A Randomized, Active-controlled, Parallel Group, 16-Week Open Label Study Comparing the Efficacy and Safety of the Morning Injection of Toujeo (Insulin Glargine-U300) Versus Lantus in Patients With Type 1 Diabetes Mellitus
Phase: PHASE4
Conditions: Type 1 Diabetes Mellitus
Sponsor: Sanofi

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-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL NO. 01 
COMPOUND: Toujeo / insulin glargine / HOE901-U300 
A Randomized, Active-Controlled, Parallel Group, 16-Week Open Label Study 
Comparing the Efficacy and Safety of the Morning Injection of Toujeo  (Insulin Glargine-
U300) Versus Lantus in Patients with Type 1 Diabetes Mellitus 
STUDY NUMBER: LPS14587 
VERSION DATE / STATUS: 02 August 2016 / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 02-Aug-2016 
Clinical Trial Protocol 
Version number: 1 (electronic 1.0) 
Date : 05-Nov-2015 
EudraCT  
Not applicable 
IND Number(s) 
Not applicable 
Version Number: 
1  
WHO universal trial number 
U1111-1176-0936 
Date:
02-Aug-2016
Total number of pages: 
85 
(electronic 
NCT02688933

Amended Clinical Trial Protocol No. 01 
02-Aug-2016
LPS14587 - 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: 
Sanofi US Services Inc 
55 Corporate Drive 
Bridgewater,  
NJ 08807 
USA 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
(electronic 

Amended Clinical Trial Protocol No. 01 
02-Aug-2016
LPS14587 - insulin glargine 
Version number: 1
Property of the Sanofi Group- strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
COMPOUND: HOE901-U300 
(Toujeo insulin glargine) 
STUDY No: LPS14587 
TITLE 
A randomized, active-controlled, parallel group, 16-week open label study 
comparing the efficacy and safety of the morning injection of Toujeo (insulin 
glargine U300) versus Lantus in patients with type 1 diabetes mellitus. 
INVESTIGATOR/TRIAL LOCATION 
United States:  Multicenter 
PHASE OF DEVELOPMENT 
4 
STUDY OBJECTIVE(S) 
Primary objective: 
To demonstrate that morning injection of Toujeo compared to Lantus will 
provide better glycemic control evaluated by Continuous Glucose Monitoring 
(CGM) in adult patients with type 1 diabetes mellitus.  
Secondary objective(s): 
To demonstrate that treatment with Toujeo  compared to Lantus will provide 
x
lower incidence rate of nocturnal symptomatic hypoglycemia,
x
better glucose control coverage during the last hours of CGM before next
basal-insulin dosing;
x
less variability in CGM profile.
STUDY DESIGN 
A multicenter, randomized, active-controlled, parallel group, 16-week open-
label study. The study consists of an up to 4-week screening and CGM 
training period and a 16-week treatment period. Blinded CGM data (blinded to 
both patients and investigators) will be collected at the end of screening 
(Week -2 to 0) and the end of treatment (Week 15-16) for endpoint analyses.   
During the baseline training period, patients will wear a blinded CGM device 
for 7 consecutive days to generate a minimum 4 days of usable CGM data to 
be eligible for randomization. If a patient fails the first attempt for any reason, 
he/she will be retrained for CGM conduct and complete another course of 
blinded CGM.  
Patients satisfying the inclusion/exclusion criteria and CGM requirements will 
be randomized 1: 1  to morning injection of either Toujeo or Lantus. Given the 
potential impact of certain variables on the primary endpoint, randomization 
will be stratified by baseline HbA1c (<8, 8), frequency of the basal insulin 
injections at screening BID vs QD, current CGM use (yes/no) and mealtime 
insulin titration algorithm followed. 
Dosing will be once daily in the morning, defined as the time period between 
waking up and breakfast. The injection time will be discussed between the 
investigators and patients at randomization and should be kept consistent at 
the same time each day. The patients will also be asked to maintain a log of 
the time of injection. 
During the entire study starting after screening, patients will perform Self-
Monitoring of Plasma Glucose (SMPG) as specified in the study flow-chart 
and the protocol. SMPG readings will be used to guide insulin dose- titration 
for optimal glycemic control and the SMPG profiles will be collected for 
efficacy analyses.  
Appropriate dose titration of basal and mealtime insulin will be implemented 
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Amended Clinical Trial Protocol No. 01 
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Page 4 
as outlined in the dose regimen section. Titration of basal insulin will be 
allowed until Week14 of the study after which, the Toujeo/Lantus dose should 
remain unchanged during the period of the CGM collection (Week 15 or 16), 
while meal-time insulin dose can still be adjusted as appropriate. 
During Week15, patients will wear a blinded CGM device for 7 consecutive 
days to generate a minimum of 4 days of useable CGM data. If a patient fails 
the first attempt for any reason, he/she will be retrained for CGM conduct and 
complete another week of blinded CGM data collection during Week 16. 
At the end of the study, the patients will be followed-up within 2 (+2) days to 
collect post treatment safety information. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
x
Adult patients (male and female) with type 1 diabetes mellitus
x
Signed written informed consent
Exclusion criteria: 
x
Age <18 years or >70 years;
x
Fasting c-peptide 0.3nmol/l as per source document or central lab
test at Visit 1,
x
HbA1c 6.5% or 10.0% via central lab test at Visit 1,
x
Patients who experienced none episode of documented
symptomatic and/or severe hypoglycemia (as per the ADA
classification) during the past month prior to screening,
x
Patients who experienced >1 episode of severe hypoglycemia
resulting in coma/seizures during the last 12 months before
screening,
x
Patients receiving less than 1 year treatment with basal plus
mealtime insulin,
x
Using any basal  insulins other than long acting-insulin analogs (i.e.
Lantus, Toujeo, Levemir or Tresiba) in the past 3 months before
screening,
x
Requiring  >80 U/day basal insulin analogs and/or not on stable
dose (± 20% total dose)  within 30 days prior to screening,
x
Using fewer than 2 injections of rapid-acting insulin analog per day
within 30 days prior to screening,
x
Using human regular insulin as mealtime insulin within 30 days prior
to screening
x
Using an insulin pump during the last 6 months before screening,
x
History of unstable proliferative diabetic retinopathy  or any other
rapidly progressive diabetic retinopathy or macular edema likely to
require treatment (eg, laser, surgical treatment or injectable drugs)
during the study period,
x
Pregnant or breast-feeding women or planning pregnancy during
the duration of the study,
x
Use of any other investigational drug(s) within 1 month or 5 half-
lives, whichever is longer prior to screening,
x
Inappropriate CGM use during screening period evidenced by
failure to obtain a minimum of 4 days of usable records by the end
of screening,
x
Non-compliance with SMPG performance evidenced by failure to
demonstrate at least 5 days of 5-point SMPG records by the end of
screening.
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Page 5 
Total expected number of patients 
Approximately 616 patients randomized, aiming for approximately 
524 patients with evaluable data. 
Approximately 100 study sites. 
STUDY TREATMENT(s) 
Tested drug: Toujeo (HOE901-U300) 
Control drug: Lantus (HOE901-U100) 
Investigational medicinal 
product(s) 
 
 
Formulation: 
Testing drug: Toujeo (Insulin glargine -U300) 
Toujeo will be supplied for subcutaneous (SC) injection as a sterile, non-
pyrogenic, clear, colorless solution in a 1.5 mL Toujeo SoloStar disposable 
prefilled pen (450 Units/1.5 mL). 
Application of the drug is done using an injection pen device allowing dose 
setting in the range of 1-80 U with 1 U increment.  
Mixing of Toujeo with other insulins is not allowed nor dilution. 
Control drug: Lantus (Insulin glargine-U100) 
Lantus will be supplied for SC injection 100 U/mL in 3 mL cartridges 
assembled in a pen-injector. Lantus SoloStar prefilled (disposable) pen will be 
used for this study. 
The disposable SoloStar pen-injector allows for a dose setting in the range of 
1-80 U with minimum dose increment of 1 U. 
Mixing of Lantus with other insulins is not allowed nor dilution.  
Route(s) of administration: 
Subcutaneous injection. 
Dose regimen: 
Toujeo and Lantus will be self-administered by SC injection once daily in the 
morning, which is defined as the time period between waking up and pre-
breakfast. The clock time for the morning injection (hh:mm) will be established 
at the discretion of the patient/investigator at the time of randomization and 
will be maintained for the duration of the study. 
x 
On the randomization day (Day 1), the initiation dose of glargine (Toujeo 
and Lantus) is the patient’s current dose of their basal-insulin analogs.   
For patients taking the basal insulin in any time other than morning 
injection previously, they should switch the dosing time to morning 
injection during screening period. 
x 
 During the treatment period, dose of Toujeo and Lantus) will be titrated 
in dose steps outlined in the table below to achieve glycemic target and 
minimize the potential risk of hypoglycemia.  
x 
The target range for fasting SMPG is 80–100 mg/dL (4.4-5.6 mmol/L). 
x 
Dose adjustment for insulin glargine is based on the mean fasting (pre-
breakfast/pre-injection) SMPG values of the last 3 days without related  
hypoglycemia. 
x 
For each titration step, the insulin dose increment should not exceed 
10% of the existing glargine daily dose, irrespective of the mean fasting 
SMPG values, eg, for a daily dose of 30 U, the increment should be 3 U 
if the mean fasting SMPG is >120 mg/dl.  
x 
Titration of insulin glargine will be continued until the end of Week 14, 
after which patients will maintain a stable dose during the endpoint for 
blinded CGM collection (Weeks 15-16) except for dose reduction in the 
case of safety reasons ( eg, basal insulin related severe hypoglycemia).   
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a Prior to additional basal insulin titration, mealtime insulin should be titrated 
to achieve a bedtime and pre-breakfast glucose delta <50 mg/dL. 
Mean fasting SMPG values  
(last 3 days) 
Insulin Glargine (U-100 or U-300) 
dose adjustments (U/day) a 
120  (> 6.7 mmol/L) 
+ 4 Units, or split to 2x2 U
100 and 120 mg/dL (>5.6 and 
6.7 mmol/L) 
+ 2 Units, or split to 2x1 U
Glycemic target: mean fasting SMPG 
between 80 – 100 mg/dL 
80 and 100 mg/dL (4.4 and 
5.6 mmol/L), inclusive 
No change 
60 and <80 mg/dL (3.3 and 
<4.4 mmol/L) 
-2 Units
<60 mg/dL (3.3 mmol/L) or occurrence 
of 2 (or more) symptomatic 
hypoglycemic episodes or one severe 
hypoglycemic episode 
-4 Units or at the discretion of the
investigator or medically qualified
designee
Noninvestigational medicinal 
product(s) (if applicable) 
Formulation: 
Patients in both treatment groups will continue with their current rapid-acting 
insulin analog (eg, insulin glulisine, insulin lispro or insulin aspart) during the 
study. 
Solution for subcutaneous injection. 
Route(s) of administration: 
Subcutaneous injection. 
Dose regimen: 
x
Patients will continue on their existing mealtime insulin (rapid-acting
insulin analog) regimen at randomization.
x
The injection time and frequency of rapid-acting insulin will be at
investigator’s discretion in accordance with the prescribing information.
x
During the treatment period, the doses of the mealtime insulin analog
should be actively titrated to achieve and maintain the 2-hour
postprandial SMPG in the range 130-180 mg/dL (7.2-10 mmol/L).
x
Dose adjustment of mealtime insulin will be allowed throughout the
16 weeks of treatment period, including the endpoint period for blinded
CGM collection (Week 15-6) with the fixed doses of insulin glargine
x
Dose adjustment of mealtime insulin can be based on a pattern of post-
meal SMPG data from the prior 3 days (simple titration) OR the
carbohydrate content of the meal; both the recommended regimens are
outlined below
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Amended Clinical Trial Protocol No. 01  
02-Aug-2016 
LPS14587 - insulin glargine 
Version number: 1 
Property of the Sanofi Group- strictly confidential 
Page 7 
 
Simple titration: Titration of mealtime insulin based on a pattern of post-meal 
glucose median 130 </>180 mg/dl in the prior 3 days using the table below  
Mealtime dose 
of Insulin 
Pattern of 
Postprandial BG 
values 
<130 mg/dLa 
Postprandial BG 
values 
>180 mg/dLa 
10 Units 
Decrease dose by 1 Unit 
Increase dose by 
1 Unit 
11-19 Units 
Decrease dose by 
2 Units 
Increase dose by 
2 Units 
20 Units 
Decrease dose by 
3 Units 
Increase dose by 
3 Units 
a If more than one-half of the mealtime blood glucose (2-hours PPG) values 
for the week were above target. 
OR 
Carb counting: (insulin-to-carbohydrate ratio) group 
Starting recommendation 1 unit to 15 grams carbs 
Consider calculating insulin to carb (I:C) ratio = 500 / total daily dose (TDD) of 
insulin. 
Mealtime dose 
of Insulin 
Pattern of 
Postprandial BG 
values <130 mg/dLa 
Pattern of 
Postprandial 
BG values 
>180 mg/dLa 
1 unit/20 g 
Decrease to 1 unit/25 g 
Increase to 
1 unit/15 g 
1 unit/15 g 
Decrease to 1 unit/20 g 
Increase to 
1 unit/10 g 
1 unit/10 g 
Decrease to 1 unit/15 g 
Increase to 
2 unit/15 g 
2 unit/15 g 
Decrease to 1 unit/10 g 
Increase to 
3 unit/15 g 
3 unit/15 g 
Decrease to 2 unit/15 g 
Increase to 
4 unit/15 g 
a If more than one-half of the mealtime blood glucose values for the prior 
3 days were above target. 
Correction dose: Investigators will be provided an initial guideline of 
1800/TDD as a correction factor, if applicable, in addition to investigator 
directed change in correction factor based on glucose patterns. 
(electronic 
 
 
 
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Page 8 
ENDPOINT(S) 
Primary endpoint:  
x
Percentage (%) of time plasma glucose in target range of
70-180 mg/dL (3.9-10 mmol/L) during Weeks 15-16, obtained from
CGM.
Secondary endpoint(s): 
x
Incidence and rate of nocturnal symptomatic hypoglycemia, defined
as an event with typical symptoms of hypoglycemia accompanied
by SMPG 70 mg/dL (3.9 mmol/L) that occurs between 00:00 and
05.59 hours.
x
Percentage (%) of time glucose concentrations obtained by  CGM
within target range  of 70-140 mg/dL (3.9-7.8 mmol/L) during the
last 4 hours of CGM data collection prior to next day basal insulin
injection.
x
Total, within day and between day coefficient of variation in glucose
obtained from CGM.
Other endpoints: 
x
Frequency and distribution (nocturnal or 24 hours) of all
hypoglycemia events analyzed by hypoglycemia categories (severe,
documented symptomatic, asymptomatic, probable and relative) as
defined in the publication ADA Workgroup on Hypoglycemia, 2015.
x
Additional CGM Endpoints (data obtained during Week 15-16) :
-
Percentage (%) of time glucose concentrations within the
target range  of 70-140 mg/dL (3.9-7.8 mmol/L)  analyses
on all- time  (24 hours) CGM data,
-
Percentage (%) of time glucose concentrations 70 mg/dL
(3.9 mmol/L) and <54 mg/dL (3 mmol/L)  analyses on both
all-time (24 hours) and nocturnal (00:00–05:59 hours) CGM
data,
-
Percentage (%) of time glucose >140 mg/dL (7.8 mmol/L),
>180 mg/dL(10 mmol/L) and > 250 mg/dL (13.9 mmol/l) 
analyses on both all-time (24h) and nocturnal (00:00–
05:59 hours) CGM data,
-
Total, within day and between day coefficient of variation in
glucose concentrations
-
Area under the glucose curve (AUC) of glucose concentration
70 mg/dL (3.9 mmol/L)
-
AUC of glucose concentration >180  mg/dL( 10 mmol/L)
x
7-point SMPG profiles (pre-prandial and 2-hour postprandial plasma
glucose at breakfast, lunch and dinner, and bedtime);
x
Change from baseline to study endpoint in HbA1c
x
Change from baseline to treatment endpoint in central lab FPG
x
Insulin dose (total, basal, mealtime/bolus, ratio of basal to bolus
insulin dose)
Safety: 
Evaluation of injection site reactions, hypersensitivity reactions, adverse 
events, serious adverse events (including hypoglycemic episodes associated 
with seizures, coma or unconsciousness etc) and vital signs. 
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Page 9 
ASSESSMENT SCHEDULE 
The schedule of study-related procedures/assessments is detailed in the 
Study Flowchart. 
The study design and visit schedule is detailed in study flowchart Section 1.1. 
STATISTICAL CONSIDERATIONS 
Sample size determination: 
A sample size of 262 evaluable patients per treatment arm would provide at 
least 90% power to demonstrate superiority of Toujeo over Lantus in the 
percentage of time plasma glucose within the range of 70-180 mg/dL, using a 
2-sided test with an Į-level of 0.05.This is assuming an absolute difference of
at least 4%, a standard deviation of 14%, and an expected value of 53% in
the Lantus arm.
This sample size would also provide at least 80% power to demonstrate a 
difference in the rate of documented symptomatic nocturnal hypoglycemia 
occurring at any point post randomization, assuming a rate ratio (Toujeo over 
Lantus) of at most 0.86 events per pt-year.  
Analysis population: 
Efficacy analyses will be performed on the modified Intent-to-Treat (mITT) 
population, which will comprise of all patients who are randomized and who 
have at least one post-baseline assessment for the endpoint of interest. 
Safety analyses will be performed on the safety population, which will 
comprise of all patients who receive at least one dose of study treatment. 
Primary analysis: 
The percentage of time glucose in target range 70-180mg/dL (3.9–10mmol/l) 
during weeks 15-16 (obtained from CGM) will be calculated based from the 
denominator of total time with valid data. The percentages will be summarized 
and analyzed for differences between treatment groups using a generalized 
linear model, adjusting for key baseline characteristics (duration of diabetes, 
BMI, age and baseline value) and randomization strata. 
Analysis of secondary endpoints: 
Continuous CGM endpoints will be analyzed using a generalized linear model 
as described for the primary endpoint.  
The change in HbA1c (and FPG) from baseline to endpoint will be analyzed 
using a mixed-effect model with repeated measures (MMRM) approach under 
the missing at random framework, using an adequate contrast at endpoint. 
The model will include fixed categorical effects of treatment arm, visit, 
treatment-by-visit interaction, randomization strata, and baseline HbA1c as 
covariate as well as baseline HbA1c-by-visit interaction. 
Other categorical CGM endpoints will be analyzed using the Chi-square or 
Cochran-Mantel-Haenszel test, including randomization strata. Fisher’s Exact 
test will be employed if required. 
The incidence of hypoglycemia will be analyzed using logistic regression, 
adjusting for randomization strata and other baseline characteristics (duration 
of diabetes, BMI and age) as clinically appropriate and if the model permits. 
The rate per patient-year of hypoglycemic events will be analyzed using an 
over-dispersed Poisson regression model, adjusting for randomization strata 
and other baseline characteristics (duration of diabetes, BMI and age) as 
clinically appropriate and if the model permits. 
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02-Aug-2016 
LPS14587 - insulin glargine 
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Page 10 
DURATION OF STUDY PERIOD (per 
patient)  
The study duration consists of: 
x 
Up to 4-week screening and training period including 1-2-week 
CGM performance (allow for re-training); 
x 
14-week open-label, comparative treatment period allowing for dose 
titration in both basal and meal-time insulin; 
x 
1-2 week blinded CGM collection with fixed dose of Toujeo or 
Lantus, 
x 
2 days of post-treatment safety follow-up period after treatment 
completion or premature discontinuation of study treatment. 
The maximum study duration per patient will be around 20 weeks. 
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Page 11 
1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
V 1 
V2
V3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
-3-1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
-w k4
Toujeo®  (n = 308)
L antus®  ( n = 308)
Screening  Visits
R and om ization  
  Ph one Visit 
   On -site Visit
* Training for CGM  and SM PG perform ance, including 1 week blind baseline  C GM  between V2 and V3 for patients to dem onstrate the
C GM  com pliance   prior to random ization
** O pen-Label treatm ent including insulin titration for both basal and bolus for 14 weeks
*** 1-week blind C GM  with fixed insulin dose (no titration in basal insulin); it can be extended for one m ore week in case of failure in
C GM  perform ance
Insulin titration (basal + bolus)
EOT
V1
Follow -up 
2+2 days
C GM
1- wk
***
O pen-Label Treatment 16 w eeks**
Screening  
4 weeks*
Fixed
dose












R

R
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1.2 
STUDY FLOW CHART 
Screening and 
training  
Treatment Period (15-16 weeks) 
Follow up 
Visit  
Windows: Visit 4 - 19: ± 3 days 
1 
2 * 
3  
4a 

5a 

6a 

7  
8 a 

9a 

10a 

11  
12a 

13a 

14a 

15  
16 a 

17a 

18b  
19  
20a 

Week 
-4 
-3 -1
 (R) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
2+2 days 
Informed consent 
X 
Inclusion/Exclusion criteria 
X 
X 
X
Medical and surgical history; diabetes history 
X 
Physical examination, including neuropathy 
screening 
X 
Vital signsc  and Body weight 
X 
X
X
X
X
X
Height 
X 
Dispensation/collection of study diary 
X 
X 
X
X
X
X
X 
X
Dispensation of study medication 
X
X
X
X
IMP compliance Check; collecting and counting 
used and unused pens 
 
X
X
X
X 
X
IVRS call 
X 
X
X
X
X
X
Randomization 
X
Documentation and review of basal and bolus 
insulin dose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Change from BID to QD basal insulin injection 
(if applicable) 
X 
CGM, SMPG: 
Training and re-training: Glucometer, SMPG 
profiles, study diary  
X 
X 
X
X
X 
 
X 
X 
Dispensation glucometer, 
X 
Dispensation CGM device; Blinded CGMd 
X 
 
X 
Upload CGM to PC 
X
X
Collect CGM device 
X
X
SMPGe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
Upload SMPG to PC  
X 
X
X
X
X
X 
X
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Central Laboratory 
HbA1c,  Fasting plasma glucose (FPG) 
X 
 
X
X
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Page 13 
Screening and 
training  
Treatment Period (15-16 weeks) 
Follow up 
Visit  
Windows: Visit 4 - 19: ± 3 days 
1 
2 * 
3  
4a 

5a 

6a 

7  
8 a 

9a 

10a 

11  
12a 

13a 

14a 

15  
16 a 

17a 

18b  
19  
20a 

Week 
-4 
-3 -1
 (R) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
2+2 days 
C-peptidef
X 
Safety Laboratory 
Hematologyg, Clinical Chemistryh 
X 
Urine analysisi 
X 
Pregnancy test (WOCBP only)j 
X 
X
X
X
X
X
AE / SAE 
To be assessed and reported (if any) throughout the study (report SAE to the sponsor within 24 hours) 
Injection site reactions, hypersensitivity 
reactions 
To be assessed and reported (if any) throughout the study 
Hypoglycemia recording 
To be assessed and reported (if any) throughout the study 
* additional screening visits may be needed for patients  who cannot handle CGMS at home in order to generate 4 days of useable CGMS data prior to randomization.
a Telephone visit; Note: Telephone counseling will be available at any time as required.
b Or early termination visit. Patients who failed to provide 4 days of usable CGM data will be retrained and will  repeat the blinded CGM course.
c Heart rate and blood pressure (sitting position)
d If a patient fails the first attempt for any reason, he/she will be retrained for CGM conduct and complete another course of blinded CGM.
e SMPG to be performed by trial patients after Visit 1 and throughout the study duration:
1.
Fasting (prebreakfast/preinjection) SMPG: daily until dose optimization has been completed and fasting SMPG goal is reached. Thereafter, the number of fasting SMPG checks can be reduced according to
the investigator’s judgment, however at least 3 fasting (prebreakfast) SMPG measurements per week should be done.
Note: after randomization, the pre-breakfast SMPG (including in 5-point and 7-point SMPG profiles) should follow the time window for Pre-injection plasma glucose
2.
Pre-injection SMPG (within 30 min prior to injection of Toujeo or Lantus before breakfast) during the 16-week treatment period: at least on 5 days per week during the week prior to each on-site visit after
randomization (Visit 7, 11, 15 and 19) )  and the SMPG  value must be assigned by the patient in the diary
3.
5-point SMPG profile (prebreakfast, prelunch, predinner and 2-hour post a main meal or follow the investigator’s instruction and bedtime): at least on 5 days per week throughout the study, starting
after Visit 1. Patients should test their 2-hour post meal SMPG after main meals (e.g. lunch or dinner) or follow the investigator’s instructions for meal-time insulin titration. Once the titration goal
is reached (fasting and 2-hours postprandial SMPG stable in the target range), the number of 5-point SMPG profiles can be reduced according to the investigator’s judgment but 5-point SMPG profiles at
least on 3 days in the weeks that the5-point  SMPG data are collected (section 10.2.3.2) are mandatory.
4.
7-point SMPG profile (before and 2 hours after breakfast, lunch and dinner, and bedtime): at least ONE day during the weeks prior to  Visit 3, 15 and 19
f 
Only for patients without documented test results to assess the relevant exclusions  
g Hematology: erythrocytes, hemoglobin, hematocrit, leukocytes and platelets 
h 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, potassium 
i 
Urine analysis: pH, glucose, ketones, leucocytes, blood/hemoglobin, protein 
j 
For women of childbearing potential (WOCBP): serum pregnancy test for screening; urine pregnancy test for subsequent monitoring and if needed, it can be confirmed by a serum test.  
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TABLE OF CONTENTS 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART ..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................14 
3 
LIST OF ABBREVIATIONS ..........................................................................................................19 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
5 
STUDY OBJECTIVES ...................................................................................................................22 
5.1 
PRIMARY.......................................................................................................................................22 
5.2 
SECONDARY ................................................................................................................................22 
6 
STUDY DESIGN ............................................................................................................................23 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................23 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................24 
6.2.1 
Duration of study participation for each patient .............................................................................24 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................24 
6.3 
INTERIM ANALYSIS......................................................................................................................24 
7 
SELECTION OF PATIENTS..........................................................................................................25 
7.1 
INCLUSION CRITERIA..................................................................................................................25 
7.2 
EXCLUSION CRITERIA ................................................................................................................25 
7.2.1 
Exclusion criteria related to study methodology ............................................................................25 
7.2.2 
Exclusion criteria related to diabetes history and treatment..........................................................26 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................27 
7.2.4 
Additional exclusion criteria during or at the end of screening before randomization ...................27 
8 
STUDY TREATMENTS .................................................................................................................28 
8.1 
DIET AND EXERCISE ...................................................................................................................28 
8.2 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................28 
8.2.1 
Pharmaceutical formulation of the investigational medicinal product............................................28 
8.2.2 
Route and method of IMP administration.......................................................................................29 
8.2.2.1 
Toujeo (insulin glargine 300 U/mL solution) ..................................................................................29 
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8.2.2.2 
Lantus (insulin glargine 100 U/mL solution)...................................................................................30 
8.2.3 
Timing of IMP administration .........................................................................................................30 
8.2.3.1 
Changing injection time during screening period...........................................................................30 
8.2.4 
Starting dose of IMP.......................................................................................................................31 
8.2.5 
Adjustment of IMP..........................................................................................................................31 
8.2.6 
Evaluation of patients not meeting glycemic targets......................................................................33 
8.3 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................................33 
8.3.1 
Adjustment of NIMP .......................................................................................................................33 
8.4 
BLINDING PROCEDURES............................................................................................................35 
8.4.1 
Compensation for lack of blinding..................................................................................................35 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................35 
8.6 
PACKAGING AND LABELING ......................................................................................................36 
8.7 
STORAGE CONDITIONS AND SHELF LIFE................................................................................36 
8.8 
RESPONSIBILITIES ......................................................................................................................36 
8.8.1 
Treatment accountability and compliance......................................................................................37 
8.8.2 
Return and/or destruction of treatments ........................................................................................37 
8.8.2.1 
IMP (Toujeo or Lantus) ..................................................................................................................37 
8.8.2.2 
NIMP (mealtime insulin analogs) ...................................................................................................38 
8.9 
CONCOMITANT MEDICATION.....................................................................................................38 
8.9.1 
Prohibited medication during the study..........................................................................................38 
8.10 
POSTSTUDY TREATMENT..........................................................................................................39 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................40 
9.1 
PRIMARY ENDPOINT ...................................................................................................................40 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................40 
9.3 
OTHER EFFICACY ENDPOINTS..................................................................................................41 
9.3.1 
Hypoglycemia.................................................................................................................................41 
9.3.1.1 
Hypoglycemia classification ...........................................................................................................41 
9.3.1.2 
Hypoglycemia analyses .................................................................................................................42 
9.3.2 
Safety endpoints ............................................................................................................................43 
9.3.2.1 
Adverse events, serious adverse events .......................................................................................43 
9.3.2.2 
Vital signs.......................................................................................................................................43 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................43 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................44 
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10 
STUDY PROCEDURES ................................................................................................................45 
10.1 
VISIT SCHEDULE..........................................................................................................................45 
10.1.1 
Screening and Training Visits (Visit 1 and Visit 2).........................................................................45 
10.1.1.1 Visit 1 (Week -4).............................................................................................................................46 
10.1.1.2 Visit 2 (Week -3).............................................................................................................................47 
10.1.2 
Randomization Visit (Visit 3, Day 1/Week 0) .................................................................................47 
10.1.3 
Phone call Visits (V4-6, V8-10, V12-14 and V16-17).....................................................................48 
10.1.4 
Onsite Visits (V7, V11, V15 and V18) during treatment period .....................................................49 
10.1.5 
End of Treatment (EOT) visit (Visit19, Week 16)...........................................................................50 
10.1.6 
Follow-up Visit (Visit 20) ................................................................................................................51 
10.2 
ASSESSMENT METHODS ...........................................................................................................51 
10.2.1 
Vital signs.......................................................................................................................................51 
10.2.2 
Height and body weight .................................................................................................................52 
10.2.3 
Self-monitoring blood glucose (SMPG)..........................................................................................52 
10.2.3.1 SMPG performance .......................................................................................................................52 
10.2.3.2 Recording SMPG data and insulin dose........................................................................................54 
10.2.4 
Continuous glucose monitoring (CGM) related procedures...........................................................55 
10.2.4.1 CGM performance..........................................................................................................................55 
10.2.4.2 CGM qualification and data transfer ..............................................................................................56 
10.2.5 
Laboratory......................................................................................................................................57 
10.3 
DEFINITION OF SOURCE DATA..................................................................................................57 
10.3.1 
Source data to be found in patient´s file ........................................................................................57 
10.3.2 
Source data verification requirements for screen failures .............................................................58 
10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................58 
10.4.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................58 
10.4.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................59 
10.4.3 
List of criteria for permanent treatment discontinuation.................................................................59 
10.4.4 
Handling of patients after permanent treatment discontinuation ...................................................59 
10.4.5 
Procedure and consequence for patient withdrawal from study....................................................60 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................61 
10.5.1 
Definitions of adverse events.........................................................................................................61 
10.5.1.1 Adverse event ................................................................................................................................61 
10.5.1.2 Serious adverse event ...................................................................................................................61 
10.5.1.3 Adverse event of special interest...................................................................................................62 
10.5.2 
General guidelines for reporting adverse events ...........................................................................62 
10.5.3 
Instructions for reporting serious adverse events ..........................................................................63 
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10.5.4 
Guidelines for reporting adverse events of special interest...........................................................64 
10.5.4.1 Reporting of adverse events of special interest with immediate notification .................................64 
10.5.4.2 Reporting of adverse events of special interest without immediate notification ............................64 
10.6 
OBLIGATIONS OF THE SPONSOR .............................................................................................64 
10.7 
SAFETY INSTRUCTIONS .............................................................................................................65 
10.8 
ADVERSE EVENTS MONITORING..............................................................................................65 
11 
STATISTICAL CONSIDERATIONS..............................................................................................66 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................66 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................66 
11.3 
ANALYSIS POPULATIONS...........................................................................................................67 
11.3.1 
Efficacy populations .......................................................................................................................67 
11.3.1.1 Modified intent-to-treat population .................................................................................................67 
11.3.2 
Safety population ...........................................................................................................................67 
11.4 
STATISTICAL METHODS .............................................................................................................67 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................67 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................67 
11.4.1.2 Compliance ....................................................................................................................................68 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................68 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................68 
11.4.2.2 Analysis of secondary efficacy endpoint(s)....................................................................................68 
11.4.2.3 Multiplicity considerations ..............................................................................................................70 
11.4.3 
Analyses of safety data..................................................................................................................70 
11.5 
INTERIM ANALYSIS......................................................................................................................71 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................72 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................72 
12.2 
INFORMED CONSENT .................................................................................................................72 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............72 
13 
STUDY MONITORING...................................................................................................................74 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................74 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................74 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................74 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................75 
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13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................75 
14 
ADDITIONAL REQUIREMENTS...................................................................................................76 
14.1 
CURRICULUM VITAE....................................................................................................................76 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................76 
14.3 
CONFIDENTIALITY .......................................................................................................................76 
14.4 
PROPERTY RIGHTS.....................................................................................................................77 
14.5 
DATA PROTECTION.....................................................................................................................77 
14.6 
INSURANCE COMPENSATION....................................................................................................77 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................78 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................78 
14.8.1 
By the Sponsor...............................................................................................................................78 
14.8.2 
By the Investigator .........................................................................................................................79 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................79 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................79 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................80 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................81 
17 
APPENDICES................................................................................................................................82 
APPENDIX A 
USER GUIDE FOR DEXCOM G4 PLATINUM PROFESSIONAL MODEL.........................82 
APPENDIX B 
INSTRUCTION FOR TOUJEO® SOLOSTAR® INJECTION..............................................84 
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3 
LIST OF ABBREVIATIONS 
AE:
adverse event
AESI: 
adverse event of special interest 
ALP:
alkaline phosphatase
ALT:
alanine aminotransferase
AST:
aspartate aminotransferases
CGM: 
continuous glucose monitoring 
DBP: 
diastolic blood pressure 
DRF: 
discrepancy resolution form 
e-CRF:
electronic case report form 
FPG:
fasting plasma glucose
GCP:
good clinical practice 
GFR:
estimated glomerular filtration rate 
HbA1c:
glycated hemoglobin A1c 
HGLT:
high group level term 
HLT:
high level term 
ICH:
International Conference for Harmonisation 
IEC:
independent ethics committee
IMP:
investigational medicinal product 
IRB:
institutional review board 
IVRS:
interactive voice response system 
IWRS:
interactive web response system 
LLT:
lower level term 
MedDRA:
Medical Dictionary for Regulatory Activities 
mITT:
modified Intent-to-Treat
NIMP:
non-investigational medicinal product 
NPH:
neutral protamine Hagedorn 
PT:
preferred term
PTC:
product technical complaint 
RR:
rate ratio
SBP:
systolic blood pressure 
SC:
subcutaneous
SMPG:
self-monitoring plasma glucose
SOC:
system organ class 
USPI:
United States package insert  
WOCBP:
women of childbearing potential 
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4 
INTRODUCTION AND RATIONALE 
Insulin glargine (HOE901) is a recombinant analog of human insulin providing a 24-hour (h) 
basal insulin supply after a single-dose subcutaneous (SC) injection. Insulin glargine U100/mL 
formulation has been marketed as Lantus for 15 years (1). Its efficacy and safety are well-known 
through extensive data collection involving over 100 000 patients in clinical studies, including 
randomized, controlled clinical trials and the results of postmarketing surveillance arising from 
approximately 30 million patient-years of clinical experience.  
HOE901-U300 has the same composition as the current Lantus formulation 100 U/mL with 
adjustment of 3-times the amount of active pharmaceutical ingredient (insulin glargine) and 
corresponding zinc content and is also approved as Toujeo for once daily injection (2).   
Further information on Lantus and Toujeo, including important clinical trials performed pre and 
post-registration, can be found in the national product labels and Investigator´s Brochure HOE901 
(3). 
As evidenced in previous euglycemic clamp studies (PKD10086, PKD11627 and TDR11626) 
after a single dose or multiple doses in healthy subjects or patients with Type 1 diabetes (T1DM), 
there are differences between Lantus and Toujeo in Pharmacokinetics (PK) and 
Pharmacodynamics (PD) profiles (3). In those euglycemic clamp studies, Glargine -U300 (Gla-
U300), as compared to glargine-U100 (Gla-U100), showed less variability to the average 
concentration, displayed a flatter PK profile, and correspondingly less fluctuation in the glucose 
lowering activity. Given these features of the PK/PD profiles, Toujeo is considered to be well 
suitable for constant, peak less 24-hour basal insulin supply in diabetes management, with the 
expectation of less hypoglycemic risk at equal to tighter blood glucose control.  
Clinical implication of Toujeo in management of type 1 diabetes was investigated in clinical 
studies in patients with T1DM. The EDITION-4 phase 3 trial in patients with T1DM showed 
similar therapeutic efficacy between Gla-300 and Gla-100 with respect to glucose lowering, while 
a slightly lower risk of hypoglycemia was observed for Gla-300 (4). PDY12777 was a small-scale 
(59 patients divided into 4-treatment arms) exploratory study using continuous glucose 
monitoring system (CGM), which provided sufficient data for diurnal glucose patterns associated 
with Gla-U300 or Gla-U100 treatment. CGM analysis in participants with T1DM showed better 
glucose stability and lower intra-patient glucose variability with Gla-U300 than Gla-100.  These 
differences were more evident with the morning injection regimen. Moreover, the incidence of 
confirmed or severe hypoglycemic events was numerically lower with Gla-300 than with Gla-100.  
However, neither of the two studies was sufficiently powered to demonstrate reduced rates of 
hypoglycemia with Gla-300.  
The present study LPS14587 is designed to further explore differences between Toujeo and 
Lantus with the hypothesis that Toujeo, compared to Lantus, given as the basal insulin to patients 
with T1DM will provide a better continuous glucose profile with less, in particular nocturnal 
hypoglycemia while the conventional glycemic control as measured by HbA1c is anticipated to be 
similar between the two treatments.  
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This is a randomized, active-controlled, 16-week open-label study to  compare the efficacy of 
Toujeo with Lantus using  CGM glucose profiles, sampling ambulatory glucose level every 
5-minutes over at least 7 days at baseline and at endpoint (Week 15 or 16). CGM during screening 
and end of study period (Week 15 or 16) will be blinded to both the investigators and patients.  
Eligible patients will be randomized to either Toujeo or Lantus, both given once-daily by 
subcutaneous (sc) injection in the morning. Patients will be required to titrate their basal and 
meal-time insulin to achieve the fasting and 2-hours post-prandial SMPG targets during the first 
15 weeks of treatment. The CGM will then be performed during Week 15 or 16 during which 
period, basal insulin doses will be stable without changes. 
The primary objective of the study is to demonstrate a greater percent of time in target CGM 
glucose range of 70-180 mg/dL with Toujeo than Lantus treatment. The main secondary objective 
is to evaluate the incidence and rate of hypoglycemia and possibly to show a lower rate of 
documented nocturnal symptomatic hypoglycemia with Toujeo versus Lantus.  In addition, all 
hypoglycemia incidence and distribution (24 hours and nocturnal) will be analyzed according to 
the ADA classification (severe, documented symptomatic, asymptomatic, probable and relative) 
(5). Glucose stability and variability will be assessed between and within each group via 
measurements of diurnal glucose exposure, rate of change in median curve, interquartile range 
(IQR), mean and variation in glucose profiles, etc (6, 7). 
A relatively homogenous patient population will be selected, reducing potential confounding 
effects, so that the true differences in the therapeutic effects of Toujeo versus Lantus can be 
assessed. The study population includes patients 18-70 years of age with T1DM, on a basal plus 
mealtime insulin regimen for at least 1 year, and glycated hemoglobin A1c (HbA1c) level >6.5 
and < 10%. Lack of endogenous insulin production (C-peptide) is required to confirm type 1 
diabetes (8).  Patients must be on a stable dose of long-acting insulin analog basal/bolus regimen 
for 3 months before study entry. Furthermore, the number of prior hypoglycemia episodes is 
specified to include patients with known hypoglycemia that may benefit more from treatment with 
Toujeo.  
Approximately 616 patients will be enrolled aiming for at least 524 (85%) evaluable patients, 
which will provide over 90% statistical power to demonstrate superiority with 4% margin of 
Toujeo over Lantus for the primary endpoint analysis. The 4% difference in the percentage of 
time glucose within the target range of 70-180 mg/dL is considered clinically relevant given the 
assumption that the HbA1c will be similar between the two treatments.  
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this Phase 4 clinical study is to demonstrate that morning injection of 
Toujeo compared to Lantus will provide better glycemic control evaluated by Continuous Glucose 
Monitoring (CGM) in adult patients with type 1 diabetes mellitus.  
5.2 
SECONDARY 
The study is also aimed to demonstrate that treatment with Toujeo compared to Lantus will 
provide: 
x
lower incidence and rate of nocturnal symptomatic hypoglycemia
x
better glucose control coverage during the last hours of CGM before next basal-insulin
dosing
x
less variability in CGM profile
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
LPS14587 is a multicenter, randomized, active-controlled, parallel group, 16-week open-label 
study. The study is a postmarketing Phase 4 trial which will recruit outpatients with type 1 
diabetes mellitus who have been on basal plus mealtime insulin regimen for at least one year and 
currently taking a long-acting insulin analog (ie, Lantus, Toujeo, Levemir or Tresiba) plus rapid-
acting insulin analogs to manage their diabetes.  
This is a comparative study of Toujeo versus Lantus and the comparator is Lantus.  The study has 
an open-label design, as the injection volume of the concentrated formulation of Toujeo (glargine-
U300 is distinguishable from that of the Lantus (glargine-U100) formulation of insulin glargine. 
The study will be conducted in the United States with approximately 100 participating sites. It’s 
planned to recruit 616 patients in two parallel treatment groups: 
x 
Toujeo  group, n=308 patients 
x 
Lantus group, n=308 patients 
The study consists of an up to 4-week screening and CGM training period and a 16-week 
treatment period. Blinded CGM (blinded to both patients and investigators) will be conducted 
during the weeks of the end of screening (Week -2 to 0) and end of treatment (Week 15 to 16). 
The CGM data will be collected for efficacy analyses.   
During the screening and baseline training period, patients will wear a blinded CGM device for 
7 consecutive days to generate a minimum of 4 days of usable CGM data to be eligible for 
randomization. Patients satisfying the inclusion/exclusion criteria and CGM requirements will be 
randomized  1:1 to morning injection of either Toujeo or Lantus.  The randomization will be 
stratified by baseline HbA1c (<8, 8), frequency of basal insulin injections BID vs QD at Visit 1, 
current CGM use (yes/no)  at Visit 1 and mealtime insulin titration algorithm.  
The protocol-mandated background therapy is mealtime insulin analogs, ie, rapid insulin analogs 
(eg, insulin glulisine, insulin lispro or insulin aspart), which has been used for at least 30 days 
before screening visit and which will be continued throughout the study.  Any other glycemic 
lowering medications or other types of basal/bolus insulin are prohibited in this study.  
Appropriate dose titration of basal and mealtime insulin will be conducted as specified in 
Section 8. Titration of basal insulin will be allowed until the end of week 14, after which, 
Toujeo/Lantus dose should remain unchanged during Week 15-16 for blinded CGM collection, 
while meal-time insulin dose can still be appropriately adjusted.  
During the entire study starting after screening, patients will perform Self-Monitoring of Plasma 
Glucose (SMPG) which is specified in Section 1.2 and Section 10.2.3.  SMPG readings will be 
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used to guide insulin dose-titration for optimal glycemic control and the SMPG profiles will be 
collected for study analyses.  
During Week 15, patients will wear a blinded CGM device for 7 consecutive days to generate 
minimum 4 days of useable CGM data. If a patient fails the first attempt for any reason, he/she 
will be retrained for CGM conduct and complete another course of blinded CGM in Week 16. 
At the end of the study, the patients will be followed-up for 2 (+2) days to collect post- treatment 
safety information. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study duration consists of: 
x
An up to 4-week screening and training period including 1-2-week CGM performance
(allow for re-training). The screening starts from signed consent form.
x
A 16-week open-label comparative treatment period, which includes 14 weeks of dose
titration for both basal and meal-time insulin to achieve the glycemic targets and a
1-2 weeks of CGM performance when basal insulin (Toujeo and Lantus) doses are stable
without changes.
x
A 2-day (+2 d) post-treatment safety follow-up after treatment completion or premature
discontinuation of study treatment.
For an individual patient, the maximum study duration is about 20 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 20).   
6.3 
INTERIM ANALYSIS 
No interim analysis is planned for this study. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Adult patients (male and female) with type 1 diabetes mellitus; 
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 sub-sections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <18 years or >70 years 
E 02. Night shift worker, 
E 03. Use of investigational drug(s) within 1 month or 5 half-lives, whichever is longer prior to 
screening, 
E 04. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one 
week or more within 3 months prior to screening, 
E 05. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol (eg, acetaminophen/paracetamol during CGM period) and refusing to take 
alternative treatment, 
E 06. Mental condition rendering the patient unable to understand the nature, scope and possible 
consequences of the study and to perform blood glucose monitoring requirements, 
including the documentation of SMPG data and insulin dosing, or evidence of an 
uncooperative attitude and/or inability to return for follow-up visits, and unlikely to 
complete the study, 
E 07. Patients with severe unstable hepatic, gastrointestinal, cardiovascular (including congestive 
heart failure NYHA III/IV), respiratory, neurological, psychiatric, hematological, renal, 
endocrine, dermatological disease, active malignant tumor, other major systemic disease or 
patients with short life expectancy or any other medical condition that might interfere with 
the evaluation of study medication according to investigator’s medical judgment, 
E 08. Hemoglobinopathy or hemolytic anemia, transfusion of blood or plasma products within 
3 months prior to screening, 
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E 09. History of drug or alcohol abuse within 6 months prior to screening, 
E 10. Pregnant or breast-feeding women or women who intend to become pregnant during the 
study period as glycemic control may be unstable and insulin doses may be variable during 
this period, 
E 11. Patients unable to speak, read and write, 
E 12. 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 diabetes history and treatment 
E 13. Patients with type 2 diabetes mellitus, 
E 14. HbA1c  6.5% or  10% measured by the central lab test at Visit 1, 
E 15. Patients with fasting c-peptide  0.3 nmol/l as per source document or central lab test at 
Visit 1, 
E 16. Patients experienced  none episode of documented symptomatic and/or severe 
hypoglycemia (as per the ADA classification) during the month prior to screening, 
E 17. Patients experienced > 1 episode of severe hypoglycemia resulting in coma/seizures in the 
last 12 months before screening, 
E 18. Patients receiving less than 1 year of treatment with basal plus mealtime insulin, 
E 19. Using any basal  insulins other than the long-acting insulin analogs (i.e. Lantus, Toujeo, 
Levemir or Tresiba) in the past 3 months before screening,  
E 20. Requiring  >80 U/day basal insulin analogs within 30 days prior to screening, 
E 21. Not on stable dose of basal insulin analogs (± 20% total dose) within 30 days prior to 
screening, 
E 22. Using human regular insulin as mealtime insulin within 30 days prior to screening,  
E 23.  Using less than 2 injections of rapid-acting insulin analog within 30 days prior to 
screening,  
E 24. Using an insulin pump in the last 6 months before screening, 
E 25. Initiation of any glucose-lowering agents in the last 3 months before screening, 
E 26. Weight change of 5 kg in the last 3 months before screening. 
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7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 27. Any contraindication to use of insulin glargine as defined in the national product label, 
E 28. End stage renal disease (creatinine clearance <15 mL/min or on renal replacement 
treatment), 
E 29. Unstable proliferative diabetic retinopathy or any other rapidly progressive diabetic 
retinopathy or macular edema likely to require laser, surgical treatment or injectable, 
E 30. Women of childbearing potential (premenopausal, not surgically sterile for at least 
3 months prior to the time of screening) not protected by highly-effective method(s) of 
birth control (as defined for contraception in the Informed Consent Form). 
7.2.4 Additional exclusion criteria during or at the end of screening before randomization 
E 31. Patient who has withdrawn consent before randomization (starting from signed informed 
consent form), 
E 32. Inappropriate CGM use during screen period evidenced failure to obtain minimum 4 days 
of usable records by the end of screening, 
E 33. Non-compliance with SMPG performance evidenced by failure to demonstrate at least 
5 days of 5-point SMPG records by the end of screening, 
E 34. Despite screening of the patient, enrollment/randomization is stopped at the study level. 
E 35. Off-label use of any oral antidiabetic medication or non-insulin injectable agents during 
the 3 months prior to screening 
Note: one time re-screening is allowed at the investigator’s medical judgment for any manageable 
reasons that caused screening failure and the patient is likely to be eligible before the enrolment 
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8 
STUDY TREATMENTS 
8.1 
DIET AND EXERCISE  
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.  
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.  
8.2 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The IMP is insulin glargine (HOE901). It will be provided as either Toujeo (glargine U-300, the 
tested drug) or Lantus (glargine U-100, the comparator/control drug)  
An instruction leaflet (Appendix B) will be provided which explains how to use the disposable 
pen-injectors for Toujeo. Patients will be trained or checked by study staff on how to use the pen 
correctly, how to store it and how to change the needle for both pen-injector devices. 
8.2.1 Pharmaceutical formulation of the investigational medicinal product 
The tested drug 
Toujeo (insulin glargine 300 U/mL solution) is supplied for SC injection as a sterile, non-
pyrogenic, clear, colorless solution in a 1.5 mL TOUJEO SoloStar disposable prefilled pen 
(450 U/1.5 mL).  
Toujeo has the same composition as the Lantus formulation 100 U/mL with adjustment of 3-times 
the amount of active pharmaceutical ingredient (insulin glargine) and corresponding zinc content. 
The higher concentration of insulin glargine in U-300 will result for the same dose of insulin 
glargine in lower injection volumes as compared with the conventional U100 basal insulin 
formulations. 
Application of the drug is done using the pen device allowing dose settings in the range of 1-80 U 
with 1U increments.  
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The control drug 
Lantus is supplied as insulin glargine solution for SC injection 100 U/mL in 3 mL cartridges 
assembled in a pen-injector. The SoloStar prefilled (disposable) pen will be used and it allows for 
a dose setting in the range of 1-80 U with minimum dose increment of 1 U.  
Note: Mixing of insulin glargine (either U-300 or U-100) with other insulins is not allowed 
nor dilution. 
8.2.2 Route and method of IMP administration 
Toujeo or Lantus, is self-administered once daily by deep subcutaneous injection, in the left or 
right anterolateral or left or right posterolateral abdominal wall or thighs or upper arms. The area 
of the injection will be consistent with the habits of the individual patient. 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 area of the injection sites of IMP should be consistent throughout the 
study.  
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 Lantus) or NIMP (mealtime insulin). 
Patients will be provided with the pen injection devices specifically labeled for the use in the 
study.  
The following pen needles will be provided for use with the injection pen devices: 
x
BD Ultra Fine Needles 31 G x 5 mm
x
BD Ultra Fine Needles 31 G x 8 mm
Handling procedures of the pen and needles and administration technique is provided in specific 
manuals (see Appendix B). The patients are trained on the use of the study drug pen and needles 
by the study staff and provided with an instruction leaflet during the randomization visit (V3, Day 
1).  
For the duration of the study, the patients will be required to use the same type of study drug 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. 
Injection pens should never be shared with others. 
8.2.2.1 Toujeo (insulin glargine 300 U/mL solution) 
Patients randomized to Toujeo (U300) will be supplied with the appropriate number of disposable 
pens for 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 
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Doses can be set in increments of 1 unit up to a maximum single injection of 80 U.  Toujeo will 
be injected once daily in the morning throughout the study. Patients who require greater than 80 U 
per day in Lantus dose before the study will be excluded at screening. But during the study 
treatment period, if a dose greater than 80 units is required, it will be given as two or more 
consecutive subcutaneous 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. 
8.2.2.2 Lantus (insulin glargine 100 U/mL solution) 
Patients randomized to Lantus will be supplied with the appropriate number of disposable Lantus 
SoloStar pens and needles. Pens will be specifically labeled for the use in the study.  
Each Lantus SoloStar pen contains a cartridge with a total of 300 units of insulin glargine. Doses 
can be set in increments of 1 U up to a maximum single injection of 80 U. Patients who require 
greater than 80 U per day in Lantus dose before the study will be excluded at screening. But 
during the study treatment period, if a dose greater than 80 units is required, it will be given as 
two or more consecutive subcutaneous 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. 
8.2.3 Timing of IMP administration 
Toujeo or Lantus will be injected once daily subcutaneously as randomized in the morning, which 
is defined as the time period between wakeup and breakfast.  The injection will be always at the 
same time in the morning. The clock time of the once daily Toujeo or Lantus injection (hh:mm) in 
the morning is at the discretion of the patient and/or investigator. However, once that time is set, 
the IMP must be given within a ±1 hour window, which should be maintained for the duration of 
the study. 
Treatment with the IMP will last until the end of treatment visit (Visit 19). 
8.2.3.1 Changing injection time during screening period 
Patients taking Lantus or other basal insulin analogs (i.e. Toujeo, Levemir or Tresiba) at anytime 
(eg, evening) other than in the morning should switch their injection time to the morning during 
the screening period after Visit 1. The instruction on changing injection time should be given by 
the investigator in concordance with the Lantus or other manufacture labels (1). On the day of 
switching injection time, the total dose of basal insulin analogs and the pre-breakfast (if 
applicable) rapid-action insulin may need to be reduced based on the physician’s medical 
judgment.  
For example, to change evening Lantus to morning injection:  
On the day before changing injection time, the dose should be changed to ~ 1/2 - 2/3 of the 
total daily dose and will be injected in the evening as the patient’s usual injection time.  
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On the second day the dose will be equal to the total daily basal insulin dose and injected in the morning 
before breakfast. 
8.2.4 Starting dose of IMP 
The starting dose of IMP at randomization is the patients’ current Lantus or other basal insulin 
dose, ie, the dose on the day prior to Visit 3, for all patients who randomized to either Toujeo or 
Lantus.  
The first injection of IMP should occur on the day of randomization (V3) under the supervision of 
investigator or the designated study staff. If for any reason, the patient could not inject the first 
dose at the study site, the first dose can be administered in the morning of the next day and the 
date and time will be documented in the eCRF for basal insulin.  
8.2.5 Adjustment of IMP 
After randomization, dose of Toujeo or Lantus will be titrated in dose steps outlined in Table 1 to 
achieve glycemic targets without hypoglycemia. The upward dose titration should continue until 
the patient reaches the target fasting (pre-breakfast/pre-injection) 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 
Week 14, after which, dose of  Toujeo or Lantus should be unchanged during the CGM 
collection (Week 15 - 16) except in the case of dose reduction for safety reasons, eg, a basal 
insulin associated severe hypoglycemia.   
The target range for fasting (pre-breakfast/pre-injection) plasma glucose is 80-100 mg/dL (4.4 and 
5.6 mmol/L), inclusive. 
As recommended in Table 1, changes in the Toujeo or Lantus dose are based on the average 
fasting pre-breakfast SMPG values of past 3 days measured by the patients. Other pre-prandial 
(pre-lunch, pre-dinner) SMPG measurements may also be taken into account.   
If considered as 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 pre-breakfast glucose delta <50 mg/dL.  
  
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Table 1 - Titration of IMP dose 
Mean fasting SMPG values (prebreakfast) from 
preceding 3 days 
Insulin glargine (U-100 and U-300) dose 
adjustments (U/day) 
>120 mg/dL (6.7 mmol/L) 
+ 4 U, or split to 2 x 2 U  
>100 and 120 mg/dL (5.6 and 6.7 mmol/L) 
+ 2 U or split to 2 x 1 U  
 80 and 100 mg/dL (4.4 and 5.6 mmol/L) 
No change 
60 and <80 mg/dL (3.3 and 4.4 mmol/L) 
- 2 U 
<60 mg/dL (3.3 mmol/L) or occurrence of 2 (or more) symptomatic 
hypoglycemic episodes or one severe hypoglycemic episode (requiring 
assistance) documented in the preceding week. 
- 2 to -4 U or at the discretion of the investigator or 
medically qualified designee 
 
Good clinical judgment is to be exercised while titrating the basal insulin dose. 
Regular self-monitoring of plasma glucose is very important in order to achieve the blood glucose 
targets. It is recommended to perform daily fasting/pre-breakfast SMPG and 5-point profiles 
(Section 10.2.3.1) to support the titration process. More frequent SMPG at other time-point (eg, 
post-breakfast and post-dinner) may be needed at the investigator’s discretion.  
Patients will be familiarized with the adjustment schedule so that they will be able to monitor the 
dose adjustment with the assistance of the investigator or medically qualified designee. During the 
study, 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 onsite), patients will 
report their SMPG data, insulin doses and hypoglycemia to the study site.  
If needed, additional contacts will be made available for patients to discuss dose adjustments in-
between the scheduled visits. It is at the discretion of the investigator to allow well-trained 
patients to make their IMP insulin dose adjustments in between the scheduled visits without prior 
consultation of the site personnel.   
Dose adjustment in cases of hypoglycemia: 
x 
Upward titration is to be stopped for 1 week after a case of severe hypoglycemia 
(requiring assistance) or  two 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,  
x 
Doses of basal insulin or meal-time insulin may be reduced or modified at any time for 
hypoglycemia during the study, 
x 
Small decreases of the insulin dose (eg, 1 unit) are at the discretion of the investigator or 
medically qualified designee, if SMPG is below 80 mg/dL (4.4 mmol/L) or if relevant 
hypoglycemia occurs, 
x 
Patients who experienced mild to moderate hypoglycemia as a result of a missed meal, 
unusual exercise or alcohol use will be counseled on the correction of those behaviors and 
should not reduce their insulin dose. 
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8.2.6 Evaluation of patients not meeting glycemic targets 
In case the target fasting glycemic goal cant not 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: 
x 
Plasma glucose was actually measured in fasting condition (eg, before breakfast within 
30 minutes window prior to injection), 
x 
IMP and mealtime insulin are properly injected, 
x 
There is no inter-current disease which may jeopardize glycemic control (eg, infectious 
disease), 
x 
Compliance to diet and lifestyle is appropriate, 
x 
If any of the above can reasonably explain the insufficient glycemic control, the 
investigator should take appropriate action, eg: 
- 
Adjust the IMP dose and mealtime insulin dose, 
- 
Check the compliance of IMP and mealtime insulin injection, 
- 
Evaluate and treat intercurrent disease (to be reported in adverse event (AE)/serious 
adverse event (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. 
8.3 
NON-INVESTIGATIONAL MEDICINAL PRODUCT(S) 
The non-investigational medicinal products (NIMP) are the protocol-mandated mealtime insulins, 
ie, rapid insulin analogs (insulin glulisine, insulin lispro or insulin aspart), which have been used 
by the patients since at least 30 days before the screening visit.  
The patients in both treatment 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 
(insulin glargine) 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.  
8.3.1 Adjustment of NIMP  
The dose of the mealtime insulin analogs (glulisine, lispro or aspart) will be titrated to achieve a 
target of 2-hour postprandial plasma glucose. The dose adjustment regimen can be titrated based 
on a pattern of postprandial plasma glucose results of SMPG (simple titration) OR based on the 
carbohydrate content of the meal (carb counting).  
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x 
The titration goal is a 2-hour postprandial SMPG in the range of 130 and 180 mg/dL 
(7.2-8.9 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. 
x 
While basal insulin doses are increased, mealtime insulin doses may be reduced to avoid 
daytime hypoglycemia as deemed appropriate by the investigator.  
x 
Appropriate adjustment in mealtime insulin will continue throughout the entire treatment 
period (Week 0-16).   
The two 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. 
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8.4 
BLINDING PROCEDURES 
As Toujeo and the control drug Lantus are distinguishable, this study is an open-label design. The 
day- time of injection is not blinded either. Administration of all forms of insulin glargine during 
the trial is to be open-label, and no attempt will be made to blind day-time of injection. 
8.4.1 Compensation for lack of blinding 
Despite the open-label administration of study insulins, assessment of outcomes, where possible, 
will be based on objectively collected data, which are assessments for blinded CGM (primary 
endpoint) and SMPG data. The SMPG data stored in the glucose meter will be uploaded to the site 
computer for the study staff to verify the diary entries that will be documented onto the eCRF to 
support the analyses of the 7-point SMPG profile and the confirmed hypoglycemia (secondary 
and other endpoints).   
Neither the Investigator nor the Sponsor will have access to the individual data for the primary 
efficacy parameter (CGM records) obtained in each patient. However, the study team may review 
the data for the primary efficacy parameter in descriptive statistics with the name of the 
investigational medicinal product (IMP) treatment masked during data review meetings.  
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The Trial Supply Chain Manager compiles the batch number list and the Study Biostatistician 
provides the randomization scheme (including stratification, Section 11) to the centralized 
treatment allocation system (IVRS - Interactive Voice Response System /IWRS - Interactive web 
response system). Then, the IVRS/IWRS generates the patient randomization list according to 
which it allocates treatment arms to the patients.  
x 
The treatment kits, open-label boxes identified with batch numbers, are allocated to the 
patients by the IVRS/IWRS using the treatment number of the boxes. 
x 
At the screening visit the investigator or designee has to call the IVRS/IWRS to receive 
the patient number. The patient identification (patient number) is composed of 9-digit 
number containing the 3-digit country code, the 3-digit center code and the 3-digit patient 
chronological number (which is 001 for the first patient screened in a center, 002 for the 
second patient screened in the same center, etc). 
x 
Randomization will be stratified by HbA1c obtained at the screening visit (<8.0%; 
8.0%), Lantus (and other basal insulin analogs) injection at screening BID vs QD, current 
CGM use (yes/no) and mealtime insulin titration algorithm followed. For each region the 
IVRS/IWRS will be configured as to reach a minimum of 20% randomized patients per 
HbA1c strata. 
x 
On V3 (D1), for first treatment kit(s) allocation, the investigator or designee has to call the 
IVRS/IWRS to provide some information (such as patient number provided by 
IVRS/IWRS at screening visit, date of birth, etc). Afterwards the IVRS/IWRS is called 
again each time a new treatment kit(s) allocation is necessary, ie, the visits as indicated in 
the study flowchart (Section 1.2).  
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x 
A randomized patient is a patient who has been allocated to a randomized treatment 
regardless whether the treatment kit was used or not (ie, patient registered by the 
IVRS/IWRS). 
x 
A patient cannot be randomized more than once in the study.  
8.6 
PACKAGING AND LABELING 
Toujeo (insulin glargine 300 U/mL solution) is supplied for SC injection as a sterile, non-
pyrogenic, clear, colorless solution in a 1.5 mL Toujeo SoloStar disposable prefilled pen 
(450 Units/1.5 mL). 
Lantus (Insulin glargine) 100 U/mL solution) is supplied as insulin glargine solution for SC 
injection 100 U/mL in 3 mL cartridges assembled in a pen-injector. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
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 3 disposable pens for insulin glargine 300 U/mL and Lantus will be supplied 
in boxes of 5 disposable pens for insulin glargine 100 U/mL 
8.7 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing 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 IMPs 
labels and in the instruction leaflet. 
8.8 
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. 
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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 IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party allow the IMP to be used 
other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.8.1 Treatment accountability and compliance 
At each contact to the patient, either by phone or during on-site visit, the Investigator or his/her 
delegate has to ask the patient about administered doses of IMP (Toujeo or Lantus).  
Returned and dispensed IMP 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 packs 
and compare to dosing records documented in the patients’ diaries. Discrepancies have to be 
addressed to the patient for clarification of real treatment administration. For unused IMP, pens 
will have to be stored accordingly. 
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 glycaemia 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. 
8.8.2 Return and/or destruction of treatments 
Patients have to return all the used, in-use and unused IMP at each on-site visit except for the visit 
where re-supply is not planned (at this visit, unused pen will be left home) (or final assessment on 
treatment visit in case of permanent premature discontinuation).  
8.8.2.1 IMP (Toujeo or Lantus) 
All partially-used or unused treatments (inject devices with inserted cartridges; disposable 
Solostar pens) will be retrieved by the Sponsor. A detailed treatment log of the returned IMP will 
be established with the Investigator (or the pharmacist) and countersigned by the Investigator and 
the monitoring team. 
The Investigator will not destroy any IMP unless the Sponsor provides written authorization. A 
detailed treatment log of the 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. 
8.8.2.2 NIMP (mealtime insulin analogs) 
As the mealtime insulin is not provided by the study sponsor, no NIMP return and destruction are 
required.  
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 
eCRF (NIMP name, dosage, daily total dose, injection compliance and dose-titration 
recommendation etc.) as specified in this protocol (Section 8.3). 
8.9 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to IMP 
treatment. Any treatment which are continued during the study and/or initiated or changed during 
the study must be recorded in source data and in the e-CRF. 
The IMP includes basal insulin of Toujeo and Lantus as the testing and control medications, 
respectively. Mealtime insulin analogs (glulisine, lispro or aspart) are the study required 
concomitant antidiabetic medication, which is defined as the NIMP in this study.  
8.9.1 Prohibited medication during the study 
During the study following medications are prohibited. 
x 
Any antidiabetic agents other than the study medications mentioned above, including oral 
or injectable antihyperglycemic agents, other type of basal insulin (eg, NPH, Detemir, pre-
mixed insulin), and human regular insulin, 
x 
Insulin pump therapy is not allowed during the course of the study, 
x 
Initiation of any weight loss drugs is not allowed; previous treatment with weight loss 
drugs can be continued and doses must remain stable throughout the study, 
x 
Systemic glucocorticoids for more than 10 consecutive days (topical or inhaled 
applications are allowed), 
x 
Medications containing acetaminophen/paracetamol during the period of CGM 
performance as these medications can interact with the glucose sensor of the CGM device. 
Other medications which are unlikely to interfere with the IMP and the study variables are 
allowed as needed and discussed with the investigator. However, doses of chronically 
administered medicines should be kept fixed during the trial if at all possible. 
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8.10 
POSTSTUDY TREATMENT 
Upon discontinuation of the study treatment, either scheduled or early permanent discontinuation 
with IMP, patients may either continue with their basal insulin during the study, both available in 
the market, or take a treatment alternate, approved form of basal insulin. 
The choice of the basal insulin used after the end of study and dosing instructions are at the 
discretion of the treating physician. After the transition to post-study basal insulin, the doses of 
the new post-study basal insulin and the short-acting mealtime insulin should be adjusted based on 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The primary efficacy endpoint is the percentage (%) of time of glucose concentrations within the 
range of 70-180 mg/dL (3.9-10 mmol/L) during Week 15 (or 16), as obtained by CGM.  
During Week 15, each patient will wear the CGM device for 7 consecutive days to generate at 
least 4 days of useable CGM records for the primary efficacy endpoint assessment. If a patient 
fails to provide at least 4 days (not necessarily consecutive) of useable CGM data over the 7-day 
CGM performance, he/she will repeat the CGM performance during Week 16.   
x 
CGM data are blinded to both the patients and investigators, 
x 
During the CGM performing week , the IMP insulin ( Toujeo or Lantus) dose is fixed 
without a change, while the mealtime insulin dose can still be adjusted appropriately, 
x 
Useable CGM data for a day are defined as at least 85% time of records without a gap 
(missing data) lasting for  2 hours per 24 hours. At least 4 days of qualified 24-h CGM 
records for each patient will be used for primary endpoint analyses, 
x 
If a patient prematurely withdraws from the study before Week 15 (V18) the CGM data 
will be missing for the individual patient and the patient will be excluded from the primary 
efficacy analyses (see Section 11). 
Further methods to handle missing data will be applied in the context of a sensitivity analysis and 
will be specified in the Statistical Analysis Plan (SAP).  
9.2 
SECONDARY ENDPOINTS 
The secondary efficacy endpoints include:  
x 
Incidence and rate of nocturnal symptomatic hypoglycemia, defined as an event with 
typical symptoms of hypoglycemia accompanied by SMPG 70 mg/dL (3.9 mmol/L) that 
occurs between 00:00 and 05.59 hours, 
x 
Percentage (%) of time glucose concentrations obtained by  CGM within target range  of 
70-140 mg/dL (3.9–7.8 mmol/L) during the last 4 hours of CGM data collection prior to 
next day basal insulin injection, 
x 
Total, within day and between day coefficient of variation in glucose values obtained from 
CGM. 
 
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9.3 
OTHER EFFICACY ENDPOINTS  
x 
Frequency and distribution (nocturnal or 24 hours) of all hypoglycemia events analyzed by 
hypoglycemia categories (severe, documented symptomatic, asymptomatic, probable and 
relative) as defined in the publication ADA Workgroup on Hypoglycemia, 2015 (5), 
x 
Additional CGM Endpoints (data obtained at Week 15 or 16) : 
- 
Percentage (%) of time glucose concentrations within the target range  of 
70-140 mg/dL (3.9–7.8 mmol/L),  analyses on all- time  (24 h) CGM data, 
- 
Percentage (%) of time glucose concentrations 70 mg/dL (3.9 mmol/L) and 
<54 mg/dL (3 mmol/L),  analyses on both all-time (24h) and nocturnal (00:00-05:59 h) 
CGM data, 
- 
Percentage (%) of time glucose >140 mg/dL (7.8 mmol/L), >180 mg/dL(10 mmol/L) 
and > 250 mg/dL (13.9 mmol/L),  analyses on both all-time (24h) and nocturnal 
(00:00–05:59 h) CGM data, 
- 
Total, within day and between day coefficient of variation in glucose concentrations, 
- 
Area under the glucose curve (AUC) of glucose concentration 70 mg/dL 
(3.9 mmol/L), 
- 
AUC of glucose concentration >180 mg/dL (10 mmol/L), 
x 
7-point SMPG profiles (pre-prandial and 2-hour postprandial plasma glucose at breakfast, 
lunch and dinner, and bedtime), 
x 
Change from baseline to study endpoint in HbA1c, 
x 
Change from baseline to treatment period endpoint in central lab FPG, 
x 
Insulin dose (total, basal, mealtime/bolus, ratio of basal to bolus insulin dose). 
9.3.1 Hypoglycemia  
9.3.1.1 Hypoglycemia classification 
Hypoglycemia events will be categorized [5] as follows: 
x 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with 
sufficient neuroglycopenia to induce seizure, unconsciousness or coma. Plasma glucose 
measurements may not be available during such an event, but neurological recovery attributable to 
the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration. 
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  
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Note that “requiring assistance of another person” means that the patient could not help himself or 
herself to treat the hypoglycemia. Assisting a patient out of kindness, when assistance is not 
required, should not be considered a “requires assistance” incident. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure must be reported as an 
SAE. In addition, any hypoglycemic event, which at Investigator discretion, qualifies as serious 
adverse event must also be reported as an SAE. 
x 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia accompanied by a measured plasma glucose concentration of 70 mg/dL 
(3.9 mmol/L).  
In addition, hypoglycemia episodes with plasma glucose of < 54 mg/dL (3.0 mmol/L) will also be 
analyzed. 
Clinical symptoms that are considered to result from a hypoglycemic episode are, eg, increased 
sweating, nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations, 
headache, sleep disorder, confusion, seizures, unconsciousness, or coma. 
x 
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).   
In addition, hypoglycemia episodes with plasma glucose of < 54 mg/dL (3.0 mmol/L) will be 
analyzed. 
x 
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms 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.  
x 
Relative hypoglycemia 
Relative hypoglycemia is an event during which the person with diabetes reports any of the 
typical symptoms of hypoglycemia, and interprets the symptoms as indicative of hypoglycemia, 
but with a measured plasma glucose concentration greater than 70 mg/dL (3.9 mmol/L). 
9.3.1.2 Hypoglycemia analyses 
All hypoglycemia by above classification will be analyzed and presented as incidence rate per 
patient year and proportion (%) of patients with at least one hypoglycemic episode.  
Hypoglycemia episodes will also be analyzed by their diurnal distribution (0:00-24:00) and in 
addition by time of the day: 
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x 
nocturnal hypoglycemia defined by time of the day: any hypoglycemia of the above 
categories that occurs between 00:00 and 05:59 AM hours 
x 
daytime hypoglycemia: any hypoglycemia of the above categories that occurs between 
6:00 AM to 23:59. 
The rate ratio (RR) of hypoglycemia of Toujeo versus Lantus will be assessed.  Analytic 
methodology will be specified in Section 11 Statistic Consideration and the SAP. 
9.3.2 Safety endpoints  
Adverse events (AEs) spontaneously reported by the patient or observed by the Investigator, will 
be monitored. 
The following safety parameters will be analyzed in this study: 
x 
Adverse events, serious adverse events including injection site and hypersensitivity 
reactions 
x 
Vital signs, including body weight 
x 
Hypoglycemia 
9.3.2.1 Adverse events, serious adverse events 
All AEs and SAEs will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, “High 
Level term (HLT)”, “High Group Level Term (HLGT)” and associated primary “System Organ 
Class (SOC)” using the version of MedDRA (Medical Dictionary for Regulatory Activities) 
currently in effect at the sponsor at the time of database lock. The occurrence of AEs and SAEs is 
recorded from the time of signed informed consent until the end of the study. 
If an AE/SAE is ongoing and not resolved by the end of the study observation period (defined as 
the time from randomization until the end of the study, Section 6.2.1) and leads to subsequent 
death of the patient, it will have to be reported. 
9.3.2.2 Vital signs 
Vital signs include:   
Vital signs include: sitting blood pressure, and pulse measurements which will be recorded with 
the patient in a sitting position for 5 minutes before the measurement is taken.  
9.4 
FUTURE USE OF SAMPLES 
Not applicable 
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9.5 
APPROPRIATENESS OF MEASUREMENTS  
The primary efficacy analysis will test superiority of Toujeo compared to Lantus in terms of 
percentage of time CGM data in the range 70-180 mg/dL (3.9-10 mmol/L). The tested CGM will 
be collected during the last week of IMP treatment with stable doses (unchanged dose) for either 
Toujeo or Lantus.  Continuous glucose monitoring system allows frequent glucose measurements 
(every 5 min) and the ability to analyze glucose distributions in real time (9). Use of this approach 
in a clinical study provides the opportunity to better understand glucose metabolism associated 
with the study IMP.  This approach has been employed previously in studies of the efficacy of 
long-acting insulins in patients with diabetes. 
The 15-week treatment is considered sufficient for Toujeo, in the first 1-2 weeks, to achieve the 
steady state conditions after changing over from Lantus in a stable dose (< 20% +/-) prior to the 
study entry and for both Toujeo and Lantus to reach the optimal dose by following fasting SMPG-
orientated dose titration regimen during the rest of treatment weeks. Mealtime insulin titration will 
also be implemented to achieve the postprandial SMPG targets.  Thus, the glycemic control 
measured by laboratory HbA1c and FPG at the end of treatment is expected to be similar between 
the two treatments.   
Secondary analyses will be performed to evaluate the therapeutic feature of a flatter  and longer 
duration of Toujeo compared to Lantus over at least 24 hours, which should result in more 
sustained glycemic control, especially during the last a few hours before the next injection,  and 
less hypoglycemia during nighttime. The assessment will be measured by the secondary endpoints 
of: the incidence rate of nocturnal documented symptomatic hypoglycemia, the percentage of time 
CGM in the target range during the last 4 hours prior to injection and the variability analyses of 
CGM profiles. 
The other efficacy endpoints include a thorough hypoglycemia analysis on incidence rate, 
proportion of patients with hypoglycemia and the diurnal distribution of hypoglycemia. The 
analyses will be performed based on the SMPG and the hypoglycemic events reported by the 
patients. Patients will be instructed to measure SMPG whenever they feel hypoglycemic. This 
aims to detect and confirm as many hypoglycemic episodes as possible. 
Frequent SMPG will be performed throughout the entire study period after Visit 1 (Section 10.2.3 
and Section 1.2).  SMPG values will be used to guide the insulin dose titration and to support the 
analyses of 7-point SMPG profile and hypoglycemia reports. To ensure the accuracy of the 
glucose records, SMPG data will be uploaded from the glucose meter onto the site computer via 
the 
 at each onsite visit so that the investigator and study staff are able to 
verify the glucose values documented by the patients in the study diary. 
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10 
STUDY PROCEDURES 
This is an approximately 20-week outpatient study and consists of 8 onsite visits and 
12 mandatory telephone visits. Additional, optional telephone visits to monitor and support the 
progress of insulin titration should be scheduled whenever considered necessary by the 
investigator.  Two repeated onsite visits at the end of screening and/or study treatment may be 
scheduled for patients who fail the first attempt of CGM performance. 
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 
and/or CGM), diaries and IMP (used, in-use or unused) to sites and to be in the fasted status if 
required at some visits.    
For phone-call 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 3 as reference is acceptable.  
If one visit date is changed, the next visit should take place according to the original schedule, ie, 
counting from Day 1 on Visit 3. 
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 
This paragraph describes how the visits are carried out, in chronological order (according to the 
flow chart and identical to the order shown in the CRF). 
10.1.1 Screening and training Visits (Visit 1 and Visit 2) 
The duration of screening and training period will be up to 4 weeks. Screening and training 
procedures will be carried out at Visit 1 and Visit 2, and completed at Visit 3. For a complete list 
of procedures scheduled for each study visit please refer to the study flow chart (Section 1.2). 
As soon as a patient is found ineligible, the patient must not enter the randomized treatment 
phase and IVRS/IWRS has to be contacted in order to register the patient as a screening failure. 
Patients can be re-screened one time before randomization in case of non-evaluable exclusion 
criteria (eg, not evaluable screening laboratory findings) or in case of manageable exclusion as 
deemed by the investigator. Re-screened patients will be subject to the screening visit 
procedures/assessments (see below) including new informed consent signed and allocation of a 
new patient number. 
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10.1.1.1 Visit 1 (Week -4) 
Written informed consent must be obtained from the patient prior to any study-specific 
procedures. The patient will receive verbal 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. In particular, blinded CGM will be specified in the consent form for patient to make 
an informed decision.  
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  (Section 7.2). The source documents include (but not limited 
to) a physician’s note, hospital/ER discharge note, printouts of glucose meter (or electronic data) 
or documents in the patient’s diary. 
Medical/surgical history may include macrovascular complications [heart, brain, legs] as well as 
all non-diabetic diseases. 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. If the patients have been on 
Lantus or other basal insulin analogs twice a day and or at other injection time than morning 
injection, the investigator will instruct the patients to switch their basal insulin analog to 
once daily morning injection regimen.  
In women of child-bearing potential (WOCBP), the contraceptive methods, if used, have to be 
documented. According to CPMP/ICH/286/95 (10), “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.” 
A physical examination, including a screening for diabetic neuropathy (eg such as assessment 
of appearance of feet, ankle, reflexes, vibration perception at the great toes) has to be performed. 
Check for injection site reactions. 
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.  
Patients will be provided with appropriate study materials: blood glucose meter with 
corresponding supplies (lancets, control solutions, test strips etc.). A control test will be 
completed and recorded to assure glucose meter accuracy. Patients will be shown how to 
accurately measure plasma glucose values with the blood glucose meter. CGM naïve patients 
should be introduced to CGM, eg, introducing  DexCom CGM web portal.   
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A patient diary will be given to patients in order to perform self-measurement of plasma glucose 
and its recording. The patient diary further contains sections for the recording of time and dose 
of insulin injection, times of SMPG measurement, SMPG values, and hypoglycemia signs and 
symptoms. Patients should bring the used diary to each on-site visit, as it will be collected and 
exchanged by a new diary. 
If needed, diet and life style counseling (including training in carbohydrate counting) should be 
provided. 
IVRS/IWRS will be called for allocation of patient number (see Section 8.5), registration of 
screening, collection of demographic information. 
10.1.1.2 Visit 2 (Week -3) 
Visit 2 will occur about 1 week after Visit 1 when the investigator has received laboratory reports 
for the screened patients in order to assess Exclusion E14 and E15 (Section 7.2).  
At this visit, patients will be trained with the blinded CGM performance. During the training the 
purpose of blinded CGM, the duration of CGM conduct, the requirement of daily calibration with 
SMPG and how to handle the device will be thoroughly explained and all questions be answered 
(Section 10.2.4). After the training, the patients will perform CGM sensor insertion under the 
supervision of the investigator or the study staff.  Patients will stay at the study site for 2 more 
hours to complete the first calibration process and to receive additional training if needed. All 
patients will be instructed to wear the CGM device for 7 consecutive days.  
Furthermore, following will be assessed: 
x 
Changes from BID to QD Lantus injection and/or the injection time to morning injection 
from any other time (if applicable), 
x 
Compliance with SMPG performance and at least 5 days of 5-point SMPG during the next 
week for randomization eligibility will be enforced. (Section 7.2.4), 
x 
Any AE/SAE, including hypoglycemia since Visit 1 for eCRF documentation, 
x 
Schedule for Visit 3 should include one day to perform the 7-point SMPG. 
10.1.2 Randomization Visit (Visit 3, Day 1/Week 0)  
Visit 3 will occur 7 days after Visit 2. If a patient is not able to keep the visit date for any reason, 
he/she should inform the study site immediately to reschedule the visit as soon as possible. In 
such a case, the CGM system will automatically stop working and the sensor/transmitter may be 
removed by the patient at home or at the site later (Section 10.2.4).  Before the visit day, patients 
should be reminded to be fasted for about 8 hours and not to inject their Lantus at home in the 
morning of Visit 3 since the basal insulin (Toujeo or Lantus) will be injected at the site after 
randomization under the supervision of investigator or designees.   
At this visit, quality of baseline CGM of each patient will be assessed to determine eligibility for 
randomization.  Investigators will upload the CGM data via DexCom/
 and 
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review the CGM summary to determine the quality of CGM performance (Section 10.2.4.2).  
Study procedures at Visit 3 will also include SMPG data uploading, diary collection, AE/SAE 
including hypoglycemia, collection and 7-point SMPG collection. 
Patients with qualified CGM records who do not meet any exclusion listed in Section 7.2.4 will 
proceed to randomization allocation.  Patients will be provided with boxes containing prefilled 
pens for administration of IMP along with the instruction leaflet and corresponding supplies 
(needles, control solution, test strips etc.).  
A patient card, including emergency contact details and treatment arm will be provided to every 
patient who participates in the study. 
x 
Patients who are randomized to Toujeo will be instructed by the study staff on how to 
properly use the Toujeo pens (Appendix B), 
x 
IMP administration will be explained to patients including communication of the IMP 
dose, time of the once daily administration and dose titration requirements (Section 8.2), 
x 
The patients will inject their first IMP dose (Toujeo or Lantus) under the supervision of 
investigator or designee. The first injection dose is the patient’s current Lantus dose, i.e., 
the dose injected in the morning before the day of Visit 3, 
x 
Training on the correct usage of the blood glucose meter and patient diary will be 
repeated, if necessary. 
All patients are asked to self-titrate their IMP (Toujeo or Lantus) according to the algorithm 
provided (Section 8.2.5). The short-acting insulin analog will be continued for mealtime insulin 
requirements and correction of SMPG according to recommendation (Section 8.3.1). Investigators 
and their study staff are required to offer adequate training, thus enabling patients to successfully 
self-titrate their insulins.  
Patients who fail to provide at least 4 days of qualified CGM data will be retrained and will repeat 
the CGM performance for another week (Section 10.2.4.2).  Randomization will be delayed 
accordingly.  
For a complete list of procedures scheduled for each study visit please refer to the Study flowchart 
(Section 1.2). 
10.1.3 Phone call Visits (V4-6, V8-10, V12-14 and V16-17) 
During the study treatment period, 11 weekly phone call visits are scheduled between each on-site 
visit.  The purpose of the weekly phone contact with the patients is to monitor the patients’ 
compliance with SMPG and insulin titration and to collect injection information, AE/SAE, 
including hypoglycemia, as well as any change in concomitant medications.  
Patient 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. These visits are mandatory telephone visits, but can optionally be 
performed as onsite visits.  
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During the phone call the following points have to be addressed: 
x 
Did you adjust IMP insulin since last visit? What are your actual IMP and mealtime 
insulin doses? 
x 
Ask the patient about SMPG, and IMP and mealtime insulin doses during the last 7 days 
prior to the visits. 
x 
Provide diet and life style counseling (including training in carbohydrate counting), if 
needed. 
x 
Did you experience any new medical event, disease or symptom since the last visit? 
(Please pay attention to any possible hypoglycemic event or symptom, possible allergic or 
injection site reactions). 
x 
Did you experience any change in a preexisting medical event or disease or symptom since 
the last visit? 
x 
Did you change or add any concomitant medication since the last visit?  
x 
Do you feel comfortable in handling the diary, glucose meter and IMP injection device or 
do you need any more explanation? 
Further following procedures will be performed: 
x 
Instruct patients on further insulin dose adjustment according to their SMPG values 
x 
Remind the patients to measure required SMPG and complete the diary. 
x 
Remind patients to perform the 7-point SMPG prior to Visit 15 and Visit 19 
x 
Document change of concomitant medication and actual basal and mealtime insulin doses 
in the e-CRF. 
x 
Report AE/SAE and hypoglycemia if any. 
x 
Remind patients to be fasting prior to Visit 11 and Visit 19 and remind patient not to 
inject the IMP and/or breakfast mealtime insulin (if applicable) at home because the IMP 
will be injected at the study site after blood drawn for laboratory measurements. 
x 
Remind patients to bring glucometer , diary and IMP ( used, in use or unused) to 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 visits (V7, V11, V15 and V18) during treatment period 
Four onsite study visits before the end of treatment are scheduled for dispensation of study 
material and IMP, SMPG data uploading and face-to-face discussion about 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).  
Patients will bring their glucose meter, diary and IMP boxes to the study site at each visit.  
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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 onsite visit. Appropriate titration will be continued 
until target fasting SMPG without hypoglycemia has been reached. 
SMPG data stored in the glucose meter will be uploaded to the study computer via 
 and the report will be available for the investigator to review and source document for 
tracking patients’ SMPG performance and for the titration recommendation.   
IMP compliance (collecting and counting used and unused cartridges and syringes and SMPG 
compliance (pre-injection SMPG, 5 point SMPG) will be checked and addressed with the patients.  
Consultation for Diet and life-style modification should be provided during the onsite visits if 
needed.  
Additional assessments will be performed at the specific visits: 
x 
Visit 11: patients should be fasted and blood will be drawn for measurements of HbA1c 
and FPG at central laboratory, 
x 
Visit 15: one day 7-point SMPG will be verified and data collected onto the eCRF, 
x 
Visit 18: following will be performed: 
- 
Dispensation of CGM device and training for CGM conduct if needed, 
- 
CGM sensor insertion under the supervision of investigator or designees, 
- 
Patient will start wearing the blinded CGM device for 7 days,  
- 
The patients should be reminded that the IMP insulin (Toujeo or Lantus) dose should 
not be changed during the next week while the mealtime insulin dose can still be 
adjusted appropriately. 
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 (Visit19, Week 16) 
End of Treatment visit (Visit 19) will occur 7 days after Visit 18 when the patients have 
completed the blinded CGM. If a patient is not able to keep the visit date for any reason, he/she 
should inform the study site immediately to reschedule the visit as soon as possible. In such a 
case, the CGM system will automatically stop working and the sensor/transmitter may be 
removed by the patient at home or at the site later (Section 10.2.4).  Before the visit day, patients 
should be reminded to be fasted for about 8 hours and to bring the CGM device, glucose meter, 
study diary, used and all unused IMP to the sites. Patient should be reminded not to inject the 
IMP and/or breakfast mealtime insulin at home if applicable since the IMP will be injected at the 
study site.   
At this visit, quality of CGM performance will be assessed before the end of treatment.  
Investigators will upload the CGM data via DexCom
and review the CGM 
summary to determine the quality of CGM performance (Section 10.2.4.2).  
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At this visit patients will inject the last dose of IMP which will be given after blood is drawn for 
laboratory measurements. In addition to all the performances done at each onsite visit, the EOT 
procedure will include CGM device collection, physical examination and vital signs and endpoint 
laboratory tests. SMPG will be uploaded, 7-point SMPG checked and all unused IMP collected.  
Patients who fail to provide at least 4 days of qualified CGM data will be retrained and repeat the 
CGM for another week (Section 10.2.4.2).  End of treatment will be delayed accordingly. All 
the procedures will be done or redone at the postponed EOT visit.  
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 20)  
Following the last administration of IMP (Toujeo or Lantus) either as scheduled or prematurely, a 
posttreatment follow-up should be scheduled for all the patients in 2 (+2) days after permanent 
discontinuation of the study treatment. This visit can be a phone call visit, or an on-site visit in 
case of ongoing or new adverse event during the posttreatment 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 visits has to be asked 
(Section 10.1.3), except IMP related questions. 
IWRS/IVRS has to be called in order to register end of study. 
10.2 
ASSESSMENT METHODS 
10.2.1 Vital signs 
Determination of the reference arm for blood pressure measurements: At visit 1 after the 
patient has rested comfortably for at least 10 minutes, blood pressure has to be measured on both 
of the patient´s arms while the patient is in sitting position and then again after two minutes on 
both arms. The arm with the higher diastolic blood pressure will be determined at this visit, 
identifying the reference arm for future measurement throughout the study. The highest value will 
be recorded in the e-CRF (all blood pressure values are to be recorded in the source data). 
Blood pressure at all subsequent visits should be measured when the patient is quiet and seated 
and with their determined reference arm outstretched in line with mid-sternum and supported. 
Measurement at all subsequent visit should be taken under standardized conditions, approximately 
at the same time of the day, on the reference arm, with the same device (after the patient has 
rested comfortably for at least five minutes) and the values are to be recorded in the e-CRF. Both 
systolic blood pressure (SBP) and diastolic blood pressure (DBP) should be recorded. Devices for 
blood measurement should be regularly recalibrated according to manufacturers´ instructions. 
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Heart rate will be measured at the time of the blood pressure measurement.  
10.2.2 Height and body weight 
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. Self-reported weights are not 
acceptable and patients must not read the scales themselves. 
10.2.3 Self-monitoring blood glucose (SMPG) 
Blood glucose values will be self-measured by the patients using the sponsor-provided glucose 
meter and corresponding supplies (lancet, control solutions, test strips etc).  Patients should not 
use their own glucose meter during the study period starting after Visit 1.  
10.2.3.1 SMPG performance 
At Visit 1 patients will be shown how to accurately measure plasma glucose values with the blood 
glucose meter. The investigator or a member of the investigational staff will explain the need to 
measure glucose at the times requested for profiles and how to correctly record the values and 
times. Training is repeated as often as necessary at the study visits and the investigational staff 
reviews the patient’s diary at each visit. 
The performance of SMPG is outlined in Table 4 and also specified also in Section 1.2 Flow 
Chart.  
Table 4 - Instruction for SMPG performed during the study 
Frequency 
SMPG 
Definition 
Recommended 
Mandatory  
Prior to study 
visit  
Fasting 
(prebreakfast) 
Within one hour prior to 
breakfast; after randomization, 
prebreakfast, = preinjection 
Daily until achieving 
fasting SMPG target  
Apply to preinjection 
SMPG 
Apply to preinjection 
SMPG 
Fasting 
Preinjection  
within 30 min prior to injection 
of Toujeo or Lantus before 
breakfast 
5 days per week 
5 days during the week 
prior to each onsite visit 
Visit 7, 11, 15, and 19 
5-points  
prebreakfast, prelunch,  
predinner  + 2-hour post a main 
meal or as per investigator’s 
instruction, and bedtime 
5 days per week  
3 days during the week 
prior to the visits that the 
SMPG data will be 
collected in the eCRF 
Visits in Table 5 
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Frequency 
SMPG 
Definition 
Recommended 
Mandatory  
Prior to study 
visit  
7-points 
before and 2 hours after 
breakfast, lunch and dinner, 
and bedtime 
As needed  
1 day during Week  -1, 
11, and 14 
Visit 3, 15, and 19 
 
SMPG 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.  
Fasting SMPG 
Before breakfast: will be measured daily until uptitration has been completed and fasting pre-
breakfast SMPG is stable in the target range.  
Note: After randomization, before breakfast SMPG = Pre-injection SMPG 
Pre-injection SMPG:  Within 30 min prior to injection of Toujeo or Lantus before breakfast: on 
the day of the first injection of the IMP (Day 1) and daily until uptitration has been completed and 
fasting pre-breakfast SMPG is stable in the target range, and then, at least 5 days per week before 
each onsite visit.   
5-point SMPG profiles  
Before breakfast (pre-injection after randomization), before lunch, before dinner and 2-hours post 
one of any meals and at bedtime (the post-meal SMPG may be done 2 hours after the patient’s 
main meal, e.g. lunch or dinner, or as per investigator’s instruction) at least 5 days per week 
during the week before the baseline until the fasting and postprandial glucose targets have been 
reached. However, it is mandatory to perform at least 3 days during the week prior to the visits 
that the SMPG data will be collected in the eCRF (Section 10.2.3.2).   
7-point SMPG profiles  
Before (pre-injection after randomization) and 2 hours after breakfast; before and 2 hours after 
lunch; before and 2 hours after dinner and at bedtime: at least one day in the week before the 
baseline visit and before Visit 15 and 19.  
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SMPG during symptomatic hypoglycemia 
Whenever the patients feel hypoglycemic symptoms, plasma glucose should be measured by the 
patient (or others, if applicable), if possible. Patients should be instructed to measure plasma 
glucose levels prior to carbohydrate intake/administration of glucose whenever symptomatic 
hypoglycemia is suspected, unless safety considerations necessitate immediate 
carbohydrate/glucose rescue prior to confirmation with the SMPG.   
Patients have to document hypoglycemic events appropriately in their diaries and 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. 
Hypoglycemia events fulfilling the criteria of a SAE will be documented on the SAE form in the 
e-CRF. 
10.2.3.2 Recording SMPG data and insulin dose 
Patients will document their SMPG values with the testing times in the sponsor-provided diary or 
an equivalent diary. When SMPG is recorded by the patient in a non-sponsor provided diary, the 
Investigator (or designee) and patient will sign/initial the data so that the dairy can be kept in the 
study source documents.   
At each onsite visit starting at Visit 2, SMPG data stored in the individual’s glucose meter will be 
uploaded via the
 A summary including all measured glucose values will be 
promptly available for the Investigator (or designee) to review. For SMPG data to be captured in 
the eCRF, the investigators or study staffs must verify the accuracy with the data that are 
uploaded from the glucose meter.  Once an error is identified, only the corrected data should be 
entered in the eCRF and erroneous data in the diary will be corrected by the patient and initialed. 
Insulin dose and injection time for both basal insulin (Toujeo or Lantus) and mealtime insulin will 
be documented in the patients’ diary on a daily basis. ALL doses of mealtime insulin analog 
during the day as taken for all meals and all snacks must be recorded. 
Documentation of the SMPG and insulin dose in the corresponding e-CRF is specified in below 
table.  
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Table 5 - Documentation of SMPG and insulin dose in the e-CRF 
Visit  
3  
4 
 
5 
 
6 
 
7 
8 
 
9 
 
10 
  
11 
12 
  
13 
 
14 
  
15  16 
  
17 
  
18 
19 
Week 
(R) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
5-point SMPGa  
 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
 
7-point SMPG 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
x 
SMPG hypoglycemia  
Whenever documented in the patient diary 
 associated with a hypoglycemic event 
Basal insulin dose (IMP) 
Xb 
Daily dose as per the eCRF instruction  
Meal time insulin dose (NIMP)c 
x 
x 
x 
x 
x 
x 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
a 5-point SMPG profile: on 3 past days (not necessarily to be consecutive) during the week prior to these visits 
b Baseline Lantus: total daily dose and injection time during the past 3 days prior to randomization 
c Meal time insulin analogs: the total daily mealtime insulin dose and the number of injections (eg, 1, 2, 3 or >3) on 3 past days (not 
necessarily to be consecutive) during the week prior to these visits 
10.2.4 Continuous glucose monitoring (CGM) related procedures 
The CGM device to be used in the study is DexCom G4 Platinum professional (DexCom Inc., 
6340 Sequence Drive, San Diego CA 92121 USA). All patients must use the CGM device 
provided by the sponsor during the blinded CGM collection periods.  No personal CGM can be 
used during the weeks for the study specified CGM performance.  
During the study, when the protocol required CGM is not performed (Week 1 through Week 14), 
patients who use CGM as a part of their routine diabetes management before the study entry are 
allowed to resume using their personal CGM. However, patients cannot initiate CGM system 
during the study if they have not applied the CGM as their glycemic monitoring regimen at the 
study entry, ie, the answer to the question of currently using CGM is “No” at Visit 1 (to be 
collected in the V1 eCRF).  
10.2.4.1 CGM performance 
Two sets of blinded CGM will be conducted by the study patients. Baseline CGM will start at 
Visit 2 and stop at randomization visit (Visit 3). The end-of-treatment CGM will start at Visit 18 
and stop at the EOT visit (Visit 19). Patients must be well trained to understand the importance of 
the CGM performance and compliance of the manufacture (DexCom) instruction  
All patients will undergo Webinar CGM training at Visit 2 (re-training as needed) provided by 
DexCom regardless previous experience with CGM. After the training, patients should understand 
the process of CGM and how to handle the CGM device at home, including daily calibration with 
SMPG, the distance of receiver and effect of temperature on the device etc. The CGM receiver’s 
screen will be blocked of displaying data.  Neither patients nor investigators will be able to see the 
glucose values.  
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Insertion of CGM sensor will occur at Visit 2 and Visit 18 under the supervision of the 
investigators or the designees.  After the CGM sensor being implanted, the transmitter being 
attached, the patients will stay in the study site for 2 hours to perform one time calibration at the 
site. During the next 7 days when the patients are operating the CGM, they must: 
x Calibrate the CGM with the SMPG twice a day, which can be done during the protocol 
specified SMPG performance (Section 10.2.3.1), 
x Carry the CGM receiver with them all the time; the receiver must be placed within 20 feet 
(6 meters) from the patients’ body in order to capture the data measured by the device.   
Patients will receive a user guide of instruction included in the DexCom G4 Platinum Professional 
device kit. Technique support via a 24/7 help-line service for trouble shooting will be provided by 
the manufacture, DexCom. The patients should immediately contact the sites if they encounter 
any devise malfunction or device related events eg, sensor fracture. The investigator or a site staff 
will help patients contact the DexCom service line for problem solving.  
10.2.4.2 CGM qualification and data transfer 
After Visit 2 and Visit 18, each patient will wear the CGM for 7consecutive days to generate a 
minimum of 4 days (not necessarily to be consecutive) of usable CGM records. One day of 
qualified CGM data is defined as 85% recorded time over 24 hours without a gap lasting for 
2 hours.  
Next visits (Visit 3 and Visit 19) will occur after 7 days of CGM performance. If a patient cannot 
come for the site visit as scheduled he/she should inform the site immediately, as the CGM device 
will be automatically turned off. The patient may remove the sensor/transmitter by themselves at 
home or keep the “expired sensor” in place and remove it later during the site visit. Patients must 
bring the CGM device to the site at Visit 3 and Visit 19. The CGM will be uploaded into the study 
computer with
 and a report summary with daily CGM performance will be 
available immediately.  Investigators will not be able to see the recorded glucose values, nor will 
the report include any real glucose data. The CGM summary will be used for the investigators to 
review the patient’s daily performances and determine the quality of CGM.   
Investigators must review and print out the 
 summary (to be source documents). One 
day of CGM record is considered as qualified and useable if it meets follows: 
x 
the daily performance hours are marked as 24 hours ie, a record of <24 hours does not 
count for a day 
x 
the percentage of captured records is  85% of time (calculated by the system) over 
24 hours 
x 
during the 24 hours of a day, there is no gap (missing records) lasting for  2 hours 
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Only patients with 4 days of above qualified CGM records that are indicated in the
 
CGM report will proceed to randomization or end-of-treatment.  If for any reason, a patient fails 
to complete the qualified CGM, he/she will repeat the course of CGM. In such a case, all efforts 
should be made to help the patient find the root-cause of the failure and succeed in the next 
attempt.   
In such a case, completion of procedures at Visit 3 for randomization or Visit 19 for the end 
of treatment will be postponed.   
10.2.5 Laboratory 
Blood sampling for central laboratory assessments will be performed at 3 visits during the study 
(flow chart, Section 1.2). Urine samples will be collected at Visit 1. 
x 
Hematology: blood count (erythrocytes, hemoglobin, hematocrit, leukocytes, platelets); 
x 
Clinical chemistry: total bilirubin (in case of values above the normal range, 
differentiation in conjugated and non-conjugated bilirubin), AST, ALT, alkaline 
phosphatase (ALP), creatinine, estimated GFR, sodium, potassium; 
x 
C-Peptide at Visit 1 only for those patients that a documented C-Peptide value is not 
available in the source document. 
x 
Urine analysis (assayed by the central laboratory): pH, glucose, ketones, leucocytes, 
blood/hemoglobin, protein; 
x 
Serum pregnancy test in women of childbearing potential (WOCBP) at screening and 
urine pregnancy test at most onsite visits will be performed. Urine pregnancy tests can be 
performed more often if needed and confirmed by a serum test if positive. 
Note: Any abnormal laboratory value estimated as clinically significant by the investigator should 
be immediately rechecked (whenever possible using the central laboratory) for confirmation 
before making a decision of permanent discontinuation of IMP for the concerned patient. Any 
confirmed laboratory abnormality estimated as clinically significant by the investigator must be 
reported as an AE/SAE as applicable. 
10.3 
DEFINITION OF SOURCE DATA 
10.3.1 Source data to be found in patient´s file 
All evaluations recorded in the e-CRF must be supported by appropriately signed source 
documentation related but not limited to the following: 
x 
Agreement and signature of informed consent form with the study identification, 
x 
Study identification (name), 
x 
Patient number, Confirmation of randomization, Treatment batch number (treatment arm), 
dates and doses of study medication administration, 
x 
Medical, surgical, diabetes history, including information on: 
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- 
Demography, inclusion and exclusion criteria, 
- 
last participation in a clinical trial, 
- 
Contraception method for women of childbearing potential (WOCBP), 
- 
Previous and concomitant medication, 
x 
Dates and times of visits and assessments including examination results (Vital signs, 
height, body weight, laboratory reports), 
x 
The printouts of CGM performance summary that are provided by
 for 
both the baseline and EOT weeks, 
x 
Printouts of uploaded SMPG that will be available via 
at each onsite 
visit, 
x 
Insulin dose (both basal and mealtime) titration assessment and recommendation for 
insulin dose adjustment, 
x 
Investigator/Physician notes, Nursing notes, Dietician’s notes,  
x 
Adverse events and 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. 
x 
Date of premature study discontinuation (if any) and reason. 
x 
Patient diaries. 
10.3.2 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. 
10.4 
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 CRF. In any case, the 
patient should remain in the study as long as possible. 
10.4.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator or the attending 
physician(s) for adverse events (eg, treated with IV insulin). 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 
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responsibility of the IMP in the occurrence of the concerned event was unlikely and if the 
selection criteria for the study are still met (refer to 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 e-CRF pages when considered as confirmed.  
Temporary treatment discontinuation decided by the Investigator corresponds to more than 1 dose 
not administered to the patient. 
10.4.2 Permanent treatment discontinuation with investigational medicinal product(s) 
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. 
10.4.3 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 reasons for treatment discontinuation and this should be documented in the e-CRF. 
Criteria for permanent treatment continuation include: 
x 
At the patient’s own request, eg, withdrawal of consent for treatment  
x 
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)  
x 
Pregnancy 
x 
Specific request of the sponsor. 
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient.  
10.4.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as 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. 
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After permanent discontinuation of the IMP, patients will return to standard of care based on 
investigator and patient healthcare providers’ clinical recommendation. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
10.4.5 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 should return for an onsite visit and assessed using the procedure planned for 
the end-of-study visit (Visit 19).   
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.  
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient (eg, contacting patient’s family or private physician, reviewing 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)  
Patients who have withdrawn from the study cannot be rerandomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
The SAP will specify how these patients lost to follow-up for their primary endpoints will be 
considered. 
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10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.5.1 Definitions of adverse events  
10.5.1.1 Adverse event 
An adverse event (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. 
10.5.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
x 
Results in death, or 
x 
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. 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization, or 
x 
Results in persistent or significant disability/incapacity, or 
x 
Is a congenital anomaly/birth defect, 
x 
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 as a medically important event. The list is not 
intended to be exhaustive: 
x 
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). 
x 
Development of drug dependence or drug abuse, 
x 
ALT >3 x ULN + total bilirubin >2 x ULN or asymptomatic ALT increase >10 x ULN, 
x 
Suicide attempt or any event suggestive of suicidality, 
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x 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling), 
x 
Bullous cutaneous eruptions. 
10.5.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
List of AESI: 
x 
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a 
female partner of a male subject entered in a study with IMP/NIMP, 
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female 
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.5.1.2), 
- 
In the event of pregnancy in a female participant, IMP should be discontinued, 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined, 
x 
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, 
- 
Of note, asymptomatic overdose has to be reported as a standard AE, 
10.5.2 General guidelines for reporting adverse events 
x 
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 CRF. 
x 
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
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).  
x 
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 
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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.  
x 
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. 
x 
Laboratory, vital signs or ECG 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 
10.5.3  Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator or any designees must immediately: 
x 
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. 
x 
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 
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. 
x 
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. 
x 
A back-up plan (using a paper 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. 
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10.5.4 Guidelines for reporting adverse events of special interest   
10.5.4.1 Reporting of adverse events of special interest with immediate notification 
ENTER (within 24 hours) the information related to the AESI in the appropriate AESI form of the 
e-CRF. 
For AESIs with immediate notification, the AESI support documentation will be faxed to 
Quintiles Lifecycle Safety within 1 working day, even if not fulfilling a seriousness criterion, 
using the e-CRF. 
Pregnancy : 
- 
Pregnancy will be recorded as an AESI with immediate notification in all cases. It will 
be qualified as an SAE only if it fulfills the SAE criteria, 
- 
In the event of pregnancy, IMP should be discontinued,  
- 
Follow-up of the pregnancy is mandatory until the outcome has been determined, 
x 
Symptomatic overdose with IMP/NIMP : 
- 
An symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the Investigator or spontaneously notified by the patient and resulting in 
clinical symptoms and/or signs and considered a “significant overdose” by the 
Investigator. It will be recorded in the e-CRF as an AESI with immediate notification 
“Symptomatic OVERDOSE (accidental or intentional)” in all cases and will be 
qualified as an SAE only if it fulfills the SAE criteria. 
10.5.4.2 Reporting of adverse events of special interest without immediate notification 
Asymptomatic overdose (accidental or intentional) with the IMP/NIMP is defined as any 
“significant” overdose, without clinical symptoms and/or signs, either suspected by the 
Investigator or spontaneously notified by the patient (not based on accountability assessment). It 
will be recorded as an AE “Asymptomatic Overdose (accidental or intentional)”. 
10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
x 
all SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the health authorities, IECs/IRBs as appropriate and to the Investigators,    
x 
all SAEs that are expected and at least reasonably related to the IMPs to the health 
authorities, 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 United States 
Package Insert (USPI) for Lantus ((1) and Toujeo (2)]. 
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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. 
10.7 
SAFETY INSTRUCTIONS 
Safety instructions are provided for SMPG (see Section 10.2.3), CGM (see Section 10.2.4), 
Hypoglycemia (see Section 8.2.5 and Section 9.3.1), AE, SAE (see Section 10.5.1.2),  Vital Signs 
(see Section 10.2.1), and Obligation of the investigator regarding safety reporting (see 
Section 10.5). 
The Investigator is the primary person responsible for taking all clinically relevant decisions on 
safety issues. 
If judged necessary, the opinion of a Specialist should be envisaged in a timely manner (eg, acute 
renal failure, convulsions, skin rashes, angioedema, cardiac arrest, electrocardiographic 
modifications, etc.). 
10.8 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
The material in Section 11 of the clinical trial protocol constitutes the statistical analysis plan for 
the study. In case this plan needs revision during the study to accommodate clinical trial protocol 
amendments or to adapt to unexpected issues in study execution and data that affect planned 
analyses, a statistical analysis plan will be developed before first patient is enrolled and issued 
prior to database lock. 
11.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of 262 evaluable patients per treatment arm would provide at least 90% power to 
demonstrate superiority of Toujeo over Lantus for the primary efficacy variable of the percentage 
of time plasma glucose within the range of 70-180 mg/dL during Weeks 15-16 of the study. The 
calculations were based on a superiority hypothesis using a t-test at a 2-sided 5% significance 
level and assumes an absolute difference of at least 4% of time in range, a common standard 
deviation of 14% (assumed based on the prior AM data from the PDY12777 study), and an 
expected value of 53% in the Lantus arm. As a generalized linear model will be used for the 
primary analysis, the power should be somewhat higher due to reduced estimate variability versus 
the t-test.  
Considering prior data from the AM arms of the PDY12777 and EDITION-4 studies, this sample 
size would also provide at least 80% power to demonstrate a difference in the key secondary 
endpoint of the rate of documented symptomatic nocturnal hypoglycemia occurring at any point 
post randomization, assuming a rate ratio (Toujeo over Lantus) of at most 0.86 events per pt-year. 
Testing of this key secondary endpoint will be considered informative if superiority of the primary 
endpoint is met. 
Calculations were made using nQuery Advisor v6.01. 
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 patients who have been allocated a treatment kit number as 
recorded in the IVRS/IWRS database, regardless of whether the treatment kit was used or not. 
Patients treated without being randomized will not be considered as randomized and will not be 
included in any efficacy population.   
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. 
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The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
The randomized population will include any patient who has bene allocated to a randomized 
treatment regardless of whether the treatment kit was used or not.  
11.3.1 Efficacy populations 
11.3.1.1 Modified intent-to-treat population 
The efficacy analysis population will be the modified Intent-to-Treat (mITT) population, which 
will consist of all patients who are randomized and who have at least one post-baseline 
assessment of the endpoint of interest.  
11.3.2 Safety population 
The safety population will be comprised of all patients who take at least one dose of randomized 
treatment, and will be analyzed as-treated (according to the treatment actually received).  In 
addition: 
x 
Nonrandomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
x 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
x 
For patients receiving more than one study treatment during the trial, the treatment group 
allocation for as-treated analysis will be the treatment group in which he/she is treated for 
longer.  
11.4 
STATISTICAL METHODS 
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received 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, ignoring temporary drug discontinuation. It will be calculated as (Date of the last IMP 
administration – date of the first IMP administration) + 1. The exposure to IMP will be 
summarized categorically (counts and percentages) on the safety population. If appropriate, 
exposure will also be summarized by starting dose.  
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Also dose changes from baseline at the end of treatment for IMP (U and U/kg) will be 
summarized by starting dose groups for the safety population.  
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.  Overall treatment compliance is defined as the 
actual number of days with at least one administration of IMP compared to the planned number of 
days with IMP administration during the open-label treatment periods up to treatment 
discontinuation.  
Treatment compliance, above-planned and under-planned dosing percentages will be summarized 
descriptively (N, Mean, SD, Median, Min, and Max). The percentage of patients with compliance 
of <80% will be summarized. In addition, the number and percentage of patients with at least 
1 above-planned dosing administration will be given, as well as the number and percentage of 
patients with 0, (0, 20%], and >20% under-planned dosing administrations. No imputation will be 
made for patients with missing or incomplete data. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
The percentage of time plasma glucose within target range of 70-180 mg/dL (3.9–10 mmol/L) 
during Weeks 15-16 (obtained from CGM) will be calculated based on the total time within 
glycemic range in the evaluable assessment interval, divided by the total time of the evaluable 
assessment interval.  
The evaluable assessment interval for the calculation will comprise of 24-hour periods during 
Weeks 15-16 for which there is sufficient non-missing data. In order to be evaluable for analysis, 
a patient needs at least 4 days of 24-hour data meeting this criterion and should not receive 
protocol prohibited medication. 
The endpoint will be summarized by treatment group using mean, median, standard deviation, 
minimum and maximum.  
Differences between treatment groups will be explored using a generalized linear model, adjusting 
for key baseline characteristics (duration of diabetes, BMI, age and baseline value) and 
randomization strata. Adjusted mean estimates for each treatment with standard errors, the 
adjusted estimate of treatment mean difference with standard error and a 95 % confidence interval 
for the treatment mean difference will be provided. The statistical test will be for superiority of 
Toujeo over Lantus, two-sided and at a 5% significance level. 
11.4.2.2 Analysis of secondary efficacy endpoint(s) 
Nocturnal symptomatic hypoglycemia will be defined as an event with typical symptoms of 
hypoglycemia accompanied by SMPG  70 mg/dL (3.9 mmol/L) that occurs between 00:00 and 
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05:59 hours. The incidence will be analyzed using logistic regression, adjusting for randomization 
strata and other baseline characteristics (duration of diabetes, BMI and age) as clinically 
appropriate and if the model permits. 
The rate per patient-year of nocturnal symptomatic hypoglycemic events will be analyzed using 
an over-dispersed Poisson regression model, adjusting for randomization strata and other baseline 
characteristics (duration of diabetes, BMI and age) as clinically appropriate and if the model 
permits. 
The percentage of time glucose concentrations obtained by CGM within the target range of 
70-140 mg/dL (3.9-7.8 mmol/L) during the last 4 hours of CGM data prior to the next day basal 
insulin injection will be calculated as the total time within that time period that the plasma glucose 
is in the range, divided by the length of that time period of observation.  
The period of observation for the calculation will comprise of the last 4 hours during the final 
evaluable 24-hour period, where the evaluable period is defined as for the primary endpoint. 
Total, within day and between day coefficient of variation (calculated for each period as the ratio 
of the standard deviation of the glucose values to mean of the glucose values). 
Both the percentage of time glucose concentrations within the target range of 70-140 mg/dL 
(3.9-7.8 mmol/L) and the total, within day and between day coefficient of variation will be 
summarized at baseline and study endpoint by treatment group using mean, median, standard 
deviation, minimum and maximum, and will be analyzed as for the primary endpoint. 
Other endpoints 
The frequency and rates (nocturnal or 24 hours) of all hypoglycemic events will be analyzed for 
the  hypoglycemia categories of severe, documented symptomatic, asymptomatic, probable and 
relative, as defined in the publication of the ADA Workgroup on Hypoglycemia, 2015. These 
hypoglycemia categories will be analyzed as for symptomatic hypoglycemia described previously. 
The percentage of time plasma glucose in target range 70-140 mg/dL (3.9–7.8 mmol/L), and the 
percentage of time plasma glucose 70 mg/dL (3.9 mmol/L) and <54 mg/dL (3 mmol/L) will be 
calculated and analyzed as for the primary endpoint. For these endpoints, the time period of 
observation will be all evaluable time (24hours) and nocturnal, where nocturnal is defined as the 
period between 00:00-05:59 within the evaluable assessment interval. 
The area under the curve (AUC) of glucose concentration 70 mg/dL (3.9 mmol/L) will be 
derived as the area above the CGM profile (ie, the median curve) and below this lower limit of the 
glycemia range, divided by the length of the evaluable assessment interval. The median curve will 
be obtained by superimposing the date-time-stamped glucose values collected by CGM into 
24 nominal hourly baskets from which the point-wise median is calculated. 
The AUC of glucose concentrations >180 mg/dL (10 mmol/L) will be derived as the area below 
the CGM profile (ie, the median curve) and above the upper limit of the glycemia range, divided 
by the length of the assessment interval. The median curve will be derived as defined previously. 
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All of the continuous CGM endpoints will be summarized, and will be analyzed using a 
generalized linear model as described for the primary endpoint. 
The absolute values and change in 7-point SMPG profiles (pre-prandial and 2-hour post-prandial 
plasma glucose at breakfast, lunch and dinner, and bedtime) from baseline to Week 12, Week 16 
and the last on-treatment value (study endpoint) will be presented descriptively by treatment 
group. 
Summary statistics will also be presented for the absolute values and the change from baseline in 
HbA1c and central lab FPG to Week 8, Week 16 and last on-treatment value (study endpoint). 
The change from baseline to study endpoint will be analyzed using a mixed-effect model with 
repeated measures (MMRM) approach under the missing at random framework, using an 
adequate contrast at endpoint. The model will include fixed categorical effects of treatment arm, 
visit, treatment-by-visit interaction, randomization strata, and baseline HbA1c as covariate as well 
as baseline HbA1c-by-visit interaction. 
Insulin dose (total daily dose (units, units/kg), basal, mealtime/bolus, ratio of basal to bolus 
insulin dose) will be descriptively summarized for absolute values and change from baseline. 
11.4.2.3 Multiplicity considerations 
Results of the secondary analyses are considered as informative only if the primary analysis is 
positive, and will be examined in a hierarchical step-down manner.  Therefore the study overall 
type I error does not need to be adjusted for multiplicity. 
11.4.3 Analyses of safety data 
All safety and tolerance results will be presented by treatment group and on the safety population 
using the following common rule that the baseline value will be defined generally as the last 
available value prior to the first injection of IMP. 
For all safety data, the observation period will be divided into three segments: 
x 
The pre-treatment phase is defined as the time between when the patients give informed 
consent and time of the first IMP administration (excluded). 
x 
The on-treatment phase is defined as the time from the first IMP administration (included) 
until 1 day after the last dose of IMP (until midnight of day after last IMP dosing day). 
The post-treatment phase is defined as the time after the on-treatment phase until the end of 
treatment. 
Adverse events 
The primary focus of AE reporting is on TEAEs. Pre- and post-treatment AEs are described 
separately. If an AE date/time of onset (occurrence, worsening, or becoming serious) is 
incomplete, an imputation algorithm is used to classify the AE as pre-treatment, TEAE, or post-
treatment. The algorithm for imputing date / time of onset is conservative and classifies an AE as 
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a treatment emergent unless there is definitive information to determine it is pre- or post-
treatment.  
The following TEAEs will be summarized: Overall TEAEs, serious TEAEs, TEAEs leading to 
death, TEAEs leading to permanent treatment discontinuation. TEAEs will also be summarized by 
relationship to study treatment, and by severity. All treatment emergent SAEs will also be 
presented separately. 
Adverse event incidence tables will present the number and percentage of patients experiencing 
an AE by SOC, high level group term (HLGT), high level term HLT and preferred term (PT) 
sorted by internationally agreed order for SOC and in alphabetical order of HLGT, HLT and PT 
within a SOC for each treatment group.  Multiple occurrences of the same event in the same 
patient is counted only once in the tables within a treatment phase. The denominator for 
computation of percentages is the safety population within each treatment group. 
Injection site reactions and hypersensitivity reactions 
The number and percentage of patients experiencing injection site reactions and hypersensitivity 
reactions will be summarized separately. 
Death 
The following deaths summaries will be generated: 
x 
Number (%) of patients who died by study period (TEAE, on-study, poststudy) and 
reasons for death (if available), summarized on the safety population by treatment 
received. 
x 
Deaths in nonrandomized patients or randomized and not treated patients.   
All TEAEs leading to death will be summarized by primary SOC, HLGT, HLT and PT, showing 
the number (%) of patients sorted by SOC internationally agreed order. The other levels (HLGT, 
HLT, PT) will be presented in alphabetic order. 
Vital signs 
Summary statistics for absolute values and changes from baseline of all vital signs variables, 
including body weight, will be calculated from the absolute values and changes from baseline for 
each visit or study assessment (baseline, each post baseline time point, last on-treatment during 
the on-treatment period of the study) by treatment. 
The incidence of potentially clinically significant abnormalities (PCSA)s at any time during the 
on-treatment period will be separately summarized by treatment group whatever the baseline 
level. 
11.5 
INTERIM ANALYSIS 
No interim analysis is planned. 
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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, delegated Investigator staff 
and subinvestigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, 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  
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient 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 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
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 
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, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
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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. It 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 
Investigator’s Brochure will be sent to the IRB/IEC. 
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 Sub 
investigators 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. 
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 
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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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ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub investigator 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 Sub investigators shall be bound by the same obligation as the Investigator. The Investigator 
shall inform the Sub investigators of the confidential nature of the clinical trial. 
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The Investigator and the Sub investigators 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 
x 
The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
x 
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. 
x 
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, Good Clinical Practice 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:  
x 
The information on the product leads to doubt as to the benefit/risk ratio; 
x 
Patient enrollment is unsatisfactory; 
x 
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; 
x 
Non-compliance 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; 
x 
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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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 of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, 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 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 re-collected if 
necessary. 
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BIBLIOGRAPHIC REFERENCES 
1. LANTUS (insulin glargine injection) solution for subcutaneous injection Prescribing
Information – Initial U.S. Approval:2000.
2. TOUJEO (insulin glargine injection) –U300, for subcutaneous use – initial U.S. Approval:
2015.
3. Investigator’s Brochure Edition 14: Insulin Glargine (HOE-901), 2015.
4. Home PD, Bergenstal RM, Bolli GB, Ziemen M, Rojeski M, Espinasse M, et al.  New Insulin
Glargine 300 Units/mL Versus Glargine 100 Units/mL in People With Type 1 Diabetes: A
Randomized, Phase 3a, Open-Label Clinical Trial (EDITION 4). Diabetes Care. ePublished
2015 Jun 17. p 9.
5. Defining and Reporting Hypoglycemia in Diabetes: A Report from American diabetes
Association Workgroup on hypoglycemia Diabetes Care. 2005 May;28(5):1245-9.
6. Mauras N, Fox L, Englert K, Beck RW.  Continuous glucose monitoring in type 1 diabetes.
Endocrine. 2013 Feb;43(1):41-50.
7. Effectiveness of continuous glucose monitoring in a clinical care environment: evidence from
the Juvenile Diabetes Research Foundation continuous glucose monitoring (JDRF-CGM) trial.
Diabetes Care. 2010 Jan;33(1):17-22.
8. Davis AK, DuBose SN, Haller MJ, Miller KM, DiMeglio LA, Bethin KE, et al. Prevalence of
detectable C-Peptide according to age at diagnosis and duration of type 1 diabetes. Diabetes
Care. 2015 Mar;38(3):476-81.
9. Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, et al.
Continuous glucose monitoring and intensive treatment of type1 diabetes. Juvenile Diabetes
Research Foundation Continuous Glucose Monitoring Study Group.  N Engl J Med. 2008 Oct
2;359(14):1464-76.
10. ICH Topic M 3 (R2) Non-Clinical Safety Studies for the Conduct of Human Clinical Trials
and Marketing Authorization for Pharmaceuticals, Note for guidance on non-clinical safety
studies for the conduct of human clincial trials and marketing authorization for
pharmaceuticals (CPMP/ICH/286/95) June 2009.
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