AS 
only) 
    Include: any time taken off from work due to problem; doctor visits for problem; trip to 
pharmacy to get medication for problem; side effect of medication for problem; reason was partly 
problem and partly something else.  Exclude: if it happened today; if the respondent is not sure,  
ie, can't say if it was problem or something else. 
Work time missed due to other health reasons (WPAI:GH/SHP only) 
   Include: time taken off from work for health reasons unrelated to target disease; visits to doctor, 
dentist, and pharmacy.  Partly health, partly something else, eg, couldn't shovel snow to get car 
out because of back problem.  Says no health problem, just had a pain, cold, fatigue, etc.   
Exclude: hours missed due to specified problem; non-health reasons. 
 
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Work time missed due to any other reasons (WPAI:GH and WPAI:GH/SHP only) 
   Include: time taken off from work for vacations, holidays, compensatory time; time missed 
because of required study visits.  Exclude: hours missed for any health reason. 
Work time missed due to any other reasons (WPAI:SHP only) 
   Include: time taken off from work for vacations, holidays, compensatory time; time missed 
because of required study visits; hours missed due to health that is unrelated to specified 
problem.  Exclude: hours missed due to specified problem. 
Actual hours worked (WPAI:GH, WPAI:SHP, WPAI:GH/SHP only) 
   Include: actual hours worked, including overtime (paid, unpaid).  Exclude: vacation, holidays, 
sick time, personal leave; any paid hours not actually worked, eg. compensatory time. 
Productivity 
Respondent is asked for overall productivity on days actually went to work.  If productivity 
differed greatly from day to day, for example, one day was 0 and one day was 10, ask him to 
respond for all days, on average.  Probe: "Thinking of all the days together, what was the average 
effect on your work?" 
Regular daily activities 
Regular activities are expected to be different for every respondent.   Regular activities could be 
exercising, watching television, gardening, sewing, etc.  The intention of the question is to have 
the respondent think of his activities and then make a global evaluation of how difficult it was to 
do these activities.  If impairment differed greatly from day to day or from activity to activity, 
probe:  "Thinking of all the days together, and all of your usual activities, what was the average 
effect on your daily routine?" 
3.  Coding Rules for Self-Administration 
Employment status: 
If Q1 = YES or Q1 = NO or missing and hours missed or worked  >0, then employed.   
If Q1 = missing and hours missed and worked = 0, then not employed. 
Hours missed 
If hours worked = 0, then productivity while at work is not applicable. 
If the line or box is slashed through or there is a response of NA, code as zero.  If respondent 
enters a range of hours, enter the midpoint.  If respondent records "+" after the number of hours, 
ignore the "+".. 
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Missing or unreadable response 
Responses from other assessments should not be used to eliminate missing data.  For example, if a 
subject indicates he works 40 hours at one assessment, but leaves that question blank on a 
subsequent assessment, the blank response is coded missing.   
Productivity questions 
If the words at the end of the scale are circled, enter the corresponding number, ie, a "0" or "10". 
 
 
 
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Appendix E 
  
 
 
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Appendix F 
  
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Appendix G 
  
 
 
 
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Appendix H 
  
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Appendix I 
  
 
 
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Appendix J 
  
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Appendix K 
  
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