A 24-week, Multicenter, Randomized, Open-Label, Parallel-group StudyComparing the Efficacy and Safety of Toujeo® and Tresiba® in Insulin-NaivePatients With Type 2 Diabetes Mellitus Not Adequately Controlled With OralAntihyperglycemic Drug(s) ± GLP-1 Receptor Agonist
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
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-002579 VERSION N°13.0 (17-SEP-2015) 
Page 1 
CLINICAL TRIAL PROTOCOL 
TITLE: A 24-week, Multicenter, Randomized, Open-label, Parallel-group Study 
Comparing the Efficacy and Safety of Toujeo® and Tresiba® in Insulin-Naive 
Patients with Type 2 Diabetes Mellitus not Adequately Controlled with Oral 
Antidiabetic Drug(s) ± GLP-1 receptor agonist 
COMPOUND: Toujeo®/Insulin Glargine 300 U/mL/HOE901 
STUDY NUMBER: LPS14584 
STUDY NAME: NA 
Version 
Number: 
1  
Universal Trial Number:  
U1111-1177-6327 
Date: 
18-Dec-2015
Total number of pages: 
95 
(electronic 1.0)
NCT02738151

Clinical Trial Protocol  
18-Dec-2015 
HOE901/LPS14584 - insulin glargine 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 2 
NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
  
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
  
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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Clinical Trial Protocol  
18-Dec-2015 
HOE901/LPS14584 - insulin glargine 
Version number: 1 
 
Property of the Sanofi Group - strictly confidential 
Page 3 
CLINICAL TRIAL SUMMARY 
 
COMPOUND: Toujeo®/Insulin 
Glargine 300 U/mL/HOE901 
STUDY No: LPS14584 
TITLE 
A 24-week, multicenter, randomized, open-label, parallel-group study 
comparing the efficacy and safety of Toujeo® and Tresiba® in insulin-naive 
patients with type 2 Diabetes Mellitus not adequately controlled with Oral 
Antidiabetic Drug(s) ± GLP-1 receptor agonist 
INVESTIGATOR/TRIAL LOCATION 
Multinational 
PHASE OF DEVELOPMENT 
4 
STUDY OBJECTIVE(S) 
 
Primary objective: 
To demonstrate non-inferiority in the efficacy of Toujeo in comparison with 
Tresiba in terms of change of glycated hemoglobin A1c (HbA1c) from 
baseline to Week 24 in insulin-naive patients with Type 2 Diabetes mellitus 
(T2DM) not adequately controlled with Oral Antidiabetic Drugs (OADs) with or 
without GLP-1 receptor agonist. 
Secondary objective(s): 
To assess the effects of Toujeo in comparison with Tresiba on: 
x 
Change in HbA1c over Week 12, 
x 
Change in Fasting plasma glucose (FPG) over Week 12 and 
Week 24, 
x 
Change of Fasting Self-Monitored Plasma Glucose (SMPG) and 
4-point and 8-point SMPG profile over Week 12 and Week 24, 
x 
Change of mean 24-hour plasma glucose over Week 12 and 
Week 24, 
x 
Change in variability of fasting SMPG and 24-hour plasma glucose 
over Week 12 and Week 24, 
x 
Percentage of patients reaching HbA1c targets <7% and  6.5% at 
Week 12 and Week 24, 
x 
Percentage of patients reaching HbA1c targets <7% and  6.5% at 
Week 12 and Week 24 without severe and/or confirmed 
hypoglycemia during the12 week and 24-week treatment period, 
x 
Percentage of patients requiring rescue therapy during the 24-week 
treatment period. 
To assess the frequency of occurrence and diurnal distribution of 
hypoglycemia by category of hypoglycemia (symptomatic, asymptomatic, 
nocturnal, severe, probable and pseudo). 
To assess the safety in each treatment group over 24 weeks of treatment. 
To assess the treatment effects in each treatment group on Patient Reported 
Outcomes (PROs) measured by the following questionnaires: 
x 
Diabetes Treatment Satisfaction Questionnaire (DTSQ, status version 
and change version), 
x 
Hypoglycemia Attitude and Behavior Scale (HABS). 
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Clinical Trial Protocol  
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STUDY DESIGN 
A 24 weeks, multinational, multicenter, randomized, open-label, 2-arm 
parallel-group trial. Patients will receive in a 1:1 ratio either Toujeo or Tresiba. 
Randomization will be stratified by value of HbA1c obtained at the screening 
visit (<8.0%; 8.0%) and sulphonylurea (SU) or meglitinides use before the 
day of screening (Yes; No). 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
x 
Adult patients with T2DM inadequately controlled with OADs 
therapy with/without GLP-1 receptor agonist at stable dose for at 
least 3 months, 
x 
Signed written informed consent. 
 
Exclusion criteria: 
x 
Age <18 years at time of informed consent,  
x 
HbA1c <7.5% or >10.5% (at screening visit), 
x 
BMI<25 kg/m2 or >40 kg/m2, 
x 
History of T2DM for less than 1 year before screening, 
x 
Less than 6 months before screening on OADs treatment and 
GLP-1 receptor agonist (if taken), 
x 
Current or previous insulin use except for a maximum of 
8 consecutive days or totally 15 days (eg, acute illness, surgery) 
during the last year prior to screening, 
x 
Initiation of new glucose-lowering medications and/or weight loss 
drug in the last 3 months before screening visit, 
x 
Patient receiving only non-insulin antidiabetic drugs not approved 
for combination with insulin according to local labelling/ local 
treatment guideline, 
x 
History of hypoglycemia unawareness or repeated episodes of 
severe hypoglycemia or metabolic acidosis, including hospitalization 
for diabetic ketoacidosis during the last 12 months prior to 
screening, 
x 
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 
End stage renal disease (defined as estimated GFR (MDRD) 
<15 ml/min/1.73 m2 or being on hemodialysis), 
x 
Any acute or chronic condition that in the opinion of investigator 
would affect the patient safety, compliance or study results,  
x 
Any contraindication to use of Toujeo or Tresiba as defined in the 
national product label, hypersensitivity to Toujeo or Tresiba active 
ingredients or one of the excipients, 
x 
Pregnant or breast-feeding women. 
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Clinical Trial Protocol  
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Total expected number of patients 
Approximately 920 patients 
(Toujeo:  n = 460; Tresiba: n = 460) 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation: 
Tested drug: Toujeo (insulin glargine 300 U/mL) 
Toujeo will be supplied as a sterile, non-pyrogenic, clear, colorless solution in 
the Toujeo SoloStar prefilled (disposable) pen (insulin glargine 300 units/mL 
solution for subcutaneous (SC) injection). Each Toujeo® SoloStar® contains in 
total 450 units of insulin glargine (1.5 mL of 300 units/mL insulin glargine 
solution). This pen allows dose setting in the range of 1–80 units with 
minimum of 1 unit increment. Mixing of Toujeo with other insulin products is 
not allowed nor dilution. 
Control drug: Tresiba® (insulin Degludec 100 U/mL) 
Tresiba® will be supplied as a sterile, non-pyrogenic, clear, colorless solution 
in the marketed Tresiba® FlexTouch prefilled (disposable) pen (insulin 
degludec 100 units/mL solution for SC injection).  
Each Tresiba FlexTouch contains in total 300 units of insulin degludec 
(3.0 mL of 100 units/mL insulin degludec solutions). This pen allows dose 
setting in the range of 1–80 units with minimum of 1 unit increment. 
Mixing of Tresiba with other insulin products is not allowed nor dilution. 
Route(s) of administration: 
Toujeo and Tresiba will be self-administered by SC injections once daily 
between 6:00 PM and 8:00 PM throughout the study treatment period. 
Dose regimen: 
Starting dose: 
The recommended daily starting dose of each basal insulin is defined per 
label with once daily as below followed by individual dose adjustment: 
x 
Toujeo: 0.2 units/kg 
x 
Tresiba: 10 units  
Dose adjustment 
During the study, doses of either basal insulin, Toujeo or Tresiba will be 
titrated to achieve glycemic targets without hypoglycemia according to the 
same algorithm as below.  
x 
After randomization, the dose will be titrated at least weekly (but no 
more often than every 3 days), until the patient reaches a target 
fasting SMPG of 80 to 100 mg/dL (4.4 to 5.6 mmol/L) while avoiding 
hypoglycemia episodes.  
x 
Thereafter, until the end of the study, the dose will be adjusted as 
necessary to maintain this fasting SMPG target. 
x 
Dose adjustments are based on a median of fasting SMPG values 
from the last 3 measurements, which includes the value measured 
on the day of titration, measured by the patient using glucometers 
and accessories supplied by the sponsor. 
The best efforts should be made to reach the target glucose by 8-12 weeks 
after randomization. 
 
 
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Clinical Trial Protocol  
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HOE901/LPS14584 - insulin glargine 
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Page 6 
Table 1 - Dose adjustment algorithm 
Median# Fasting SMPG from last 3 
measurement (mg/dL) 
Toujeo and Tresiba dose 
change* 
>140 (>7.8 mmol/L) 
+ 6 U 
>120 and 140 (>6.7- 7.8 mmol/L) 
+ 4 U 
>100 and 120 (>5.6 – 6.7 mmol/L) 
+ 2 U 
80 and 100 (4.4 - 5.6 mmol/L) 
No change 
<80 (<4.4 mmol/L) or occurrence of 
1 symptomatic confirmed hypoglycemia 
episode documented in the preceding week 
-2U or at the discretion of 
the investigator 
* Dose adjustment should not be more often than every 3 days. 
# Median refers to intermediate SMPG value (the value between the lowest 
and the highest SMPG values when the values are ranked in a growing 
order). 
 
Noninvestigational medicinal 
product(s) (if applicable) 
 
Formulation: 
Background therapy: OADs and GLP-1 receptor agonist (if taken) will be 
considered as NIMP(s).  
Rescue medication will be considered as NIMP(s): anti-diabetic medication 
(should be based on Investigator’s decision and local labeling documents). 
Route(s) of administration: 
OADs: Oral administration  
GLP-1 receptor agonist (if taken): SC injection 
Dose regimen: 
 
The type and dose of anti-diabetic background therapy will remain unchanged 
during the study; unless agents not approved in combination with insulin 
according to local labeling/local treatment guideline or identified safety 
concerns necessitate a reduction in dose or discontinuation of non-insulin 
antidiabetic drug(s).  
 
Rescue therapy:  
Routine fasting SMPG, central laboratory FPG measurements and central 
laboratory alerts on HbA1c are set up to ensure that glycemic parameters 
remain under predefined threshold values. The threshold values for rescue 
are defined as follows: 
From Visit 14 (Week 12): FPG >200 mg/dL (11 mmol/L) and / or 
HbA1c>8.5%. 
In case of FPG or HbA1c above the target values and/or SMPG are not 
improving as expected in spite of successive IMP dose titration (note: the 
investigator should ensure that no reasonable explanation exists for 
insufficient glucose control and undertake appropriate action to decrease 
FPG/HbA1c under the threshold values), intensification of the treatment is to 
be considered.  
The choice of the anti-diabetic treatment to be added to the basal insulin 
should be based on Investigator’s decision and local labeling documents, 
adding prandial insulin may be the preferred option. The addition of a new 
antidiabetic drug or increase in dose of background antidiabetic medication 
(“rescue”) should not be decided based on a single FPG or HbA1c value but 
be based on a thorough evaluation of the patient’s glycemic control. 
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Clinical Trial Protocol  
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HOE901/LPS14584 - insulin glargine 
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The type of rescue therapy, reason for initiating rescue therapy and the day of 
starting rescue therapy along with the dose will be documented. 
All assessments for primary and secondary efficacy and safety parameters 
planned in final on treatment assessment visit (Visit 20) should be performed 
before starting the “rescue medication” (adding new antidiabetic agent or 
increase in dose of existing background antidiabetic medication.) 
Then the patient continues the IMP and stays in the study in order to collect 
safety information. 
ENDPOINT(S) 
 
Primary endpoint: 
HbA1c (change from baseline to endpoint [Week 24]) 
 
Secondary endpoint(s): 
Secondary efficacy endpoints 
x 
HbA1c: change from baseline to Week 12 
x 
FPG: change from baseline to Week 12 and Week 24 
x 
Fasting SMPG: change from baseline to Week 12 and Week 24, 
x 
Change in 4-point and 8-point SMPG profiles per time-point from 
baseline to Week 12 and Week 24, 
x 
Change of mean 24-hour plasma glucose based on 8-point SMPG 
from baseline to Week 12 and Week 24, 
x 
Change in variability of fasting SMPG and 24-hour plasma glucose 
based on 8-point SMPG from baseline to Week 12 and Week 24, 
x 
Percentage (%) of patients reaching target HbA1c <7% and 6.5% 
at Week 12 and Week 24; 
x 
Percentage (%) of patients reaching target HbA1c <7% and 6.5% 
at Week 12 and Week 24 without severe and/or confirmed 
hypoglycemia (70 mg/dL and 54 mg/dL as cut off point) event 
during the 12-week and 24-week treatment period, 
x 
Percentage (%) of patients with SU or meglitinide dose 
reduction/discontinuation due to hypoglycemia during 24 weeks 
treatment period, 
x 
Percentage of patients requiring rescue therapy during 24 weeks 
treatment period, 
x 
Basal insulin dose (U and U/kg body weight): change from baseline 
to Week 12 and Week 24. 
 
Safety endpoint: 
Safety analyses will be based on all hypoglycemia events, local tolerability at 
injection site, hypersensitivity reactions, other adverse events (AE) or serious 
adverse events (SAE) including Adverse events with special interest (AESI) 
and other safety information including vital signs, body weight. 
Hypoglycemia will be classified as ADA category and analyzed using the 
following variables: 
x 
Percentage of patients with at least one episode of confirmed 
hypoglycemia (cut off value 70 or 54 mg/dL) and event rate during 
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Clinical Trial Protocol  
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HOE901/LPS14584 - insulin glargine 
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24 weeks treatment periods, 
x 
Rate of hypoglycemia per month computed as: 365.25/12 x 
(number of episodes of hypoglycemia)/(number of days exposed in 
time window), 
x 
Percentage of patients and event rate of Hypoglycemia by study 
period (for 12 weeks, for >12 weeks to 24 weeks) to evaluate the 
potentially increased risk of hypoglycemia during the initial 12-week 
after starting treatment with basal insulin, 
x 
The diurnal distribution of the occurrence of each episode of 
documented hypoglycemia by category will be presented by two-
hour timeframe over 24 hours during the 24 weeks treatment 
period. 
Other endpoint(s): 
x 
Patient reported outcome (PRO): 
o 
Diabetes Treatment Satisfaction Questionnaire status 
version (DTSQs) and change version (DTSQc). 
o 
Hypoglycemia Attitudes and Behavior Scale (HABS)  
ASSESSMENT SCHEDULE 
The schedule of study-related procedures/assessments is detailed in the 
Study Flowchart 
Early termination: 
For all patients who prematurely and permanently discontinue the study 
treatment, assessments scheduled at the “End of treatment visit” and the 
“Post-treatment safety follow up visit”, will be performed as soon as possible. 
Afterward, the patients should continue in the study up to the scheduled date 
of study completion. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
Number of subjects: N=920 
A sample size of 920 patients (460 with Toujeo and 460 with Tresiba) will 
ensure that the upper confidence limit of the two-sided 95% CI for the 
adjusted mean difference between Toujeo and Tresiba would not exceed 
0.3% HbA1c with 90 % power assuming that standard deviation (SD) is 1.4%, 
and that the true difference between Toujeo and Tresiba is zero in HbA1c. 
General aspects of the analyses: 
For efficacy analyses, the baseline for both treatment groups is defined as the 
last available value prior to randomization. 
Analysis population: 
The primary efficacy population will be the ITT (intent-to-treat) population, 
which includes all randomized patients who received at least one dose of 
IMP, irrespective of the treatment actually being received, analyzed according 
to the treatment group allocated by randomization. 
The safety population is defined as all randomized patients who received at 
least one dose of IMP, regardless of the amount of treatment administered. 
Patients will be analyzed according to the treatment actually received. 
Primary analysis: 
The primary efficacy endpoint (change in HbA1c from baseline to endpoint 
[Week 24]) using available data during the 24-week on-treatment period will 
be analyzed using a mixed-effect model with repeated measures (MMRM) 
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Clinical Trial Protocol  
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Page 9 
approach, using the missing at random framework carried out via SAS PROC 
MIXED using adequate contrasts. The model will include fixed categorical 
effects of treatment group, visit, treatment-by-visit interaction, randomization 
stratum of use of SU or meglitinide at screening (Yes versus No) and the 
continuous fixed covariates of baseline HbA1c value and baseline HbA1c 
value-by-visit interaction. 
A stepwise closed testing approach will be used for the primary efficacy 
variable to assess non-inferiority and superiority sequentially. 
x 
Step 1 will proceed to assess non-inferiority Toujeo versus Tresiba. 
To assess non-inferiority, the upper bound of the two-sided 95% CI for the 
difference in the mean change in HbA1c from baseline to Week 24 between 
Toujeo and Tresiba will be compared with the predefined non-inferiority 
margin of 0.3% HbA1c. Non-inferiority will be demonstrated if the upper 
bound of the two-sided 95% CI of the difference between Toujeo and Tresiba 
on ITT population is <0.3%. 
x 
Step 2 will test superiority of Toujeo over Tresiba, only if non-
inferiority of Toujeo versus Tresiba has been demonstrated. 
The superiority of Toujeo over Tresiba will be demonstrated if the upper 
bound of the two-sided 95% CI for the difference in the mean change in 
HbA1c from baseline to Week 24 between Toujeo over Tresiba on ITT 
population is <0 (zero). 
 
Analysis of secondary endpoints: 
All secondary efficacy endpoints will be analyzed or summarized on the 
24-week on treatment period using the ITT population. 
Safety analyses will be descriptive, based on the safety population. 
DURATION OF STUDY PERIOD (per 
patient)  
The study consists of:  
x 
Up-to 2 weeks screening period; it can be exceptionally extended 
up to one additional week,  
x 
A 24-week open label comparative efficacy and safety treatment 
period,  
x 
A 7-day post-treatment safety follow-up period for all the patients 
after permanent investigational medical product(IMP) 
discontinuation(except for patients who prematurely discontinue the 
study treatment but continue in the study) 
In total the maximum study duration will be approximately 27 weeks per 
patient: 
2 weeks + 24 weeks ± 5 days + 7 days 
 
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Clinical Trial Protocol  
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
R*
Toujeo®
once daily
Tresiba®
once daily
460 patients
460 patients
Screening
week
visit
-2
1
D1
2
1
3
2
4
3
5
4
6
5
7
6
8
7
9
8
10
9
11
10
12
11
13
12
14
14
15
16
16
18
17
20
18
22
19
24w+7d
21
24
20
Treatment  period
End of 
Treatment
Post 
treatment 
Follow up
On-site visit
Phone call visit
If 7.5% < =HbA1c <=10.5% at screening.1:1 randomization stratified by value of HbA1c at screening visit (<8%, 8%) 
and SU or meglitinides use before the day of screening (Yes; No)
Baseline 
Last IMP
Primary endpoint 
HbA1c
R
•
T2D with 
OAD±GLP-
1RA and 
insulin naive
•
HbA1c: 7.5-
10.5 % 
Titration target: Fasting SMPG 80-100mg/dL without hypoglycemia
•
Background OADs and GLP-1RA will be continued with stable dose
•
Starting dose: Toujeo 0.2U/Kg; Tresiba 10U 
•
The first 12 weeks are intended for titration of Toujeo or Tresiba; The last 12 weeks are intended as stable treatment up to the final visit
•
T2D: type 2 diabetes; SU:sulfonylurea; SMPG: Self-Monitored Plasma Glucose
 
 
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Page 11 
1.2 
STUDY FLOW CHART 
 
Screening 
Treatment period 
Post-treatment 
observations 
 
 
VISIT 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Visit 3-9: ± 3 days / vs. baseline 
Visit 10-20: ± 5 days/ vs. 
baseline 
Visit 21:  -1~+3 days vs. visit 20 
Wk-2 
D1 
baseline 
Wk1
b 
Wk2 Wk3 
b 
Wk4 Wk5 
b 
Wk6 
b 
Wk7 
b 
Wk8 Wk9 
b 
Wk10 
 b 
Wk11 
 b 
Wk12 Wk14 
b 
Wk16 Wk18 
b 
Wk20 
Wk22 
b 
Wk24 end 
of 
treatment 
V20+7days 
b 
End of study 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography, medical history; 
diabetes history, prior 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Height  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight  
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Dispensation of glucometer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation diary  
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Training of glucometer and diary 
and SMPG profilec 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Collection of diary  
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Collection of glucose meter (if 
mandatory by local regulation) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Diet and lifestyle counseling  
Provided at on site visit if needed throughout the study 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IVRS/IWRS call 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
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Clinical Trial Protocol  
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Screening 
Treatment period 
Post-treatment 
observations 
 
 
VISIT 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Visit 3-9: ± 3 days / vs. baseline 
Visit 10-20: ± 5 days/ vs. 
baseline 
Visit 21:  -1~+3 days vs. visit 20 
Wk-2 
D1 
baseline 
Wk1
b 
Wk2 Wk3 
b 
Wk4 Wk5 
b 
Wk6 
b 
Wk7 
b 
Wk8 Wk9 
b 
Wk10 
 b 
Wk11 
 b 
Wk12 Wk14 
b 
Wk16 Wk18 
b 
Wk20 
Wk22 
b 
Wk24 end 
of 
treatment 
V20+7days 
b 
End of study 
Treatment  
 
Pre-filled disposable pen 
(SoloStar® or FlexTouch®) and 
self-injection trainingc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of Study 
medication   
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Counting / collecting used and 
unused study medicationd 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Compliance Check (Review of 
diary) 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Documentation of the IMP dose 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
including antihypergycemic 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Efficacy  
 
Fasting condition visite 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
HbA1c (central lab) 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Fasting plasma glucose (central 
lab) 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
SMPGf 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
4-point SMPGf 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
8-point SMPGf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
DTSQs (status version)g 
HABS 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
DTSQc (change version)g 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
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Screening 
Treatment period 
Post-treatment 
observations 
 
 
VISIT 
1a 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
Visit 3-9: ± 3 days / vs. baseline 
Visit 10-20: ± 5 days/ vs. 
baseline 
Visit 21:  -1~+3 days vs. visit 20 
Wk-2 
D1 
baseline 
Wk1
b 
Wk2 Wk3 
b 
Wk4 Wk5 
b 
Wk6 
b 
Wk7 
b 
Wk8 Wk9 
b 
Wk10 
 b 
Wk11 
 b 
Wk12 Wk14 
b 
Wk16 Wk18 
b 
Wk20 
Wk22 
b 
Wk24 end 
of 
treatment 
V20+7days 
b 
End of study 
Safety 
 
AE/SAE/Hypoglycemia/ injection 
site reaction 
Continuously assessed and recorded all along the study(report SAE/AESI to the sponsor within 24 hours) 
Vital signsh 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyi, Clinical 
Chemistry(central lab)j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine analysis(central lab)k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH and estradiol 
(Menopausal women 
only(central lab) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (WOCBP only)l 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Rescue therapy 
 
 
All assessments planned in V20 should be performed before starting rescue therapy, patients then continue the study treatment (including 
background therapy), and all visits and assessments should be performed as scheduled; 
 
Prematurely permanent IMP 
discontinuation 
 
 
Patients should have a visit as soon as possible with the assessments normally planned in V20. Afterward, the patients should continue in 
the study up to the scheduled date of study completion. They should be followed up according to the study procedures as specified in the 
protocol (except for the 7-day safety post-treatment follow-up). 
 
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a 
If any of the laboratory parameters are not available upon the end of the screening period (eg, sample material damaged during transport etc) a retest can be performed. If this is the case (and exceptionally in 
other situations if justified) the screening period can be extended of one additional week, ie, baseline visit (V2, Day 1) can be scheduled no later than 3 weeks after screening visit (V1, Week -2) 
b 
Mandatory telephone visit or optional clinical visit. During up-titration, until a stable basal insulin dose is achieved, as well as throughout the later course of the study, additional contacts (phone, on-site visit) will 
be made available for patients to discuss dose adjustments in-between the scheduled visits. The frequency of the contacts is at the discretion of the investigator and will be determined by the needs of the 
patient  
c 
Training repeated as often as necessary  
d 
Visit 4: collecting used study medication only.  
e 
Fasting condition: patient to come after a fasting period of at least 8 hours: during this time, no food or liquid intake other than water.  
f 
Self-monitored plasma glucose (SMPG): 
Fasting pre-breakfast SMPG: test and collected daily until up-titration has been completed and fasting pre-breakfast SMPG is stable in the target range. Thereafter, fasting pre-breakfast SMPG are mandatory 
on at least 3 days per week. On the day of 4-point blood glucose profile performed, fasting SMPG will be considered as the first point of measurement, ie, pre-breakfast time point.  
4-point blood glucose profiles (pre-breakfast, pre-lunch, pre-dinner and bedtime): on at least one day in the 5 days before Week 4 and Week 8 on site visit. 
8-point blood glucose profiles (03:00 at night, before and 2 hours after breakfast, before and 2 hours after lunch, before and 2 hours after dinner, at bedtime): on at least one day in the 5 days before the 
baseline visit and before Week 12 and Week 24 on site visit. Special attention should be paid that the 3:00 AM. SMPG value is recorded. 
SMPG in case of hypoglycemic symptoms: whenever experienced (prior to countermeasure if possible). 
g 
DTSQs and HABS are tested at baseline, Week 12 and Week 24.  DTSQc is only tested at Week 12 and Week 24. At 12 and 24 weeks, DTSQs will be administered before the DTSQc. 
h 
Heart rate, blood pressure in sitting condition on reference arm. At screening visit (V1) only: additionally determination of the reference arm for blood pressure measurements during the study (in sitting 
condition). 
i 
Hematology: Erythrocytes, hemoglobin, hematocrit, leukocytes and platelets. 
j 
Clinical chemistry: total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), AST, ALT, ALP, creatinine, estimated GFR (MDRD), sodium, potassium. 
k 
Urine analysis: pH, glucose, ketones, leucocytes, blood/hemoglobin, protein 
l 
For women of childbearing potential (WOCBP): Serum pregnancy test for screening (central laboratory); urine pregnancy test at site for subsequent monitoring 
Note: Telephone counseling will be available at any time as require 
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2 
TABLE OF CONTENTS 
 
CLINICAL TRIAL PROTOCOL.......................................................................................................................1 
1 
FLOW CHARTS.............................................................................................................................10 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................10 
1.2 
STUDY FLOW CHART ..................................................................................................................11 
2 
TABLE OF CONTENTS ................................................................................................................15 
3 
LIST OF ABBREVIATIONS ..........................................................................................................20 
4 
INTRODUCTION AND RATIONALE.............................................................................................22 
5 
STUDY OBJECTIVES ...................................................................................................................26 
5.1 
PRIMARY.......................................................................................................................................26 
5.2 
SECONDARY ................................................................................................................................26 
6 
STUDY DESIGN ............................................................................................................................27 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................27 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................27 
6.2.1 
Duration of study participation for each patient .............................................................................27 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................27 
6.3 
INTERIM ANALYSIS......................................................................................................................28 
7 
SELECTION OF PATIENTS..........................................................................................................29 
7.1 
INCLUSION CRITERIA..................................................................................................................29 
7.2 
EXCLUSION CRITERIA ................................................................................................................29 
7.2.1 
Exclusion criteria related to study methodology ............................................................................29 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......31 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................31 
7.2.4 
Additional exclusion criteria during or at the end of screening before randomization ...................31 
8 
STUDY TREATMENTS .................................................................................................................32 
8.1 
DIET AND EXERCISE ...................................................................................................................32 
8.2 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ..........................................................................32 
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8.2.1 
Formulations ..................................................................................................................................32 
8.2.2 
Injection devices and training to use injection devices ..................................................................32 
8.2.2.1 
Injection devices.............................................................................................................................32 
8.2.2.2 
Training to use injection devices....................................................................................................33 
8.2.3 
Dosage schedule ...........................................................................................................................34 
8.2.4 
Starting dose and dose adjustments..............................................................................................34 
8.3 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) ..................................................................35 
8.3.1 
Anti-diabetic background therapy ..................................................................................................35 
8.3.2 
Rescue therapy:.............................................................................................................................36 
8.4 
BLINDING PROCEDURES............................................................................................................37 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................37 
8.6 
PACKAGING AND LABELING ......................................................................................................38 
8.7 
STORAGE CONDITIONS AND SHELF LIFE................................................................................38 
8.8 
RESPONSIBILITIES ......................................................................................................................39 
8.8.1 
Treatment accountability and compliance......................................................................................39 
8.8.2 
Return and/or destruction of treatments ........................................................................................40 
8.9 
CONCOMITANT MEDICATION.....................................................................................................40 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................42 
9.1 
PRIMARY ENDPOINT ...................................................................................................................42 
9.1.1 
Primary endpoint............................................................................................................................42 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................42 
9.2.1 
Secondary efficacy endpoint(s)......................................................................................................42 
9.2.1.1 
Fasting plasma glucose .................................................................................................................43 
9.2.1.2 
Self-measured plasma glucose (SMPG) and glucometer, patient diaries and training.................43 
9.2.1.3 
Dose of IMP ...................................................................................................................................46 
9.2.1.4 
SU or meglitinide dose reduction/discontinuation due to hypoglycemia........................................46 
9.2.2 
Safety endpoints ............................................................................................................................46 
9.2.2.1 
Adverse events ..............................................................................................................................47 
9.2.2.2 
Hypoglycemia.................................................................................................................................48 
9.2.2.3 
Body weight....................................................................................................................................48 
9.2.2.4 
Laboratory safety variables............................................................................................................48 
9.2.2.5 
Physical examination .....................................................................................................................48 
9.2.2.6 
Vital signs.......................................................................................................................................48 
9.3 
OTHER ENDPOINTS.....................................................................................................................49 
9.3.1 
Patient Reported Outcomes (Health-related Quality of Life) .........................................................49 
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9.4 
FUTURE USE OF SAMPLES ........................................................................................................50 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................50 
10 
STUDY PROCEDURES ................................................................................................................52 
10.1 
VISIT SCHEDULE..........................................................................................................................52 
10.1.1 
Screening period (Week -2 to Week 0)..........................................................................................52 
10.1.1.1 Screening visit: V1 (Week-2) .........................................................................................................53 
10.1.2 
Open-label randomized treatment period (Week 0 to Week 24) ...................................................54 
10.1.2.1 Baseline visit (V2, Week 0, Day 1).................................................................................................54 
10.1.2.2 On-Site Visits: V4 (Week 2); V6 (Week 4);V10 (Week 8);V14 (Week 12); V16 (Week 16); 
V18 (Week 20) ...............................................................................................................................55 
10.1.2.3 Phone call Visits: V3 (Week 1); V5 (Week 3); V7, 8, 9 (Week 5, 6, 7); V11, 12, 13 (Week 9, 
10, 11); V15 (Week 14); V17 (Week 18); V19 (Week 22)..............................................................56 
10.1.2.4 Final on-treatment assessment/end of treatment visit (V20, Week 24).........................................57 
10.1.3 
Post-treatment follow-up phone call visit (V21) .............................................................................57 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................58 
10.2.1 
Source data to be found in the patient’s files.................................................................................58 
10.2.2 
Source data verification requirements for patients not randomized ..............................................59 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................59 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................59 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................60 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................60 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................60 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................61 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................61 
10.4.1 
Definitions of adverse events.........................................................................................................61 
10.4.1.1 Adverse event ................................................................................................................................61 
10.4.1.2 Serious adverse event ...................................................................................................................62 
10.4.1.3 Adverse event of special interest...................................................................................................63 
10.4.2 
General guidelines for reporting adverse events ...........................................................................63 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................64 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................65 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................65 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................66 
10.6.1 
Hypoglycemia.................................................................................................................................66 
10.6.2 
Local tolerability at injection site and hypersensitivity reactions....................................................67 
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10.7 
ADVERSE EVENTS MONITORING..............................................................................................68 
11 
STATISTICAL CONSIDERATIONS..............................................................................................69 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................69 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................69 
11.3 
ANALYSIS POPULATIONS...........................................................................................................70 
11.3.1 
Efficacy populations .......................................................................................................................70 
11.3.1.1 Intent-to-treat population................................................................................................................70 
11.3.1.2 Per-protocol population..................................................................................................................70 
11.3.2 
Safety population ...........................................................................................................................71 
11.3.3 
PRO population..............................................................................................................................71 
11.4 
STATISTICAL METHODS .............................................................................................................71 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................71 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................71 
11.4.1.2 Compliance ....................................................................................................................................72 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................72 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................72 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................75 
11.4.2.3 Multiplicity considerations ..............................................................................................................76 
11.4.3 
Analyses of safety data..................................................................................................................76 
11.4.3.1 Observation period of safety endpoints: ........................................................................................76 
11.4.3.2 Safety endpoints ............................................................................................................................77 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................79 
11.4.5 
Analyses of Patient Reported Outcomes (Health-related Quality of Life/health economics 
variables.........................................................................................................................................79 
11.5 
INTERIM ANALYSIS......................................................................................................................79 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................80 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................80 
12.2 
INFORMED CONSENT .................................................................................................................80 
12.3 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC)...................................................................................................80 
13 
STUDY MONITORING...................................................................................................................82 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................82 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................82 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................82 
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13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................83 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................83 
14 
ADDITIONAL REQUIREMENTS...................................................................................................84 
14.1 
CURRICULUM VITAE....................................................................................................................84 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................84 
14.3 
CONFIDENTIALITY .......................................................................................................................84 
14.4 
PROPERTY RIGHTS.....................................................................................................................85 
14.5 
DATA PROTECTION.....................................................................................................................85 
14.6 
INSURANCE COMPENSATION....................................................................................................85 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................86 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................86 
14.8.1 
By the Sponsor...............................................................................................................................86 
14.8.2 
By the Investigator .........................................................................................................................87 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................87 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................87 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................88 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................89 
17 
APPENDICES................................................................................................................................91 
APPENDIX A 
THE DIABETES TREATMENT SATISFACTION QUESTIONNAIRE STATUS 
VERSION (DTSQS) .......................................................................................................................91 
APPENDIX B 
THE DIABETES TREATMENT SATISFACTION QUESTIONNAIRE CHANGE 
VERSION (DTSQC).......................................................................................................................92 
APPENDIX C HABS (HYPOGLYCEMIA ATTITUDES AND BEHAVIOR SCALE) ....................................93 
APPENDIX D GUIDANCE ON CONTRACEPTIVE METHODS ................................................................95 
 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
CI: 
confidence interval 
DBP: 
diastolic blood pressure 
DTSQ: 
diabetes treatment satisfaction questionnaire 
ECG: 
electrocardiogram 
FPG: 
fasting plasma glucose 
FSH: 
follicle stimulating hormone, serum follicle stimulating harmone 
GLP-1: 
glucagon like peptide-1 
HbA1c: 
glycated hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high level term 
IMP: 
investigational medicinal products, investigational medicinal product 
IRB/IEC: 
Institutional Review Board/Independent Ethics Committee  
ITT: 
intent-to-treat 
IVRS/IWRS: 
interactive voice response system/interative web response system 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
mixed-effect model with repeated measures 
NIMP: 
non-investigational medicinal product 
NYHA: 
New York Heart Association 
OADs: 
oral antihyperglycemic drugs 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PK: 
pharmacokinetic 
PRO: 
patient reported outcome 
PT: 
preferred term 
PTC: 
product technical complaint 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SBP: 
systolic blood pressure 
SC: 
subcutaneous 
SD: 
standard deviation 
SMPG: 
self-monitored plasma glucose 
SOC: 
system organ class  
SU: 
sulphonylurea 
T2DM: 
type 2 diabetes mellitus 
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TEAE: 
treatment emergent adverse event 
ULN: 
upper limit of normal 
 
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4 
INTRODUCTION AND RATIONALE 
The progressive nature of type 2 diabetes requires introducing insulin therapy to achieve 
appropriate glycemic control in many patients at certain stage of the disease. Clinicians face 
challenge when advising patients to start insulin despite clear evidence that good glycemic control 
reduce microvascular, and to a lesser degree, macro-vascular complication. The key barriers 
appear to be both patient and physician related factors: fear of pain and needles, concern of side 
effects of insulin (ie, hypoglycemia, weight gain etc) and the complexity of delivering the insulin 
despite marked improvement in the delivery process. The major facilitators of insulin initiation 
focus on clinical benefits of insulin in reducing symptoms and complications as well as improving 
survival and quality of life (1). 
Basal insulin forms the cornerstone of many treatment regimens for type 2 diabetes. Basal insulin 
alone is recommended by American Diabetes Association (ADA) as the most convenient initial 
insulin regimen (2). Recently two new basal insulin preparations (Toujeo® and Tresiba®) have 
been introduced to clinical practice with the potential to address some of the concerns around 
initiating insulin therapy will facilitate patients and physicians to make decision on insulin 
initiation and keep better compliance and then contribute to long term glycemic control for 
patients. Comparison of these new basal insulins in insulin naive patients with type 2 diabetes 
inadequately controlled with OADs would provide meaningful information on their use for 
clinical practice. 
Insulin glargine U100 (Lantus®) is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg human insulin, a 
recombinant analog of human insulin providing a 24-hour basal insulin supply after a single-dose 
SC injection. Its efficacy and safety are well-known through extensive data collection involving 
over 200 000 patients in clinical studies and observational studies (3). 
HOE901-U300 (Toujeo) has the same composition as the current Lantus formulation 100 U/mL 
with adjustment of 3-times the amount of active pharmaceutical ingredient and corresponding Zn 
content. The time-action profile of Toujeo was investigated in preclinical and clinical 
pharmacology studies and can be characterized as more even and prolonged profile of the glucose 
lowering activity (up to 36 hours) compared to insulin Lantus. Its efficacy and safety were 
demonstrated in the EDITION program. The glucose lowering effect of Toujeo was comparable 
with Lantus but lower hypoglycemia risk in type 2 diabetes mellitus (T2DM) population. 
EDITION 3 study which studied an insulin naive population demonstrated that in comparison 
with Lantus, hypoglycemia risk was reduced in nocturnal severe and/or confirmed hypoglycemia 
(plasma glucose <3.9 mmol/L) and severe and/or confirmed hypoglycemia<3.0 mmol/L in any 
time of the day.  Toujeo has been approved in the US, the European Union, Japan, and other parts 
of the world. Further information on Toujeo, including important clinical trials performed pre- 
and post-registration, can be found in the national product label or in the Product Information (4) 
and Investigators Brochure HOE901 (3). 
Tresiba 100 unit/mL solution for injection in pre-filled pen (insulin degludec) is a new 
recombinant analog of human insulin providing basal insulin supply beyond 42 hours after 
injection in euglycemic clamp conditions in type 1 diabetes (5). Its efficacy and safety were 
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demonstrated in BEGIN program. The impact of Tresiba on glycated hemoglobin A1c (HbA1c) 
was comparable with insulin Lantus but with reduced risk of hypoglycemia mainly during the 
protocol defined nocturnal period (6). In the BEGIN Once Long study which investigate the 
efficacy and safety with Tresiba versus Lantus in similar population as EDITION 3 (7), overall 
rates of confirmed hypoglycemia (plasma glucose <3.1 mmol/L or severe) were similar with 
Lantus. However lower nocturnal confirmed hypoglycemia was shown in favor of Tresiba (8). It 
has been approved in the US, European Union, Japan and other parts of the world. Further 
information on Tresiba can be found in the Product label Information on FDA website (5). 
Both Toujeo and Tresiba took Lantus as active comparator and demonstrated comparable efficacy 
and lower hypoglycemia risk in T2DM but no head-to-head comparison was performed. This trial 
is designed to confirm Toujeo’s efficacy and safety in comparison with Tresiba in insulin-naïve 
patients with T2DM inadequately controlled with non-insulin anti-diabetic medication and 
requiring basal insulin initiation. It will test the hypothesis that glucose control with Toujeo is 
non-inferior to Tresiba. Based on the currently available medical evidence and the application of 
the treat-to-target concept, comparable efficacy is expected. HbA1c reflects the average glycemia 
over 2-3 months and has strong predictive value for diabetes complications. It is accepted by 
regulatory agencies, scientific association as an appropriate primary endpoint to support a claim 
based on glycemic control (9),(10). 
In the EDITION trials Toujeo was associated with lower hypoglycemia risk than Lantus during 
the initial phase (first two months when most of the insulin titration occurred) and the 
hypoglycemia benefit was maintained until the end of the trials (6 months) in T2DM. Tresiba 
demonstrated comparable hypoglycemia risk to Lantus during the titration phases (0-15 weeks of 
treatment) and in favor of Tresiba with lower hypoglycemia risk beyond Week 16 in insulin naive 
population (6). Hence, the results from this head to head comparison of Toujeo with Tresiba in 
term of hypoglycemia will be of particular interest. 
Secondary objectives are to assess the effects of Toujeo versus Tresiba on percentage of patients 
reached HbA1c target, including not only reaching the target but also without severe and/or 
confirmed hypoglycemia. The analysis of the effects of the flat insulin profile over at least 
24 hours will be assessed based on self-monitored plasma glucose (SMPG) measurements (eg, 
4-point, 8-point glucose profiles, fasting plasma glucose [FPG]). Safety evaluation will include 
the comparison of all hypoglycemia events occurrence frequency and distribution, local 
tolerability at injection site, hypersensitivity reactions and other treatment emergent adverse 
events (TEAEs). Repeat assessments of PRO will be performed during the study (Including 
patient satisfaction with treatment and patient perception of blood glucose control assessed by 
Diabetes Treatment Satisfaction Questionnaire (status and change version) (DTSQ and DTSQc) 
questionnaires (11),(12) and Hypoglycemia Attitudes and Behavior Scale (HABS) (13) with a 
particular focus on patient’s attitudes and behavior related to hypoglycemia in T2DM. Nocturnal 
hypoglycemia timeframe is defined as during standardized period (0:00 to 5:59 AM) and extended 
period (0:00 to 7:59 AM) and at sleep status to observe the hypoglycemia event when patients are 
usually at sleeping period, usually in fasting condition. The extended period allow both Toujeo 
and Tresiba effect reaches a maximum (Toujeo: reach a stable plateau from 11 to 12 hours after 
dosing. Tresiba: a median of 12 hours post-dose) which anticipate more hypoglycemia episode in 
the early morning. 
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The target study population will comprise of adult T2DM patients who are naïve to insulin use, 
and considered to be inadequately controlled on their current antidiabetic medications (HbA1c 
between 7.5 and 10.5% and pre-study antidiabetic therapy have been stable for type and dose for 
at least 3 months before screening). It is expected that the investigator will exercise sound clinical 
judgment in assessing the patient’s eligibility in meeting the study inclusion/exclusion criteria and 
the individual evaluation of the expected benefits of improved glycemic control versus treatment 
risks (eg, Hypoglycemia). The inclusion of insulin naive patients will provide valuable 
information around insulin initiation and dose titration for both compounds in this population. 
The starting dose of Toujeo and Tresiba was recommended as 0.2 U/Kg and 10 U once daily in 
accordance with product label and follow the same insulin titration algorithm. Injections of IMPs 
will be given during 6:00 PM to 8:00 PM to compare both IMP in comparable situation, such as 
avoid potential bias of timing of hypoglycemic events during the day (eg, nocturnal versus other) 
based on the different pharmacokinetic (PK) and pharmacodynamic (PD) profiles. Pen injectors 
will be used which should maximize convenience and minimize dosing errors. Background 
treatment should remain stable (type and dose) during the study, including SU and meglitinide, at 
least until basal insulin doses and HbA1c levels have stabilized, except for discontinuation of 
agents not approved in combination with insulin according to local labeling/local treatment 
guidelines before randomization and any identified safety concerns necessitating a reduction in 
dose or discontinuation of background non-insulin antidiabetic drug(s) during the trial, after 
randomization. Rescue therapy may be given for refractory hyperglycemia after Week 12. The 
choice of the anti-diabetic treatment to be added to the basal insulin should be based on 
Investigator’s decision and local labeling documents, either adding an increase in dose of one of 
the background agents the patient was taking at randomization, or in the form of another oral 
agent or an injectable such as prandial insulin may be the preferred option or a glucagon like 
peptide-1 (GLP-1) receptor agonist. 
A screening period of 2 weeks is designed to allow patients to familiarize themselves with the 
glucose meter, diary; and to be counseled in appropriate lifestyle practices as well as the symptom 
of hypoglycemia and hypoglycemia management. Only if any of the laboratory parameters are not 
available upon the end of the screening period (eg, sample material damaged during transport etc), 
a retest can be performed. If this is the case (and exceptionally in other situations if justified) the 
screening period can be extended of one additional week. Twelve (12) weeks are anticipated for 
study drug dose titration which should allow most patients have time to reach a stable dose, with 
another 12 weeks to allow HbA1c value to stabilize at this dose. A dose titration schedule will be 
recommended (dose increases for fasting SMPG values above target ranges of 80-100 mg/dL 
(4.4-5.6 mmol/L), and dose reductions for lower values or occurrence of symptomatic confirmed 
hypoglycemia). Weekly site contacts with the patient (at time of on-site visits or by phone) should 
occur during the titration period (through Visit 14) to titrate the dose of study drug based on 
review of the interval SMPG readings, any hypoglycemia events, and overall clinical situation. 
Because patients are beginning a new insulin treatment, participants in this trial will be 
encouraged to perform frequent SMPG monitoring, especially fasting values and any time if 
hypoglycemia occurred, in order to provide optimal data for study drug titration, and to confirm 
episodes of low blood glucose. Seven days post-treatment safety assessment is designed to be 
performed by phone to check for problems/AEs after completion of study treatment at the end of 
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the study or after premature discontinuation of study (except patient who prematurely discontinue 
the study treatment but continue in the study up to the scheduled date of study completion). 
A sample size of 920 patients (460 with Toujeo and 460 with Tresiba) will ensure that the upper 
confidence limit of the two-sided 95% CI for the adjusted mean difference between Toujeo and 
Tresiba would not exceed 0.3% HbA1c with 90% power assuming that standard deviation (SD) is 
1.4%, and that the true difference between Toujeo and Tresiba is zero in HbA1c. Patients will be 
stratified by their HbA1c (<8.0%; 8.0%) and SU or meglitinide using (Yes versus No) due to the 
concomitant of SU/meglitinide will increase the occurrence of hypoglycemia events overall. 
This is a Phase 4 study. Benefit and risk of both investigational medical products had been 
demonstrated by clinical studies and approved by health authorities (4),(3),(5). 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
The primary objective of this study is to demonstrate the non-inferiority of Toujeo to Tresiba in 
HbA1c change from baseline to Week 24 in insulin naive patients with type 2 diabetes not 
adequately controlled with OADs with or without GLP-1 receptor agonist. 
5.2 
SECONDARY 
The secondary objectives of this study are 
x To assess the effects of the insulin Toujeo in comparison with insulin Tresiba on: 
- 
HbA1c change over 12 weeks 
- 
Fasting plasma glucose (FPG) change over 12 weeks and 24 weeks 
- 
Fasting Self-Monitored Plasma Glucose (SMPG) and 4-point SMPG and 8-point 
SMPG profile change over 12 weeks and 24 weeks  
- 
Mean 24-hour plasma glucose over Week 12 and Week 24 
- 
Variability of fasting SMPG and 24-hour plasma glucose over Week 12 and Week 24 
- 
Percentage of patients reaching HbA1c targets <7% or 6.5% at Week 12 and 
Week 24 
- 
Percentage of patients reaching HbA1c targets <7% or 6.5% at Week 12 and 
Week 24 without severe and/or confirmed hypoglycemia during the 12 weeks and 
24 weeks treatment period 
- 
Percentage of patients requiring rescue therapy during the 24 weeks of treatment 
x To assess the frequency of occurrence and diurnal distribution of hypoglycemia by 
category of hypoglycemia (symptomatic, asymptomatic, nocturnal, severe, probable and 
pseudo) 
x To assess the safety in each treatment group over 24 weeks treatment 
x To assess the treatment effects in each treatment group on Patient Reported Outcomes 
(PROs) measured by the following questionnaires: 
- 
Diabetes Treatment Satisfaction Questionnaire (DTSQ, status version and change 
version)  
- 
Hypoglycemia Attitude and Behavior Scale (HABS) 
 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a multicenter, open-label, 1:1 randomized, active-controlled, 2-arm, parallel-group, 
24-week treatment duration Phase 4 study. 
The study will recruit outpatients with T2DM inadequately controlled on OADs with/without 
GLP-1 receptor agonist. At the end of the screening period, eligible patients will be randomized to 
one of two treatment groups: 
x Insulin Toujeo group 
x Insulin Tresiba group 
The randomization will be stratified by value of HbA1c at the screening visit (<8%, 8%) and 
sulphonylurea (SU) or meglitinides use before the day of screening (Yes; No). 
The study will comprise 3 periods: 
x An up to 2-weeks screening period. It can be exceptionally extended up to one additional 
week 
x A 24-week open-label randomized treatment period  
x A 7-day post-treatment safety follow-up period for all the patients after permanent 
investigational medical product (IMP) discontinuation (except for patients who 
prematurely discontinue the study treatment but continue in the study) 
The type and dose of antidiabetic background therapy will remain unchanged during the study 
(see Section 8.3.1). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The maximum study duration per patient will be approximately 27 weeks: an up to 2-week 
screening period, a 24-week randomized treatment period, and a 7-day post-treatment safety 
follow-up period. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as being the “last patient last visit” planned with the protocol, 
including follow-up visit. 
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6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Adult patients with T2DM inadequately controlled with OADs therapy with/without 
GLP-1 receptor agonist at stable dose for at least 3 months 
I 02. Signed written informed consent 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. HbA1c <7.5% or >10.5% (at screening) 
E 02. History of T2DM for less than 1 year before screening 
E 03. Less than 6 months before screening on OAD(s) treatment and GLP-1 receptor agonist (if 
taken); 
E 04. Current or previous insulin use except for a maximum of 8 consecutive days or totally 
15 days (eg, acute illness, surgery) during the last year prior to screening; 
E 05. Initiation of new glucose-lowering medications and/or weight loss drug in the last 
3 months before screening visit; 
E 06. Patient receiving only non-insulin antidiabetic drugs not approved for combination with 
insulin according to local labelling/local treatment guideline 
E 07. Age <18 years at time of informed consent  
E 08. Body Mass Index (BMI) <25 kg/m2 or >40 kg/m2 
E 09. History of hypoglycemia unawareness or repeated episodes of severe hypoglycemia or 
metabolic acidosis, including hospitalization for diabetic ketoacidosis during the last 
12 months prior to screening; 
E 10. Use of an investigational drug within 1 month or 5 half-lives, whichever is longer, before 
screening 
E 11. Uncontrolled treated/untreated severe hypertension (systolic blood pressure [SBP] 
>180 mmHg and/or diastolic blood pressure [DBP] >95 mmHg) at screening 
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E 12. History of myocardial infarction, stroke, or heart failure requiring hospitalization within 
the last 3 months prior to screening 
E 13. 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; 
E 14. History of drug or alcohol abuse within 6 months prior to screening  
E 15. Conditions/situations such as: 
x 
Patients with conditions/concomitant diseases making them non-evaluable for primary 
efficacy endpoint(eg, hemoglobinopathy or hemolytic anemia, receipt of blood or 
plasma products within 3 months prior to screening visit or plan to receive transfusion 
of blood or plasma products during the screening period)  
x 
Patients with severe or 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  
x 
Patients potentially at risk of noncompliance to the study procedure (eg, mental 
condition rendering the subject unable to understand the nature, scope and possible 
consequences of the study, including blood glucose monitoring requirements, the 
documentation of SMPG data and insulin dosing, evidence of an uncooperative 
attitude and/or inability to return for follow-up visits, and unlikely to complete the 
study)  
x 
Patient is the Investigator or any sub-investigator, research assistant, pharmacist, study 
coordinator, other staff or relative thereof directly involved in the conduct of the 
protocol 
E 16. Use of systemic glucocorticoids (excluding topical application or inhaled forms) for one 
week or more within 3 months prior to the time of screening  
E 17. End-stage renal disease defined as estimated GFR (MDRD) <15 mL/min/1.73 m2(14) or 
being on hemodialysis 
E 18. Active liver disease or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
>3 times upper limit of normal (ULN) or total bilirubin >1.5 times ULN (except in case of 
documented Gilbert’s syndrome) at screening 
E 19. Nightshift workers  
E 20. Likelihood of requiring non-permitted medications during the treatment period 
E 21. Pregnant or breast-feeding women 
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E 22. Women of childbearing potential with no effective contraceptive method of birth control 
and/or who are unwilling or unable to be tested for pregnancy or women who intend to 
become pregnant during the study period (see Appendix D for country specific 
requirement) 
7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 23. Any contraindication to Tresiba according to the National Product labeling; history of 
hypersensitivity to the active substance or to any of the excipients of Tresiba  
E 24. Any contraindication to the background non-insulin antidiabetic medication according to 
the respective National Product labeling 
7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 25. Any contraindication to Toujeo according to the National Product labeling; History of 
hypersensitivity to the active substance or to any of the excipients of Toujeo 
7.2.4 Additional exclusion criteria during or at the end of screening before randomization 
E 26. Patient who has withdrawn consent before randomization  
E 27. Despite screening of the patient, randomization is stopped at the study level 
Note: A patient should not be randomized more than once. Patients can be re-screened once 
before randomization in case of non-evaluable exclusion criteria or in cases where original screen 
failure was due to reasons expected to change at rescreening and based upon the Investigator’s 
clinical judgment. 
 
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8 
STUDY TREATMENTS 
8.1 
DIET AND EXERCISE 
Lifestyle and diet counseling provided before the time of screening is to be continued during the 
study. 
Compliance with the diet and lifestyle recommendations will be discussed with the patient 
throughout the study, and more specifically in case of insufficient glucose control (please refer to 
Section 8.3.2). 
8.2 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
Insulin Toujeo (Insulin glargine 300 U/mL) and insulin Tresiba (Insulin Degludec 100 U/mL) are 
considered as investigational medicinal products (IMPs). 
8.2.1 Formulations 
Toujeo (Insulin glargine 300 U/mL) 
Toujeo (Insulin glargine 300 U/mL) is supplied as a sterile, non-pyrogenic, clear, colourless 
solution for SC injection in the Toujeo® SoloStar prefilled, disposable pen. Each Toujeo SoloStar 
contains in total 450 units of insulin glargine (1.5 mL of 300 units/mL insulin glargine solution). 
Mixing of Toujeo with other insulin products or dilution is not allowed. 
Tresiba® (Insulin Degludec 100 U/mL)  
Tresiba (Insulin Degludec 100 U/mL) is supplied as a sterile, non-pyrogenic, clear, colourless 
solution for SC injection in the marketed Tresiba® FlexTouch prefilled, disposable pen. Each 
Tresiba FlexTouch contains in total 300 units of insulin degludec (3 mL of 100 units/mL insulin 
degludec solution). 
Mixing of Tresiba with other insulin products or dilution is not allowed. 
8.2.2 Injection devices and training to use injection devices 
8.2.2.1 Injection devices  
Toujeo (Insulin glargine 300U/mL) 
Toujeo will be self-administered with the prefilled, disposable Toujeo SoloStar pen specifically 
labeled for use in the study. This pen allows dose setting in the range of 1–80 units with minimum 
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of 1 unit increment.The dose of Toujeo is titrated according to the patient’s need for insulin 
glargine. 
Following pen needles will be provided for use with the disposable injection pen devices: 
x BD Ultra Fine Needles 31 G x 5 mm 
x BD Ultra Fine Needles 31 G x 8 mm 
Insulin Tresiba (Insulin Degludec 100 U/mL) 
Tresiba will be self-administered with the prefilled, disposable Tresiba FlexTouch pen specifically 
labeled for use in this study. This pen allows dose setting in the range of 1–80 units with 
minimum of 1 unit increment. The dose of Tresiba is titrated according to the patient’s need for 
insulin degludec. The following pen needles will be provided for use with the disposable injection 
pen devices: 
x NovoFine needles 
x NovoTwist needles 
Or 
x BD Ultra Fine Needles 31 G x 5 mm 
x BD Ultra Fine Needles 31 G x 8 mm 
8.2.2.2 Training to use injection devices  
An instruction leaflet will be provided which explains how to use the disposable pen and needles. 
All patients will be trained by study staff at Visit 2 (randomization) on how to use the pen 
correctly, how to store it and how to change the needle and ensure patient has the competence of 
self-injection (eg, set correct dose; change the needles; identify the correct injection area; 
complete the injection; know the appropriate storage conditions; conduct simple troubleshooting 
etc). The patient’s family member or usual caregiver, if applicable, is highly encouraged to attend 
training with the patients as he/she plays a key role and is able to support the patient with study 
related procedures during the study. Training will be repeated as often as deemed necessary by 
study site staff during the treatment period. For the duration of the treatment, the patients will be 
required to use the same type of study drug disposable pens and needles. The pen and leaflet that 
patient will need to use during the treatment period will be dispensed according to the visit. Each 
patient is supplied with the appropriate number of pens according to the dispensing scheme 
indicated in the study flowchart (see Section 1.2). 
Pen-device issues (malfunctions) must be reported to the sponsor via the procedure for product 
technical complaint (PTC), using the respective PTC form, which is described in a separate 
manual. 
Injection pens should never be shared with others, even if the needle is changed. Patients must 
always use a new needle for each injection to help ensure sterility and prevent blocked needles. 
Do not reuse or share needles with another person. 
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8.2.3 Dosage schedule 
Injection time 
Toujeo and Tresiba will be self-administered by SC injections once daily between 6:00 PM and 
8:00 PM throughout the study period. The injection time will be selected at the discretion of 
patients and investigators at V2. 
Injection site 
The IMP should be self-administered by deep SC injection, alternating between the left and right 
anterolateral and left and right posterolateral abdominal wall or thighs or upper arms. Within a 
given area, location should be changed (rotated) at each time to prevent injection site skin 
reactions. 
The injection sites for IMP and non-investigational medicinal product ([NIMP], if taken) should be 
different so that, if any, an injection site reactions can be attributed specifically either to IMP (Toujeo 
or Tresiba) or NIMP (eg, GLP-1 receptor agonist). 
8.2.4 Starting dose and dose adjustments 
Starting dose 
The recommended daily starting dose of each IMP is defined per label with once daily as below 
followed by individual dose adjustment: 
x Toujeo: 0.2 units/kg (4) 
x Tresiba: 10 units (5) 
Dose adjustment 
During the study, doses of either basal insulin, Toujeo or Tresiba will be titrated to achieve 
glycemic targets without hypoglycemia according to the same algorithm as below (Table 2). 
x After randomization, the dose will be titrated at least weekly (but no more often than every 
3 days), until the patient reaches a target fasting SMPG of 80 to 100 mg/dL (4.4 to 
5.6 mmol/L) while avoiding hypoglycemia episodes. 
x Thereafter, until the end of the study, the dose will be adjusted as necessary to maintain 
this fasting SMPG target. 
x Dose adjustments are based on a median of fasting SMPG values from the last 
3 measurements, which include the value measured on the day of titration, measured by 
the patient using glucometers and accessories supplied by the sponsor. 
The best efforts should be made to reach the target glucose by 8-12 weeks after randomization. 
 
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Table 2 - Dose adjustment algorithm 
Mediana of fasting SMPG (mg/dL)from the last 3 measurements  
Toujeo® and Tresiba® dose changeb 
>140 (7.8 mmol/L) 
+ 6 U 
>120 and 140 (>6.7 and 7.8 mmol/L) 
+ 4 U 
>100 and 120 (>5.6 and  6.7 mmol/L) 
+ 2 U 
80 and 100 (>4.4 and  5.6 mmol/L) 
No change 
<80(<4.4 mmol/L) or occurrence of 1 symptomatic confirmed 
hypoglycemia episode documented in the preceding week 
-2U or at the discretion of the investigator 
a Median refers to intermediate SMPG value (the value between the lowest and the highest SMPG values when the values are ranked in a 
growing order). 
b Dose adjustment should not be more often than every 3 days. 
 
Sound clinical judgment is to be exercised while titrate patients. Investigators may adjust or stop 
titration, or temporarily reduce dose if they believe further titration would be hazardous at that 
time. 
Patients will be educated about the titration schedule so that they can monitor it with the 
assistance of the investigator or medically qualified designee. All discussions must be properly 
documented in the patient’s record. If needed, additional contacts will be made available for 
patients to discuss dose adjustments in between the scheduled visits. It is at the discretion of the 
investigator to allow well-trained patients to make IMP insulin dose adjustments in between 
scheduled visits without prior consultation of the site personnel. 
Data relevant for IMP titration (eg, fasting SMPG, daily insulin dose, hypoglycemia occurrence) 
will be reviewed by dedicated independent persons regularly to identify patients whose basal 
insulin dose was not titrated according to the recommended dose adjustment algorithm. If needed, 
re-training of site staff (including investigator) on titration will be performed. The details on 
insulin titration monitoring will be provided in separate documents. 
8.3 
NONINVESTIGATIONAL MEDICINAL PRODUCT(S) 
Background OADs and GLP-1 receptor agonist (if taken) and rescue medication will be considered 
as NIMP(s). 
8.3.1 Anti-diabetic background therapy 
The type and dose of anti-diabetic background therapy will remain unchanged during the study 
unless agents not approved in combination with insulin according to local labeling/local treatment 
guideline (if used, they will be discontinued at the start of the IMP) or identified safety concerns 
necessitate a reduction in dose or discontinuation of non-insulin antidiabetic drug(s). 
Anti-diabetic background treatment dose and type is to be reported in the e-CRF. 
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8.3.2 Rescue therapy:  
Routine fasting SMPG, central laboratory FPG measurements and central laboratory alerts on 
HbA1c are set up to ensure that glycemic parameters remain under predefined threshold values. 
The threshold values for rescue are defined as follows: 
From visit 14 (Week 12): FPG >200 mg/dL (11 mmol/L) and / or HbA1c >8.5%. 
In case of FPG or HbA1c above the thresholds, 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 (ie, After at least 8 hours 
fasting) 
x Study treatment is being properly titrated according to the protocol, 
x There is no intercurrent disease which may jeopardize glycemic control (eg, infection), 
x Compliance to treatment, diet and lifestyle is appropriate. 
If any of the above can reasonably explains the insufficient glycemic control, the investigator 
should undertake appropriate action, ie: 
x Titrate basal insulin dose according to the protocol, 
x Initiate an evaluation and treatment of any intercurrent disease (to be reported in 
AE/SAE/concomitant medication parts of the e-CRF and the medical record), 
x Stress the absolute need to comply with treatment, diet and lifestyle recommendations, 
x Schedule an HbA1c and/or FPG assessment at the next visit (if the next visit is a phone 
call, it should be replaced by an on-site visit). 
If none of the above reasons can be found, and/or appropriate actions fail, it is recommended to 
initiate rescue therapy. The choice of the anti-diabetic treatment to be added to the basal insulin 
should be based on Investigator’s decision and local labeling documents. Adding prandial insulin 
may be the preferred option. The addition of a new antidiabetic drug or increase in dose of 
background antidiabetic medication (“rescue”) should not be decided based on a single FPG or 
HbA1c value but be based on a thorough evaluation of the patient’s glycemic control. 
The reason for initiating rescue therapy, type of rescue therapy and the day of starting rescue 
therapy along with the dose will be documented on the appropriate pages of e-CRF. 
Note: Short-term (up to 10 days maximum) uses of short/rapid-acting insulin therapy (eg, due to 
acute illness or surgery) will not be considered as rescue therapy. All such use of short/rapid-
acting insulin therapy must be reported in the e-CRF and patient record. 
All assessments for primary and secondary efficacy and safety parameters planned in final on 
treatment assessment visit (Visit 20) should be performed before adding the “rescue medication”. 
Then the patient continues the IMP and stays in the study in order to collect safety information. 
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8.4 
BLINDING PROCEDURES 
As Toujeo and the control drug Tresiba are distinguishable, this study is an open-label design, and 
no attempt will be made to blind administration. 
COMPENSATION FOR LACK OF BLINDING 
Despite the open-label administration of IMP, assessment of outcomes will be based on 
objectively collected data, which are assessments for the efficacy variable (HbA1c, FPG) by 
central laboratory blinded to study treatment groups.  
As Toujeo and the control drug Tresiba are distinguishable in terms of initial dose and following 
doses during the first weeks of the study, a process will be applied to blind this information at the 
sponsor study team level. 
The sponsor study team, except individuals who have access to patients’ source documents (eg, 
local monitoring team, auditors) will remain blinded to the treatment arm of individual patients 
and dose of IMP throughout the study up to the database lock. All analyses and data review before 
database lock will be performed blindly, except for the titration review which will be performed 
by an independent reviewer. 
Insulin titration review will be performed by reviewing the data related to fasting SMPG, 
hypoglycemia events and IMP dose titration by independent reviewer. 
The first Statistical Analysis Plan (SAP) will be written before the first patient is randomized in 
the study. 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
The Trial Supply Operations Manager provides the treatment kit number list and the Study 
Biostatistician provides the randomization scheme to the interactive voice response system 
(IVRS)/interactive web response system (IWRS). Then, the IVRS/IWRS generates the patient 
randomization list according to which it allocates treatment arms to the patients. 
The study medications are provided in open-label boxes and each type of kit is identified with a 
treatment number. 
At the screening visit the investigator or designee contacts the IVRS/IWRS center to receive the 
patient number. The 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). 
Patients are randomized to receive during the 24 weeks comparative efficacy and safety period, 
either Toujeo or Tresiba. The randomization ratio is 1:1. The randomization is stratified by 
screening HbA1c value (<8%, 8%) and SU or meglitinides use before the day of screening (Yes; 
No). 
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The treatment kits are allocated using a centralized treatment allocation system (IVRS/IWRS). On 
V2 (D1), after assessment results are reviewed and baseline assessment is completed, IVRS/IWRS 
is contacted for randomization and the 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 contacted again 
each time a new treatment kit(s) allocation is necessary, ie, at Weeks 4, 8, 12, 16 and 20. The 
IVRS/IWRS will allocate treatment kit(s) using their treatment number. 
A randomized patient is defined as a patient who is registered and assigned with a  randomized 
treatment arm from the IVRS/IWRS, as documented from IVRS/IWRS log file, regardless 
whether the treatment kit was used or not. 
A patient cannot be randomized more than once to the study. 
8.6 
PACKAGING AND LABELING 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
The appropriate number of kits will be dispensed to cover up to the next dispensing visit (please 
refer to the study flowchart in Section 1.2). 
Toujeo SoloStar disposable pre-filled pen containing a 1.5 mL solution of insulin glargine 
300 U/mL will be supplied as open label treatment kits containing 5 Toujeo SoloStar pens. 
Tresiba FlexTouch disposable pre-filled pen containing 3 mL solution of insulin degludec 
100 U/mL will be supplied as open label treatment kits containing 5 Tresiba FlexTouch pens. 
Treatment labels will indicate the treatment number used for treatment allocation. The 
Investigator’s name, the patient number, visit number and box number will be entered manually 
by the site staff on the treatment box label prior to dispensing. 
8.7 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures. 
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the compounds 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. Patients are responsible for the correct storage of “unused” 
and “in-use”pens after it is dispensed at the site. 
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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 IMPs will be dispensed in accordance with the Investigator’s prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. Pen-related 
deficiencies should be reported to the sponsor by the means of a procedure on product technical 
complain (PTC) form (please see Section 8.2.2.2). 
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, allows 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 
A Treatment Log for returned and dispensed IMP will be kept for each patient. At each on-site 
visit, patient returns to the site with used and unused IMP except for Visit 4 (collecting used study 
medication only). Investigator or delegate has to inspect IMP remaining 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. The investigator 
completes the appropriate treatment log based on the used/unused IMP (study drug pens) returned. 
The monitor will check the e-CRF data by comparing them with patient’s diary entries, treatment 
logs and unused treatment kits. 
Patients have to record the administration of their background non-insulin antidiabetic 
medication(s) and rescue therapy (if applicable) in the diary. The following information with 
regards to the NIMP will be recorded in the source data: drug(s) name, dosage, start date, stop 
date. Compliance will be checked by interviewing the patient at each visit and be documented in 
the source documents. 
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8.8.2 Return and/or destruction of treatments 
IMP 
All used, partially-used or unused treatments will be retrieved by the Sponsor. A detailed 
treatment log of the returned IMP will be established with the Investigator (or the pharmacist) and 
countersigned by the Investigator and the monitoring team. 
The Investigator will not destroy any IMP unless the Sponsor provides written authorization.  
A potential defect in the quality of IMP may initiate a recall procedure by the Sponsor. In this 
case, the Investigator will be responsible for promptly addressing any request made by the 
Sponsor, in order to recall IMP and eliminate potential hazards. 
NIMP 
As NIMP is not provided by the study sponsor, return and destruction isn’t required. 
8.9 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment received by the patient concomitantly to any IMP(s). 
Treatments in addition to the study treatment should be kept to a minimum during the study. 
However, if these are considered necessary for the patient’s welfare and are unlikely to interfere 
with the IMP, they may be given at the discretion of the investigator, with a stable dose (when 
possible). 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. 
Prohibited concomitant therapy 
The following drugs are not permitted during the screening and randomized open-label treatment 
periods: 
x Antidiabetic drugs, which are not approved in combination with insulin according to local 
labeling/local treatment guideline, are prohibited throughout the on treatment period of the 
study, 
x No other additional antidiabetic treatments (eg, meal time insulin), apart from authorized 
concomitant non-insulin antidiabetic therapy and, when applicable rescue therapy (see 
Section 8.3.2), are to be used until the end of the study, 
x Note: Short-term use (10 days) of rapid/short-acting insulin due to acute illness or 
surgery (eg, infection) is allowed, 
x Insulin pump therapy is not allowed during the course of the study, 
x Initiation of weight loss drugs during the study is not allowed. Previous treatment with 
weight loss drugs can be continued but the doses must have been stable for at least 
3 months prior to screening and must remain stable throughout the study, 
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x Use of systemic glucocorticoids for more than 10 days (topical or inhaled applications are 
allowed) is prohibited, 
x Other medications are allowed as needed; however doses of chronically administered 
medicines should be kept fixed during the trial if at all possible. 
Note: After permanent IMP discontinuation (per protocol or premature) any treatments are 
permitted, as deemed necessary by the Investigator. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
In case of using rescue therapy, all assessments planned for the Visit 20 (Week 24) are to be 
performed before initiating rescue therapy. After these assessments are completed and rescue 
therapy has been initiated, the patient will remain in the study and continue with their study 
treatment as well as background non-insulin anti-diabetic drugs if appropriate. The planned visits 
and assessments should be performed until the last scheduled visit. 
In case of premature and permanent IMP discontinuation, patients should have a visit as soon as 
possible with the assessments normally planned in Visit 20 (Week 24). Afterward, the patients 
should continue in the study up to the scheduled date of study completion. They should be 
followed up according to the study procedures as specified in the protocol (except for the 7-day 
safety post-treatment follow-up). 
Data quality being very important to fully evaluate the efficacy/safety of the IMP, investigators 
must make their best efforts educating their patients on the importance of sticking to visit 
schedules, study required procedures and assessments up to the end of the study. A particular 
effort is requested to prevent missing data. 
9.1 
PRIMARY ENDPOINT 
All biological efficacy analysis and will be performed by a Central Laboratory. Detailed 
information on samples drawing, management and analysis will be provided in a specific manual. 
9.1.1 Primary endpoint 
x Change in HbA1c from baseline to Week 24. 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
“National Glycohemoglobin Standardization Program” (NGSP) central laboratory. 
HbA1c is assayed at screening (Visit 1, Week -2); at baseline (Visit 2; Day 1); at Visit 10 
(Week 8); Visit 14 (Week 12); and Visit 20 (Week 24; final primary endpoint assessment visit). 
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoint(s) 
x Change in HbA1c from baseline to Week 12, 
x Change in FPG from baseline to Week 12 and Week 24, 
x Change in fasting SMPG from baseline to Week 12 and Week 24, 
x Change in 4-point SMPG and 8-point SMPG profiles per time-point from baseline to 
Week 12 and Week 24, 
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x Change of mean 24-hour plasma glucose based on 8-point SMPG from baseline to 
Week 12 and Week 24, 
x Change in variability of fasting SMPG and  24-hour plasma glucose based on 8-point 
SMPG from baseline to Week 12 and Week 24, 
x Percentage (%) of patients reaching target HbA1c <7% and 6.5% at Week 12 and 
Week 24, 
x Percentage (%) of patients reaching target HbA1c <7% and 6.5% at Week 12 and 
Week 24 without severe and/or confirmed hypoglycemia (70 mg/dL and 54 mg/dL as cut 
off point) during the 12 weeks and 24 weeks treatment period, 
x Percentage (%) of patients with SU or meglitinide dose reduction/discontinuation due to 
hypoglycemia over 24 weeks of treatment, 
x Percentage of patients requiring rescue therapy during 24 weeks treatment period, 
x Basal insulin dose (U and U/kg body weight): change from baseline to Week 12 and 
Week 24. 
Observation period of efficacy endpoints 
The 24-week on-treatment period for efficacy endpoints (primary and secondary efficacy 
endpoints) is defined as the time from the first injection of open-label IMP up to 7 days after date 
of last IMP administration for HbA1c, 0 day for 4-point and 8-point SMPG and insulin dose, 
1 day for FPG and fasting SMPG, 2 days for hypoglycemia after the last injection of open-label 
IMP or up to the introduction of rescue therapy, whichever is the earliest. 
The randomized 24–week period for efficacy variables is defined from first dose of IMP up to 
Week 24, regardless of study treatment discontinuation and intake of rescue therapy. 
The baseline value for efficacy endpoints is the last available value prior to the first injection of 
open-label IMP. 
9.2.1.1 Fasting plasma glucose 
Fasting plasma glucose is measured at a central laboratory. 
Blood samples for FPG measurement are taken at baseline (Visit 2; Day 1); at Visit 10 (Week 8); 
Visit 14 (Week 12); and Visit 20 (Week 24; final primary endpoint assessment visit). 
9.2.1.2  Self-measured plasma glucose (SMPG) and glucometer, patient diaries and 
training 
9.2.1.2.1 Glucometer, patient diary and training 
All the patients are supplied with a glucometer, the corresponding supplies (lancets, test strips, 
etc), a leaflet, and with diaries at the screening visit V1 (Week -2) in order to perform self-
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measurement of plasma glucose, reporting information related to hypoglycemic event and record 
IMP doses etc. The patients will be instructed in the proper use of the glucometer and diary 
including education about hypoglycemia symptoms and management (See Section 10.1.1.1) at 
Visit 1 and repeated at Visit 2 to make sure good compliance to the instruction. The training will 
be repeated as often as necessary at the study visits. The patients will be instructed to bring their 
glucometers and patient diaries with them to each site visit.  
The glucometers should be calibrated according to instructions given in the package leaflet and 
the study site should also check the glucometers regularly using the provided control solutions for 
data validity.  
Instruction on how to complete the patient diary on a daily basis will be done by site staff. At each 
on site visit: 
x The study site staff reviews the patient’s diary, 
x SMPG values stored in the glucometer memory will be downloaded, printed out, dated, 
signed and filed into the patient file. If the patient has more than one SMPG reading at the 
same time point, the Investigator/site staff should discuss with the patient to identify the 
appropriate value to be recorded in the patient diary and in the e-CRF. This information 
will help the Investigator to assess treatment effects, adjust insulin doses and compliance. 
Note: The SMPG values to be entered in the e-CRF must be checked for consistency with the 
information from the glucometer. In case of inconsistency, the reason for inconsistency has to be 
documented.  If needed, the resulting action (eg, training of the patient on correct documentation 
of the values) is also to be documented. The confirmed values will be entered in the e-CRF based 
on the glucometer output values. 
The patient diary includes but is not limited to the following information: 
x 
Time and dose of daily IMP injections and type and dose of daily non-insulin antidiabetic 
medication(s),  
- 
In case of missed IMP injection, “0 unit” should be reported during the period when 
the IMP was not taken, 
x 
Times of start of meals (breakfast, lunch and dinner) and SMPG measurements, as well as 
plasma glucose values at the day of the 4-point and 8-point SMPG test (see Section 1.2). 
x 
Changes in anti-diabetic medication treatment, 
x 
Adverse events, signs and symptoms suggesting occurrence of hypoglycemia and relevant 
onset time, countermeasure or corrective treatment, supportive test (ie, SMPG value) and 
outcome etc. 
9.2.1.2.2 SMPG measurement 
SMPG measurements include the following: 
Fasting SMPG 
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Fasting SMPG will be used by the investigator and patients if appropriate to titrate and adjust 
insulin dose and to monitor glycemic control (Section 8.2.4). The fasting SMPG should be 
measured by the patient before breakfast and before the administration of the glucose-lowering 
agents once a day during the study. When up-titration has been completed and fasting SMPG is 
stable in the target range, at least 3 days measurements per week should be performed. 
Fasting SMPG values should be recorded in the patient diary. The following daily fasting SMPG 
values will be entered in the e-CRF: 
x All available fasting SMPG values from the week prior to each site or phone call visit 
and/or prior to insulin dose titration; these include the fasting SMPG value on the day of 
titration. 
4-point (prebreakfast, prelunch, predinner, bedtime) SMPG Profile:  
4-point SMPG profiles should be measured at the following 4 points: prebreakfast, prelunch, 
predinner and bedtime. 
The patients are requested to perform 4-point SMPG profile measurement over a single 24-hour 
period on at least one day in the 5 days before V6 (Week 4) and V10 (Week 8). All SMPG values 
measured on these days will be recorded in the patient’s diary and entered in the e-CRF (see 
Section 9.2.1.2.1 and Section 1.2). 
On the days when 4-point profiles are done, fasting SMPG will be considered as the first point of 
measurement, ie, “prebreakfast” time point. 
8-point SMPG Profile:  
The 8-point SMPG profile should be measured at the following 8 points: the 3:00 AM (+/-1 hour) 
at night, pre-prandial and 2 hours postprandial for breakfast, lunch, dinner and at bedtime. Two 
hours postprandial (breakfast, lunch and dinner) is defined as 2 hours after the start of the meal. 
The patients are requested to perform 8-point SMPG profile measurement over a single 24-hour 
period on at least one day in the 5 days before baseline visit (V2), V14 (Week 12) and V20 
(Week 24, end of treatment assessment visit). Special attention should be paid that the 3:00 AM. 
All SMPG values measured on these days will be recorded in the patient’s diary and entered in the 
e-CRF (see Section 9.2.1.2.1 and Section 1.2). 
On the days when 8-point profile are done, 4-point (prebreakfast, prelunch, predinner and bedtime) 
will be used for 4-point SMPG profile analysis. 
SMPG during episodes of symptomatic hypoglycemia: 
Whenever the patient feels hypoglycemic symptoms, plasma glucose should be measured by the 
patient (or others, if applicable), if possible. Patients should be instructed to measure plasma 
glucose levels prior to the administration of glucose or carbohydrate intake whenever 
symptomatic hypoglycemia is suspected (Section 10.6.1), unless safety considerations necessitate 
immediate glucose/carbohydrate rescue prior to confirmation. 
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The SMPG values and time of SMPG measurement, relevant countermeasures, symptom of 
hypoglycemia, assistance required or not, will be recorded in the patient diary and e-CRF. 
Further SMPG: 
The investigator may decide to request more frequent self-monitoring of plasma glucose if he/she 
considers necessary for the patient. 
9.2.1.3 Dose of IMP 
The patients document daily their IMP dose and time or any missed IMP injection in the patient 
diary. 
The following values will be entered in the e-CRF: 
x 
For the first 12 weeks (prior to V14, Week 12) of randomized treatment period: 
- 
Initial IMP starting  dose of IMP 
- 
All available data on the injection time and doses administered will be entered in the 
e-CRF, including missed IMP injection 
x 
After the first 12 weeks until the end of the randomized treatment period: 
- 
Daily dose and time of injection from the week last 3 days prior to each site or phone 
visit 
- 
In the case of any change in doses administered, the dose and injection time should be 
entered in the e-CRF 
- 
Missed IMP injection 
x 
In case of symptomatic hypoglycemia (if appropriate), the dose and injection time should 
be entered in the e-CRF 
x 
All available data of IMP dose and injection time on the last 3 days before permanently 
IMP treatment discontinuation 
9.2.1.4 SU or meglitinide dose reduction/discontinuation due to hypoglycemia 
The type and dose of antidiabetic background therapy will remain unchanged during the study but 
may have identified safety concerns necessitating a reduction in dose or discontinuation. The 
changes in antidiabetic medication administration and its reason should be documented in source 
data. If the dose reduction/discontinuation is due to hypoglycemia, the reason should be 
documented in e-CRF and report hypoglycemia event, eg, SU and meglitinide dose reduction due 
to hypoglycemia. 
9.2.2 Safety endpoints  
The safety endpoints are assessed by: 
x Hypoglycemia events 
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Hypoglycemia will be classified as below category and analyzed using the following 
variables: 
- 
Percentage of patients  with at least one episode of confirmed hypoglycemia* and 
event rate during 24 weeks treatment periods, 
- 
Rate of hypoglycemia per month computed as: 365.25/12 x (number of episodes of 
hypoglycemia)/(number of days exposed in time window), 
- 
Percentage of patients and event rate of hypoglycemia by study period (for 12 weeks, 
for >12 weeks to 24 weeks) to evaluate the potentially increased risk of 
hypoglycemia during the initial 12-week after starting treatment with basal insulin, 
- 
The diurnal distribution of the occurrence of each episode of confirmed hypoglycemia 
by category will be presented by two-hour timeframe over 24 hours during the 
24 weeks treatment period. 
* Note: Confirmed hypoglycemia: Any hypoglycemia confirmed by plasma glucose 
below the cut off value (70 or 54 mg/dL). The cut-off value of 70 mg/dL (3.9 mmol/L) 
for defining hypoglycemia is in line with ADA hypoglycemia definition. The cut-off 
value of 54 mg/dL (3 mmol/L) is chosen because it represented a degree of 
hypoglycemia at which patients have typically neuroglycopenic symptom. 
- 
Adverse events (AE) or serious adverse events (SAE) , including local tolerability at 
injection site, hypersensitivity reactions, Adverse events with special interest (AESI), 
- 
Vital signs, 
- 
Body weight. 
Observation period of safety endpoints 
The observation period of safety data will be divided into 3 segments: 
x The pre-treatment period is defined as the time between the date of the informed consent 
and the first injection of open-label IMP 
x The on-treatment period is defined as the time from the first injection of open-label IMP 
up to 7 days after the last injection of open-label IMP, regardless of the introduction of 
rescue therapy. The 7-day interval is chosen based on the half-life of the IMP 
(approximately 5 times the half-life of Tresiba) 
x The post-treatment period is defined as the time starting 8 days after the last injection of 
open-label IMP (after on-treatment period) 
The baseline value for safety endpoints will be the last available value prior to the first injection 
of open-label IMP. 
9.2.2.1 Adverse events 
Refer to Section 10.4 to Section 10.7 for details. 
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9.2.2.2 Hypoglycemia  
Hypoglycemia will be assessed. Refer to Section 10.6.1 for details. 
9.2.2.3 Body weight 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The same scale should be used throughout the study, 
and calibrated on a regular basis as recommended by the manufacturer. 
The use of balance scales is recommended; if digital scales are used, testing with standard weights 
is of particular importance. The floor surface on which the scale rests must be hard and should not 
be carpeted or covered with other soft material. The scale should be balanced with both weights at 
zero and the balance bar aligned. The patient should stand in the center of the platform as standing 
off-center may affect measurement. The weights are moved until the beam balances (the arrows 
are aligned). The weight is read and recorded in the e-CRF and Source Data. Self-reported 
weights are not acceptable; patients must not read the scales themselves. The body weight is 
measured at each on-site visit. 
9.2.2.4 Laboratory safety variables 
The clinical laboratory data consist of blood analysis, including hematology, clinical chemistry, 
serum pregnancy test in females of childbearing potential and serum follicle stimulating hormone 
(FSH) and estradiol (only in females requiring confirmation of postmenopausal status) and 
urinalysis. Clinical laboratory values will be analyzed after conversion into standard 
international units. International units will be used in all listings and tables. 
Central laboratory data will be collected only at screening visit (Visit 1, Week -2) for identifying 
patients with exclusion criteria or safety consideration include serum pregnancy test will be test at 
screening visit. Urine pregnancy test at site will be performed at Visit 2 and end of treatment visit. 
9.2.2.5 Physical examination 
Physical examination is performed at screening visit (V1, Week-2), baseline visit (V2, Day 1) and 
end of treatment visit (V20, Week 24). Height is measured at V1 (see Section 1.2). 
9.2.2.6 Vital signs 
Vital signs include: systolic and diastolic blood pressure (mmHg) and heart rate (beat per minute: 
bpm). They are assessed at screening (Visit 1, Week -2); at baseline (Visit 2, Day 1), and all 
on-site visit (see Section 1.2). 
Blood pressure (mmHg) should be measured when the patient is quiet and seated and with their 
arm outstretched in line with mid-sternum and supported. Measurement should be taken under 
standardized conditions, approximately at the same time of the day, on the same arm, with the 
same device (after the patient has rested comfortably for at least five minutes) and the values are 
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to be recorded in the e-CRF. Both systolic blood pressure (SBP) and diastolic blood pressure 
(DBP) should be recorded. Devices for blood pressure measurement should be regularly 
recalibrated according to manufacturers’ instructions. 
Heart rate (bpm) will be measured at the time of the measurement of blood pressure. 
Determination of the arm for blood pressure measurements: 
At Visit 1 of the screening period, blood pressure has to be measured on both of the arms after 
5 minutes in seated position and then again after two minutes in both arms in seated position. The 
arm with the higher diastolic pressure will be determined at this visit, identifying the reference 
arm for future measurements 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). 
9.3 
OTHER ENDPOINTS 
9.3.1 Patient Reported Outcomes (Health-related Quality of Life) 
The patient reported outcomes (PROs) measures in this study are the Treatment Satisfaction 
Questionnaire (DTSQs and DTSQc versions) and the Hypoglycemia Attitudes and Behavior Scale 
(HABS). They will be administered at Week 0 (Day 1, except for DTSQc), at Week 12 and at the 
end of the treatment. The questionnaires are attached in the Appendices (see Appendix A, 
Appendix B, Appendix C) 
The patients will be requested to complete the questionnaires by themselves during selected 
clinical visits (see study flow chart) in specific booklets, independently from investigator, site 
staff and any help from friends or relatives. For validity purposes, patients will be asked to answer 
all the questions of the questionnaires at the start of the visit in a quiet place, and while on site to 
return the completed questionnaires to the investigator or his/her designee on the same day. 
In case of rescue therapy: Administration of the three questionnaires (DTSQs, DTSQc and HABS) 
prior to the administration of the rescue therapy and afterwards as normally planned. 
In case of early IMP discontinuation: Administration of the questionnaires at the visit planned for 
the last dosing day with IMP and afterwards as normally planned. 
The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) is a validated 
questionnaire to assess patient satisfaction with treatment and patient perception of blood glucose 
control (11). It consists of 8 items that are answered on a Likert scale from 0 to 6. Items 1, 4, 5, 6, 
7 and 8 are summed to produce a Total Treatment Satisfaction score ranging from 0 (no 
satisfaction) to 36 (high satisfaction with treatment). The 2 items of ‘perceived frequency of 
hyperglycemia’ (Item 2) and ‘perceived frequency of hypoglycemia’ (Item 3) are scored 
separately ranging from 0 (none of the time) to 6 (most of the time). DTSQs will be administered 
at baseline, 12 and 24 weeks in the local language. 
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The Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) was developed 
from the original DTSQ to evaluate the change in treatment satisfaction at a specific time point 
(12). The change version has the same 8 items as the status version, with a small alteration to the 
wording of Item 7. The DTSQc instructions and response options differ from those of the DTSQs 
to produce measures of relative change in satisfaction rather than measures of absolute 
satisfaction. Items are answered on a Likert scale from í3 to +3, and the sum of the treatment 
satisfaction scores range from í18 to +18. Positive scores are indicative of improvement in 
treatment satisfaction, whereas negative scores are indicative of deterioration in treatment 
satisfaction. A score of 0 represents no change. The 2 items of ‘perceived frequency of 
hyperglycemia’ (Item 2) and ‘perceived frequency of hypoqlycemia’ (Item 3) are scored from -3 
(‘much less of the time now’) to +3 (‘much more of the time now’), meaning negative scores 
indicate fewer problems with blood glucose levels and positive scores indicate more problems 
than before. DTSQc will be administered at 12 and 24 weeks in the local language. 
At 12 and 24 weeks, DTSQs (status) will be administered before the DTSQc (change). 
The HABS (Hypoglycemia Attitudes and Behavior Scale) was recently developed with type 2 
diabetic patients using or not insulin (13). It consists of 14 items within 3 domains measuring 
anxiety (5 items), confidence (5 items) and avoidance (4 items) related to hypoglycemia. Items are 
answered on a Likert scale from 1 (strongly disagree) to 5 (strongly agree), with higher scores 
indicating high avoidance, confidence and anxiety related to hypoglycemia. The questionnaire 
will be administered at baseline, 12 and 24 weeks in the local language. 
9.4 
FUTURE USE OF SAMPLES 
Not applicable 
9.5 
APPROPRIATENESS OF MEASUREMENTS 
The primary efficacy endpoint of this study is change of HbA1c from baseline to endpoint 
(scheduled Week 24). HbA1c reflects the average glycemia over 2-3 months and has strong 
predictive value for diabetes complications. It is accepted by regulatory agencies and scientific 
association as an appropriate primary endpoint to support a claim based on glycemic control. 
Twenty-four weeks duration of study treatment is considered to be sufficient for achieving steady 
state conditions with Toujeo or Tresiba enabling an adequate assessment of time-dependent 
changes in HbA1c and the concomitant risk of hypoglycemia. 
Most international consensus statements for standards of medical care in diabetes recommend to 
decrease HbA1c <7% to minimize the risk of developing complications. An even tighter threshold 
of HbA1c 6.5% is recommended in some guidelines (15). T2DM patients with HbA1c values in 
the target range and experiencing no hypoglycemia episodes are considered optimally managed 
for the disease. Secondary objectives are to analyze responder which is intended to justify clinical 
relevance of the observed reduction in HbA1c values. Therefore, analysis of responders is set up 
to compare both formulations in terms of rate of patients achieving and/or maintaining optimal 
long-term glycemia control confirmed by target HbA1c <7%  or 6.5% and without experiencing 
confirmed hypoglycemia (70 mg/dL and 54 mg/dL as cut-off point).  
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Change in FPG is an acceptable secondary efficacy endpoint by regulatory agencies (15),(16) and 
scientific association. Change in 24-hour average plasma glucose, assessed as mean of 8 
measurements in each 8-point SMPG profile, is an acceptable secondary efficacy endpoint by 
regulatory agencies. Lower diurnal fluctuation of glycemia in insulin-treated T2DM patients 
accounts for decrease in the frequency of episodes of hypoglycemia or hyperglycemia. The 
secondary endpoint of variability of plasma glucose is set up to assess if longer duration of action 
of the new formulation of insulin and less fluctuation in systemic exposure favorably affect 
variability of plasma glucose. The analysis will be based on self-monitored plasma glucose 
measurements (eg, 4-point and 8-point glucose profiles, fasting plasma glucose).  
Safety evaluation will be evaluated by standard clinical and laboratory measurement, including 
the comparison of all hypoglycemia events occurrence frequency and distribution.  Nocturnal 
hypoglycemia timeframe is defined as during standardized period (0:00 to 5:59 AM) and extended 
period (0:00 to 7:59 AM) and at sleep status to observe the hypoglycemia event when patients are 
usually at sleeping period, usually in fasting condition. Specific safety parameters of interest for a 
glucose lowering injectable peptide such as injection site reactions and hypersensitivity will also 
be assessed. Other TEAE will be evaluated and summarized. 
Repeat assessment of PROs will be performed throughout the study (Including diabetes treatment 
satisfaction, perception of hypoglycemia and hyperglycemia questionnaires [DTSQs and DTSQc] 
and Hypoglycemia Attitudes and Behavior Scale [HABS]. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments listed in the “Study Flow Chart” in Section 1.2 are 
not repeated in this section. The aim of this section is to provide details on how some of the 
procedures/assessments have to be performed. 
This is an outpatient study and consists of 9 on-site visits and 12 phone-call visits. Additional, 
optional phone call visits to monitor insulin titration should be scheduled whenever considered 
necessary by the investigator. All on-site visits should take place in the morning at approximately 
the same time (patient is in fasting conditions at Visit 1 (Week -2, screening visit), Visit 2 
(Day 1, baseline), Visit 10 (Week 8), Visit 14 (Week 12), Visit 20 (Week 24), see also Study 
Flowchart, Section 1.2). 
The fasting condition is defined as an overnight fast no less than 8 hours that consisted of no 
food or liquid intake, other than water. IMP and non-insulin antidiabetic medication should be 
administered after the fasting blood sample is drawn for all laboratory tests on the study site. 
Note: If the patient is not in fasting conditions at visits which required in fasting conditions, the 
blood sample is not collected and a new appointment should be given to the patient for the 
following day if possible, with instruction to be fasted. 
For phone-call visits, the patient is called by the investigator or qualified designee at a scheduled 
time. 
Visit window: From Visit 3 (Week 1) to Visit 9 (Week 7), a timeframe of ± 3 days is acceptable 
using the day of visit 2 (baseline) as reference (if one visit date is changed, the next visit should 
take place according to the original schedule). From Visit 10 (Week 8) up to the final primary 
endpoint assessment at Visit 20 (Week 24), a time frame of ± 5 days is acceptable. For Visit 21 
(follow up visit) a time frame of -1~+3 day post-treatment is acceptable. 
10.1.1 Screening period (Week -2 to Week 0) 
Only patients who meet the inclusion criteria as noted in Section 7.1 may be screened. It will be 
the investigator’s responsibility to confirm the diagnosis of T2DM. 
All laboratory tests measured at a central laboratory that are needed for checking the exclusion 
criteria of the patients, are performed at the screening visit. At V2 (Day 1), patient who meet the 
selection criteria at the end of screening period as noted in Section 7.2 can be randomized into on-
treatment period. 
All background non-insulin antidiabetic medications should be continued without dose and type 
change during screening period.  
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If any of the laboratory parameters are not available 2 weeks after screening visit (eg, sample 
material damaged during transport etc), a retest can be performed. As an exception, if justified 
according to the Investigator’s assessment, the screening period can be extended one additional 
week, ie, baseline visit (V2, Day 1) can be scheduled no later than 3 weeks after screening visit 
(V1, Week -2). 
Patients can be re-screened one time before randomization in case of non-evaluable exclusion 
criteria or in cases where original screen failure was due to reasons expected to change at 
rescreening and based upon the Investigator’s clinical judgment. 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.  
10.1.1.1 Screening visit: V1 (Week-2) 
 For the complete list and contents of procedures/assessments scheduled for the visits, refer to the 
“Study Flow Chart” in Section 1.2 and for detailed description of assessments to Section 9 and 
Section 10.6. 
The details of the procedures/assessments to be performed at screening on-site visits and which 
are not described elsewhere are provided below: 
Informed consent  
The patient will receive verbal information concerning the aims and methods of the study, its 
constraints and risks and the study duration at the screening visit. Written information will be 
provided to the patient and must be signed by the patient and investigator prior to any 
investigations. 
Demography, diabetes, medical/surgical, and allergy history, alcohol and smoking habits 
and medications 
Demography data such as birth date, gender and race will be collected. Collection of diabetes 
history will include documentation of duration of diabetes, concomitant anti-diabetic medication; 
Medical/surgical history including patient’s allergy history. Data for alcohol habits during the last 
12 months before screening visit and smoking habit will be collected. 
Check of previous or current medication (within the previous 3 months) refers to documentation 
of medication including the glucose-lowering agents (type and daily dose on the day before V1 
should be recorded in e-CRF). In women of child-bearing potential, the contraceptive methods 
have to be documented in source document. 
Diet and lifestyle counseling 
Please see Section 8.1. 
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IVRS/IWRS contact 
IVRS/IWRS will be contacted for notification of screening and patient number allocation  
(Section 8.5). Please note that it is important to have the IVRS/IWRS contact before any blood 
sample is drawn because the patient number is given by IVRS/IWRS and it must be reported on 
the laboratory requisition forms. 
Glucometer, diary dispensation and training 
Please see Section 9.2.1.2. 
Central laboratory testing 
x 
Blood sample is drawn for all central laboratory tests needed for checking the exclusion 
criteria. 
A 12-lead electrocardiogram (ECG) will be performed locally at screening visit for identifying 
patients with exclusion criteria or safety consideration. The 12-lead ECGs should be performed 
after at least 10 minutes rest in supine position. All original traces are kept as source data. 
From the signature of the informed consent form, AEs/SAEs (including the injection site reaction) 
will be recorded at each visit. Hypoglycemia and concomitant medications will also be recorded 
all along the study. 
An appointment is given to the patient for next visit (on-site visit). Patients are instructed to return 
to the site in the morning and to bring the glucometer, the diary on next on-site visit (V2, Day 1) 
and instructed to perform 8-point SMPG over a single calendar day on at least one day in the 
5 days prior to V2 (see Section 9.2.1.2.2). 
10.1.2 Open-label randomized treatment period (Week 0 to Week 24) 
Patients meeting all inclusion criteria and with no exclusion criteria at the end of the screening 
period are eligible to be enrolled into the open-label randomized treatment period. The duration of 
the open-label treatment period is 24 weeks ±5 days from baseline visit (V2, Week 0) to the end 
of treatment visit (V20, Week 24). 
Each patient self-administers IMP once daily during the open-label treatment period. The IMP 
dose will be adjusted according to fasting SMPG values recorded in the glucometer  
(Section 8.2.4). 
10.1.2.1 Baseline visit (V2, Week 0, Day 1)  
For the complete list and contents of procedures/assessments scheduled for the visit, please refer 
to the “Study Flow Chart” in Section 1.2 and for detailed description of assessments to Section 9 
and Section 10.6. 
The details of the procedures/assessments to be performed at this visit and which are not 
described elsewhere are provided below: 
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At this visit, the patient must return to the investigation site in the morning after 8 hours fasting 
not having their non-insulin antidiabetic medication at home. Patients will visit the site with the 
blood glucometer and the diary. 
Diet and lifestyle counseling 
Please see Section 8.1. 
Compliance check 
Compliance check includes compliance with use of glucometer, review of daily fasting SMPG 
values, and the 8-point SMPG profile and patient diary. If patient is not compliant enough with 
the study procedures, the training will be repeated by the site staff. 
IVRS/IWRS contact 
After the baseline assessments are completed and eligibility confirmed, the investigator contacts 
IVRS/IWRS for randomization. The treatment group (ie, the Toujeo or Tresiba) is notified by 
IVRS/IWRS. 
Training on self-injection devices and dispensation of IMP: 
Patients randomized to the Toujeo group or Tresiba group are instructed by the study staff how to 
use properly the SoloStar disposable pen or FlexTouch disposable pen and to store it accordingly.  
Instructions on self-injection technique are also given. The instruction leaflet is dispensed. 
Training on the relevant pen injector might be repeated if necessary. 
The Toujeo SoloStar(s) disposable pen and Tresiba FlexTouch disposable pen are dispensed 
according to randomized group for patients.  
Please refer to Section 8.2.2. 
Starting dose and dose adjustment of IMP 
Eligible patients will enter a 24-week open-label randomized treatment period to receive either 
Toujeo or Tresiba. Please see details in Section 8.2.4. 
An appointment for one week later is given to the patient for next phone call visit and two weeks 
later for next on-site visit. 
10.1.2.2 On-Site Visits: V4 (Week 2); V6 (Week 4);V10 (Week 8);V14 (Week 12); V16 (Week 
16); V18 (Week 20) 
For the complete list and contents of procedures/assessments scheduled for the visits, please refer 
to the “Study Flow Chart” in Section 1.2 and for detailed description of assessments to Section 9 
andSection 10.6. 
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The details of the procedures/assessments to be performed at visits and which are not described 
elsewhere are provided below. 
Compliance check 
Compliance check includes compliance with IMP and non-insulin anti-diabetic medication 
treatment and use of glucometer, review of daily fasting SMPG values, and patient diary. If the 
patient is not sufficiently compliant with the study, the training has to be repeated by the site staff. 
For on-site visits in V10 and V14 patients are instructed to return to the site in the morning in 
fasting condition. Patient will be instructed to perform 4-point and 8-point SMPG on the week 
before each correspondence visit (see Section 1.2). For all on-site visit, patients are instructed to 
bring the glucometer, the diary and the used/in-use/unused pens (V4, collecting used study 
medication only) and a re-supply of IMP is planned for all on-site visit (except V4). 
Upon completion of each on-site visit, an appointment for the next visit (on-site visit or phone call 
visit) will be made. 
10.1.2.3 Phone call Visits: V3 (Week 1); V5 (Week 3); V7, 8, 9 (Week 5, 6, 7); V11, 12, 13 
(Week 9, 10, 11); V15 (Week 14); V17 (Week 18); V19 (Week 22)  
The patient is 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 and informed in case AE/SAE occurred. In case of an AE, the patient may 
be asked to come to the investigational site, as appropriate. A phone call visit can optionally be 
performed as an on-site visit in case of symptomatic hypoglycemia/AE or other reasons. 
During the phone call, the following questions are to be asked: 
x 
Did you experience any new medical event, disease or symptom since the last visit?  
x 
Did you experience any changes in a pre-existing medical condition, disease or symptom 
since the last visit? 
x 
Did you miss, change, take or add any medications (including non-insulin anti-diabetic 
medication if appropriate) since the last visit? 
x 
Did you experience any symptoms or events of hypoglycemia?  
x 
Do you feel comfortable handling the diary, glucose meter and IMP injection device or do 
you need any more explanation? 
x 
Did you adjust IMP since last visit and reason? If appropriate, what is your IMP dose? 
x 
Did you measure any fasting SMPG value outside of the range 80 to 100 mg/dL 
(4.4 to 5.6 mmol/L)? 
x 
Did you experience any possible allergic symptom, or skin reaction? 
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The phone visits will also include: 
x 
Asking patient fasting pre-breakfast SMPG and insulin dose on the last week including 
day of visit, 
x 
Adjustment of the dose of IMP (insulin Toujeo and Tresiba) to continue treatment toward 
the target fasting SMPG between 100 and 80 mg/dL (5.6 and 4.4 mmol/L), inclusive, 
x 
Recording of AE and symptomatic hypoglycemia events (if any),  
x 
Recording of the use or change of any concomitant medication. 
The patient will be instructed to: 
x 
Perform required SMPG measurements, 
x 
Complete daily the diary, 
x 
Self-inject once daily IMP at the dose prescribed by the investigator between 6:00 PM and 
8:00 PM, 
x 
Contact the site in case of occurrence of adverse event, record the event in the patient’s 
diary and return to the site as deemed appropriate. 
Give an appointment to the patient for subsequent visits (on-site visit or phone call visit) and 
remind them to come in fasting condition if planned at next on-site visit and to bring their 
glucometer, diary, pens. 
10.1.2.4 Final on-treatment assessment/end of treatment visit (V20, Week 24) 
For the complete list and contents of procedures/assessments scheduled for the visit, please refer 
to the “Study Flow Chart” in Section 1.2 and for detailed description of assessments to Section 9 
and Section 10.6. 
The same procedures/assessments including IVRS/IWRS contact as planned at Visit 20 
(Week 24) have to be performed in case of prematurely permanent treatment discontinuation 
(Section 10.3.2). The IVRS/IWRS has to be contacted in order to register the end of treatment. 
An appointment for the post-treatment follow-up phone call visit will be made (except for patients 
who prematurely discontinue the study treatment but continue in the study). 
10.1.3 Post-treatment follow-up phone call visit (V21) 
Following the last injection of insulin Toujeo or the Tresiba either as scheduled or prematurely, a 
post-treatment follow-up phone call visit is performed 7 (-1/+3) days after the end of treatment 
visit for patients who completed the study or withdrew from the study at the time of the open-
label IMP discontinuation. The post-treatment follow-up phone call visit is not performed for 
patients who prematurely discontinued the open-label IMP treatment and stay in the study up to 
completion. This visit can be a phone call visit or an on-site visit in case of ongoing or new AE 
during the post-treatment period, if necessary. 
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The patient is called by the investigator or medically qualified designee at certain, previously 
agreed time point. 
During the phone call, the following questions are to be asked: 
x 
Did you experience any new medical event, disease or symptom since the last visit?  
x 
Did you experience any changes in a pre-existing medical condition, disease or symptom 
since the last visit? 
x 
Did you change, take or add any new medications since the last visit? 
x 
Did you experience any events or symptoms of hypoglycemia? 
All reports of hypoglycemic events (if any) or any adverse events are recorded. The use or change 
of any concomitant medications, including rescue therapy, is recorded. 
10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in the patient’s files 
Evaluations that are reported in the e-CRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
x 
Agreement and signature of informed consent mentioning the study identification 
x 
Patient identification, last participation in a clinical trial, medical history, associated 
diseases, and data related to the studied pathology 
x 
Contraception method for women of childbearing potential 
x 
Reason for lack of childbearing potential for concerned women (eg, postmenopausal, 
history of hysterectomy) 
x 
Previous and concomitant medication (including background anti-diabetic medication and 
rescue therapy) 
x 
Study identification 
x 
Treatment kit number, dates of administration and doses of the Toujeo or Tresiba alone 
x 
Compliance to non-insulin anti-diabetic medication if appropriate assessed by interview 
and patient’s diary 
x 
Dates of visits and assessments including the examination report 
x 
Vital signs, height, body weight 
x 
Faxed central lab reports and original report received at site (dated and signed by the 
Principal Investigator or Sub-Investigator) 
x 
IVRS/IWRS confirmation notifications by fax or e-mail (screening, screen failure, 
randomization, treatment allocation, treatment/study discontinuation, end of study, 
treatment replacement if applicable, etc) 
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x 
ECG records signed and dated 
Adverse events and follow-up: 
x 
In case of SAE, the site should file in the source document at least copies of the 
hospitalization reports and any relevant examination reports (eg, imaging reports, 
specialists’ reports, etc) documenting the follow-up of the SAE or AESI 
x 
Date of premature study discontinuation (if any) and reason 
Source documentation may be found in the following: 
x 
Patient’s identity 
x 
Medical history 
x 
Nursing notes 
x 
Dietician’s notes 
x 
Physician’s notes 
x 
Patient’s diaries 
x 
Dated and signed print-outs with SMPG downloaded from glucose meter 
10.2.2 Source data verification requirements for patients not randomized 
For patients not randomized, the source data that must be checked include the patient's 
identification details, the informed consent signed by the patient, the study identification, the dates 
of study visits and the main reasons preventing randomization. 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION 
The IMP should be continued whenever possible. In case the IMP is stopped, it should be 
determined whether the stop can be made temporarily; permanent IMP discontinuation should be 
a last resort. Any IMP discontinuation should be fully documented in the e-CRF. In any case, the 
patient should remain in the study as long as possible. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs or for other reason. In case of treatment interruption due to an AE, reinitiating of treatment 
with the IMP will be done under close and appropriate clinical/and or laboratory monitoring once 
the Investigator will have considered according to his/her best medical judgment that the 
responsibility of the IMP(s) in the occurrence of the concerned event was unlikely and if the 
selection criteria for the study are still met (refer to Section 7.1 and Section 7.2). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages of the e-CRF when considered as confirmed. 
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10.3.2 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. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
The patients may withdraw from treatment with IMP in case of the following: 
x At patient’s own request, ie, withdrawal of the consent for treatment 
x If, in the Investigator's opinion, continuation with the administration of IMP would be 
detrimental to the patient's well-being 
x At the specific request of the Sponsor 
A patient must withdraw from treatment with IMP in either of the following cases: 
x Intercurrent condition that requires discontinuation of IMP 
x Pregnancy in female participants 
x Necessity to use prohibited therapy (see Section 8.9) 
Any abnormal laboratory value will be immediately rechecked for confirmation before making a 
decision of permanent discontinuation of the IMP for the concerned patient. 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol 
(except for the 7-day safety post-treatment follow up) up to the scheduled date of study 
completion, or up to recovery or stabilization of any AE to be followed-up as specified in this 
protocol, whichever comes last. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last dosing day with the IMP (end of treatment visit). 
For PRO assessments, please refer to Section 9.3.1. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF and in the patient’s medical record when considered as confirmed. 
IVRS/IWRS should be notified when a patient prematurely discontinues treatment. 
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10.3.5 Procedure and consequence for patient withdrawal from study  
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. 
If possible, the patients are assessed using the procedure normally planned for the end-of-study 
visit. 
Patients who withdraw should be explicitly asked about the contribution of possible AEs to their 
decision to withdraw consent, and any AE information elicited should be documented. Preferably 
the patient should withdraw consent in writing and, if the patient or the patient’s representative 
refuses or is physically unavailable, the site should document and sign the reason for the patient’s 
failure to withdraw consent in writing.  
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the patient’s medical records when considered as confirmed. In the medical record, 
at least the date of the withdrawal and the reason should be documented. 
For patients who fail to return to the site, unless the patient withdraws the consent for follow-up, 
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 records (eg, times and dates of attempted telephone 
contact, receipt for sending a registered letter) 
In addition, the date of discontinuation of the study for patients who discontinued the IMP should 
be recorded by the Investigator in the appropriate pages of the e-CRF when considered as 
confirmed. 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.4.1 Definitions of adverse events 
10.4.1.1 Adverse event 
An 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. 
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10.4.1.2 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 seizure, 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 
x Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
x Bullous cutaneous eruptions 
x Cancers, except non-melanoma skin cancer, diagnosed during the study or aggravated 
during the study  
x Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study  
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10.4.1.3 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. 
All AESIs will be reported to the Sponsor in the same timeframe as SAEs, ie, within 24 hours as 
detailed in Section 10.4.3. 
The AESIs are listed below: 
x 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 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy is mandatory until the outcome has been determined. 
x Symptomatic overdose (serious or non-serious) with IMP/NIMP 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the patient (not based on systematic drug 
count) and defined as follows 
- 
For IMP and other insulin: any dose administration which, in the investigator’s 
opinion based on clinical judgment is considered significantly greater than the 
prescribed dose of insulin. 
- 
An overdose with non-insulin anti-diabetic medication is defined as at least twice 
of the intended dose within the intended/ planned therapeutic interval. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
x Increase in alanine transaminase (ALT). 
ALT 3 ULN (if baseline ALT < ULN) or ALT 2 times the baseline value (if baseline 
ALT ULN) should be notified within 24 hours to the monitoring team (see Section 
10.4.4). In addition, if ALT <3 ULN meets a seriousness criterion, the event should be 
notified within 24 hours to the monitoring team. 
10.4.2 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 e-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 
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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 
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 
Instructions for AE reporting are summarized in Table 3 
10.4.3 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. 
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Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.4 Guidelines for reporting adverse events of special interest   
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.3, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 3. 
Table 3 - Summary of adverse event reporting instructions 
10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
x All SAEs those are both unexpected and at least reasonably related to the IMP (SUSAR), 
to the regulatory authorities, IECs/IRBs as appropriate and to the Investigators. 
x All SAEs those are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
In this study, some AEs are considered related to the underlying condition (eg, blood glucose 
increased) and thus will not be considered unexpected as given in the Investigator’s Brochure for 
Toujeo (3) and Product information for Tresiba (5). 
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
AE 
form 
Safety 
Comple-
mentary Form 
Other 
specific 
forms 
Adverse Event (non-
SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited 
(within 24 hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
ALT3 ULN (if baseline ALT<ULN) 
and ALT2 x baseline (if baseline 
ALTULN) 
Yes 
No 
Yes  
Pregnancy  
Yes  
Yes  
Yes  
Adverse Event of Special 
Interest with immediate 
notification 
Expedited 
(within 24 hours) 
Symptomatic overdose 
Yes 
Yes 
No 
Note: Hypoglycemia will be reported on the dedicated hypoglycemia event page. AESI: Adverse Event of Special Interest 
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The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia 
Hypoglycemia events will be categorized as follows according to ADA category (17): 
Severe hypoglycemia 
Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with 
sufficient neuroglycopenia to induce seizure, unconsciousness or coma. Plasma glucose 
measurements may not be available during such an event, but neurological recovery attributable to 
the restoration of plasma glucose to normal is considered sufficient evidence that the event was 
induced by a low plasma glucose concentration.  
The definition of severe hypoglycemia includes all episodes in which neurological impairment 
was severe enough to prevent self-treatment and which were thus thought to place patients at risk 
for injury to themselves or others.  
Note that “requires assistance” means that the patient could not help himself or herself. Assisting 
a patient out of kindness, when assistance is not required, should not be considered a “requires 
assistance” incident.  
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria. All events of 
seizure, unconsciousness or coma must be reported as SAEs. 
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration of 70 mg/dL 
(3.9 mmol/L). 
Clinical symptoms that are considered to result from a hypoglycemic episode can include (but not 
necessarily limited to): increased sweating, nervousness, asthenia, tremor, dizziness, increased 
appetite, palpitations, headache, sleep disorder, confusion, seizures, unconsciousness, and coma. 
Patients will be instructed to measure finger stick plasma glucose levels prior to the administration 
of carbohydrates whenever symptomatic hypoglycemia is suspected, unless safety considerations 
necessitate immediate glucose rescue prior to confirmation, and then a glucose measurement 
should be performed as soon as safe, with appropriate diary documentation. Details on 
hypoglycemia episodes will be captured in the patient diaries, and patients will contact the sites as 
soon as possible following severe events to review the details and decide on any necessary 
measures to be taken. 
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Asymptomatic hypoglycemia 
Asymptomatic hypoglycemia is an event not accompanied by typical symptoms of hypoglycemia 
but with a measured plasma glucose concentration less than or equal to 70 mg/dL (3.9 mmol/L). 
Probable symptomatic hypoglycemia 
Probable symptomatic hypoglycemia is an event during which symptoms typical of hypoglycemia 
are not accompanied by a plasma glucose determination, but was presumably caused by a plasma 
glucose concentration less than or equal to 70 mg/dL (3.9 mmol/L); symptoms treated with oral 
carbohydrate without a test of plasma glucose. 
Pseudo hypoglycemia 
Pseudo-hypoglycemia is an event during which the person with diabetes reports any of the typical 
symptoms of hypoglycemia with a measured plasma glucose concentration >70 mg/dL 
(>3.9 mmol/L) but approaching that level. 
Nocturnal hypoglycemia 
Nocturnal hypoglycemia is any hypoglycemia of the above categories that occurs: 
x Between 00:00 AM and 05:59 AM or 00:00 AM and 7:59 AM, regardless whether patient was 
awake or work up because of the event. 
x Sleep status: patient was asleep between bedtime and before getting up in the morning, ie, 
before the morning determination of fasting pre-breakfast SMPG and patient woke-up due 
to the hypoglycemia 
Note: Confirmed hypoglycemia: Any hypoglycemia confirmed by plasma glucose value below 
the cut off value (1) of 70 mg/dL (3.9 mmol/L) or (2) 54 mg/dL (3 mmol/L). 
All hypoglycemia episodes will be documented on the dedicated hypoglycemia event page in the 
e-CRF. Symptomatic hypoglycemia events fulfilling the criteria of a SAE will also be 
documented on AE and SAE complementary forms in the e-CRF. 
10.6.2 Local tolerability at injection site and hypersensitivity reactions 
If the investigator or the patient recognizes any signs of local intolerability at the study drug 
injection site or hypersensitivity reactions, the event should be recorded in the adverse event page 
in the e-CRF. If a patient reports severe injection site or hypersensitivity reaction between the on-
site visits or during a phone call visit, the investigator should ask him/her to come to the study site 
on the same or the next day, so that the event can be properly assessed, reported and treated. 
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10.7 
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 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation is based on the primary efficacy variable of HbA1c change from 
baseline to Week 24. 
A sample size of 920 randomized patients (460 randomized per treatment group) will ensure that 
the upper bound of the two-sided 95% confidence interval (CI) for the adjusted mean difference 
between Toujeo and Tresiba would not exceed a non-inferiority margin of 0.3% with at least 90% 
power. This calculation assumes a common SD of 1.4% with a 1-sided test at the 2.5% significant 
level and a true difference between Toujeo and Tresiba is zero in HbA1c between the treatment 
groups. 
Calculations were made using nQuery Advisor® Software Version 7.0. 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented. 
x Screened: all patients who originally met inclusion criteria and signed the informed 
consent 
x Screen failure patients and reason for screen failure 
x Randomized: all screened patients with a treatment arm allocated and recorded in the 
IVRS/IWRS database, regardless of whether the treatment kit was used or not 
x Safety population (see Section 11.3.2) presented as treated 
x The intent-to-treat (ITT) population (Section 11.3.1.1) analyzed as randomized 
x The randomization strata (screening HbA1c categories [<8.0%, 8.0%], use of SU or 
meglitinides at screening [Yes, No]) assigned by IVRS/IWRS will be summarized. The 
discrepancy between the strata assigned by IVRS/IWRS and the information reported on 
CRF will be listed for all randomized patients 
x The Per-Protocol (PP) population (Section 11.3.1.2 analyzed as subset of ITT population 
and without major protocol deviations) 
x Patients who permanently discontinued the IMP, and the reasons for permanent treatment 
discontinuation 
For all categories of patients except screened and screen failure patients, percentages will be 
calculated using the number of randomized patients as denominator for different treatment groups. 
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Patients with the following deviations will be identified and described in separate listings: 
x Treated but not randomized 
x Randomized but not treated 
x Randomized but not treated as randomized 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. 
For any patient randomized more than once, only the data associated with the first randomization 
will be used in any analysis population. The safety experience associated with any later 
randomization will be assessed separately. 
The safety experience of patients treated and not randomized will be reported separately, and 
these patients will not be in the safety population. 
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Intent-to-treat population 
The primary efficacy population will be the ITT population, which includes all randomized 
patients who received at least one dose of IMP, irrespective of the treatment actually being 
received, analyzed according to the treatment group allocated by randomization.  
11.3.1.2 Per-protocol population 
The per-protocol population is a subset of ITT population with no major protocol deviations. This 
is an efficacy population. Patients included in this population will fulfill at least the criteria below: 
x Randomized and received only the treatment allocated at the randomization 
x HbA1c value at baseline and at Week 24 on treatment 
x Without initiating rescue therapy 
x Who did not permanently discontinue treatment  
The Per-protocol population will be fully defined in the SAP. 
 
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11.3.2 Safety population 
The safety population is defined as all randomized patients who did actually receive at least one 
dose of IMP, regardless of the amount of treatment administered. 
In the event of patients having received treatments that differed from those assigned according to 
the randomization schedule, then the safety analyses will be conducted according to the treatment 
received rather than according to the randomization groups. 
Patients will not be considered exposed if there is documented evidence that patients have not 
taken the study drug: 
x If a patient is dispensed IMP and is lost to follow-up without any documented evidence, 
the patient will be considered exposed and included in the safety population 
x Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized 
In addition: 
x Non randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately 
x For patients receiving more than one study treatment during the trial, the patient will be 
analyzed in the treatment group in which he/she was treated longer 
11.3.3 PRO population  
The analysis of PROs will be conducted on the ITT population. 
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. 
The duration of exposure to the open-label IMP during the study is defined as: 
(Date of the last IMP administration – date of the first IMP administration) + 1. 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum).  In addition, duration of treatment exposure will 
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also be summarized categorically by numbers and percentages for each of the following 
categories and cumulatively according to these categories: 
x up to 4 weeks 
x >4 to 8 weeks 
x >8 to 12 weeks 
x >12 to 16 weeks 
x >16 to 20 weeks 
x >20 to 22 weeks 
x >22 to 23 weeks 
x >23 to 24 weeks 
x >24 weeks 
11.4.1.2 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Treatment compliance percentage will be summarized descriptively (N, Mean, SD, Median, Min, 
and Max). The percentage of patients with compliance is <80% will be summarized. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
11.4.2.1.1 Primary analysis 
The primary efficacy variable, change in HbA1c from baseline to Week 24 in % as defined in 
Section 9.1.1 will be analyzed in the ITT population using available data during the 24-week on 
treatment period (defined in Section 9.2.1). A mixed-effect model with repeated measures 
(MMRM) approach will be used, under the missing at random framework carried out via SAS 
PROC MIXED using an adequate contrast at Visit 20 (Week 24). 
The model will include fixed categorical effects of treatment group, visit, treatment-by-visit 
interaction, randomization stratum of use of SU or meglitinides at screening (Yes, No) as well as, 
the continuous fixed covariates of baseline HbA1c value and baseline HbA1c value-by-visit 
interaction. 
This model will be run with an unstructured correlation matrix to model the within-patient errors. 
Parameters will be estimated using restricted maximum likelihood method with the 
Newton-Raphson algorithm. Denominator degrees of freedom will be estimated using 
Satterthwaite’s approximation. This model will provide baseline adjusted least squares (LS) 
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means estimates at Week 24 for both treatment groups, as well as, the differences of these 
estimates, with their corresponding SEs and 95% CIs. 
A stepwise closed testing approach will be used for the primary efficacy variable to assess non-
inferiority and superiority sequentially detailed in Section 11.4.2.3: 
x Step 1 will proceed to assess non-inferiority Toujeo versus Tresiba. To assess non-
inferiority, the upper bound of the two-sided 95% CI for the difference in the mean change 
in HbA1c from baseline to Week 24 between Toujeo and Tresiba will be compared with 
the predefined non-inferiority margin of 0.3% HbA1c. Non-inferiority will be 
demonstrated if the upper bound of the two-sided 95% CI of the difference between 
Toujeo and Tresiba on ITT population is <0.3%. 
x Step 2 will test superiority of Toujeo over Tresiba, only if non-inferiority of Toujeo versus 
Tresiba has been demonstrated. The superiority of Toujeo over Tresiba will be 
demonstrated if the upper bound of the two-sided 95% CI for the difference in the mean 
change in HbA1c from baseline to Week 24 between Toujeo over Tresiba on ITT 
population is <0 (zero). 
The tests for the primary endpoint (Week 24) will be performed one-sided at level Į = 0.025. 
11.4.2.1.2 Key sensitivity analysis 
A first sensitivity analysis will be conducted in the ITT population, using all available post-
baseline HbA1c values, regardless of study treatment discontinuation and rescue therapy initiation 
(analysis on the 24-week randomized period, as defined in Section 9.1). The same MMRM model 
as described for primary analysis will be used. 
A second sensitivity analysis will be performed on the change in HbA1c from baseline to Week 
24 in the Per-protocol population. The same MMRM model as described for primary analysis will 
be used. 
11.4.2.1.3 Sensitivity analyses to handle missing data 
Sensitivity analyses will be conducted to assess the robustness of primary efficacy analysis with 
regard to missing data. 
Penalized multiple imputation 
In order to assess the impact of missing data, the change in HbA1c from baseline to Week 24 in % 
using HbA1c values during the randomized 24-week period (all post baseline available data), will 
be analyzed in the ITT population using a multiple imputation approach to account for missing 
data at any time points (including missing baseline, Week 8, Week 12 and Week 24) followed by 
the testing of treatment arms using an analysis of covariance (ANCOVA) model. 
Missing data will be imputed 100 times to generate 100 complete data sets with the MI SAS 
procedure. For each simulation leading to negative imputed value, another value will be redrawn 
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for imputation using MINIMUM option of MI SAS procedure. Since in general, the missing 
pattern will not be monotone, a two-step approach will be used: 
x Step 1: the MCMC method will be used in conjunction with the IMPUTE=MONOTONE 
option to create an imputed data set with a monotone missing pattern 
x Step 2: using the monotone data set from Step 1, missing data will be imputed using the 
regression method 
The imputation model for Step 1 will include the treatment group, baseline HbA1c value, as well 
as HbA1c values at Week 8, Week 12, and Week 24. 
The imputation model for Step 2 will includes the same variables as in Step 1 with the 
randomization strata. 
For each simulation leading to negative imputed value, another value will be redrawn for 
imputation using MINIMUM option of MI SAS procedure. 
The imputed HbA1c value at Week 24 in the Toujeo group will then be penalized by adding 0.3% 
(corresponding to the non-inferiority margin) to the imputed HbA1c value whereas the imputed 
HbA1c in the Tresiba group will not be penalized. The change in HbA1c from baseline to 
endpoint will then be derived from observed and imputed (penalized or not) HbA1c value at 
Week 24.  
The 100 complete data sets will then be analyzed using an analysis of covariance (ANCOVA) 
model including the fixed categorical effects of randomization stratum of screening HbA1c 
(<8.0%, 8.0%), and randomization stratum of use of SU or meglitinides at screening (Yes, No), 
treatment group (Toujeo, Tresiba), as well as, the continuous fixed covariate of baseline HbA1c 
value. The MIANALYZE procedure will then be used to generate valid statistical inferences by 
combining results from the 100 analyses using Rubin’s formulae.  
This procedure will provide baseline adjusted least-squares means estimates at Week 24 for both 
treatment groups, as well as, the differences of these estimates, with their corresponding SEs and 
95% CIs. 
Tipping point analysis  
Robustness of the primary analysis results to departure from the MAR assumption will be 
explored in the ITT population using tipping-point analysis based on the pattern mixture model 
approach. 
The considered pattern mixture model will introduce a sensitivity parameter, į, corresponding to 
the difference in means between patients with missing data and patients with observed data. 
Estimations will be performed using the same multiple imputation approach as described above. į 
will be added to the imputed values (į = 0 corresponds to the MAR assumption). For each 
assessed value of į by treatment group will correspond an estimated mean HbA1c reduction per 
group and an estimated treatment effect. 
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To investigate how the conclusions depend on the adopted values of į, the testing will be repeated 
over a range of plausible values for the pairs (į Toujeo, į Tresiba). Results will be then 
summarized using graphs. 
Further pattern mixture models could be explored depending on the observed missing data pattern 
in the Toujeo arm. 
11.4.2.2 Analyses of secondary efficacy endpoints 
Secondary efficacy endpoints are described in Section 9.2  
All secondary efficacy endpoints will be analyzed or summarized on the 24-week on treatment 
period using the ITT population. 
The following secondary efficacy endpoint will be analyzed using the same approach as the one 
used for primary endpoint (MMRM model) as described in Section 11.4.2.1.  
x HbA1c (%): change from baseline to Week 12; 
The following secondary efficacy endpoints will be analyzed using the same approach as the one 
used for primary endpoint (MMRM model) as described in Section 11.4.2.1 The model will 
include fixed categorical effects of treatment group, visit, treatment-by-visit interaction, 
randomization stratum of use of SU or meglitinides at screening (Yes, No), randomization stratum 
of HbA1c (< 8.0 % and  8.0%), the continuous fixed covariates of the corresponding baseline 
value, and baseline value-by-visit interaction..  
x FPG: change from baseline to Week 12 and Week 24; 
x Fasting SMPG: change from baseline to Week 12 and Week 24; 
x Change in 8-point SMPG profiles per time-point from baseline to Week 12 and Week 24;  
x Change in 4-point SMPG profiles per time-point from baseline to Week 12 and Week 24;  
x Change of mean 24-hour plasma glucose based on 8-point SMPG from baseline to Week 
12 and Week 24; 
x Change in variability of fasting SMPG and  24-hour plasma glucose based on 8-point 
SMPG from baseline to Week 12 and Week 24; 
x Basal insulin dose(U and U/kg body weight): change from baseline to Week 12 and Week 
24; 
 
The following secondary endpoints will be analyzed using logistic regression model adjusted on 
randomization strata of screening HbA1c (<8.0%, 8.0%) and randomization strata of SU used at 
screening (yes/no). This model will also estimate the Odds Ratio of Toujeo and Tresiba and its 
corresponding 95% CI. 
x Percentage (%) of patients reaching target HbA1c <7% and  6.5% at Week 12 and Week 
24; 
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x Percentage (%) of patients reaching target HbA1c <7% and  6.5% at Week 12 and Week 
24 without severe and/or confirmed hypoglycemia (70 mg/dL and 54 mg/dL as cut off 
point) event during the 12 weeks treatment period and the 24 weeks treatment period; 
x Percentage (%) of patients with SU or meglitinide dose reduction due to hypoglycemia; 
x Percentage of patients requiring rescue therapy during 24 weeks treatment period 
Hypoglycemia will be determined during the 12-week on-treatment period and the 24-week on-
treatment period, respectively (used for Safety endpoint, as defined in Section 11.4.3.1)  
Patients who initiate recue therapy during the 12-week on-treatment period or during the 24-week 
on treatment period, respectively, will be considered as failure for this given period. 
Patients with missing HbA1c at a given visit will be considered as failure for this given visit. 
The 24-week on treatment period as defined for Safety endpoint will be used (refers to  
Section 9.2.2. 
11.4.2.3 Multiplicity considerations 
To control the type I error, a hierarchical step-down testing procedure described by Hochberg and 
Tamhane (18) will be applied for the primary efficacy endpoint to assess non-inferiority and 
superiority sequentially (see Section 11.4.2.1). 
x Step 1: non-inferiority comparison of the mean change from baseline to Week 24 in 
HbA1c with Toujeo compared to Tresiba 
x Step 2: only if non-inferiority of Toujeo relative to Tresiba in step 1 is demonstrated, 
superiority of Toujeo over Tresiba in changes in HbA1c from baseline to Week 24 will be 
assessed 
No multiplicity adjustment will be made on secondary efficacy variables; 95% confidence 
intervals (95% CI) and P-values presented for these endpoints will be done for descriptive purpose 
only. 
11.4.3 Analyses of safety data 
11.4.3.1 Observation period of safety endpoints: 
The observation period of safety data will be divided into 3 segments: 
x The pre-treatment period is defined as the time between the date of signed informed 
consent and the first injection of open-label IMP  
x 
The on-treatment period (24-week on-treatment period) is defined as the time from the 
first injection of open-label IMP up to 7 days after the last injection of open-label IMP, 
regardless of the introduction of rescue therapy. The 7-day interval is chosen based on the 
half-life of the IMP (approximately 5 times the half-life of Tresiba),  
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- 12-week on-treatment period is defined as the time from the first injection of IMP up to 
Week 12 or 7 days after the last injection of IMP whichever comes earlier. 
x 
The post-treatment period is defined as the time starting 8 days after the last injection of 
open-label IMP (after on-treatment period). 
The baseline value for safety endpoints will be the last available value prior to the first injection 
of open-label IMP. 
11.4.3.2 Safety endpoints 
Safety endpoints are described in Section 9.2.2. 
The summary of safety results will be presented by treatment groups.  
All safety analyses will be performed on the Safety population using the following common rules: 
x The baseline value for safety endpoints will be the last available value prior to the first 
injection of IMP  
x The following definitions will be applied to vital signs: 
- 
The potentially clinically significant abnormality (PCSA) values are defined as 
abnormal values considered medically important by the Sponsor according to 
predefined criteria/thresholds based on literature review and defined by the Sponsor 
for vital signs 
- 
PCSA criteria will determine which patients had at least one PCSA during the TEAE 
period, taking into account all evaluations performed during the on-treatment TEAE 
period, including unscheduled or repeated evaluations. The number of all such patients 
will be the numerator for the PCSA percentage during the TEAE on-treatment period 
11.4.3.2.1 Hypoglycemia 
The number and incidence of patients experiencing at least 1 hypoglycemic event will be 
presented per treatment group and type of hypoglycemic event (ADA Workgroup on 
Hypoglycemia [17], Section 10.6.1) according to time of occurrence {nocturnal (ie, 00:00 to 
05:59 AM; 00:00 to 07:59 AM), any time of the day} during the on treatment period. The Odds 
Ratio and its corresponding 95% CI of Toujeo arm over Tresiba arm for each hypoglycemic event 
will be estimated by a logistic regression model using the same approach as the one described for 
categorical efficacy endpoint. 
The number and rate of hypoglycemic events (in patient-year of exposure) will be determined per 
treatment arm and type of hypoglycemic event (ADA Workgroup on Hypoglycemia [17]), 
according to time of occurrence {nocturnal (ie, 00:00 to 05:59 AM; 00:00 to 07:59 AM), any time 
of the day} during the on treatment period. For each hypoglycemic event, the rate ratio, and its 
corresponding 95% CI, of Toujeo arm over Tresiba arm will be estimated using an over-dispersed 
Poisson regression model adjusted on randomization strata of screening HbA1c (<8.0%, 8.0%) 
and randomization strata of SU or meglitinides at screening (Yes vs No).  
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The number and incidence of patients experiencing at least 1 nocturnal hypoglycemic event 
defined by sleep status and the number and rate of  these nocturnal events (in patient-year of 
exposure) will also be presented per treatment group during the on treatment period.  
11.4.3.2.2 Adverse events 
All adverse events will be coded to a “PT” and “HLGT”, “HLT” and associated primary “SOC” 
using the version of MedDRA currently in use by the sponsor at the time of database lock. 
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), high-level group term (HLGT), high level term (HLT) and preferred 
term (PT) sorted in alphabetical order, and for each treatment arm, the number (n) and percentage 
(%) of patients experiencing at least one AE. Multiple occurrences of the same event in the same 
patient will be counted only once in the tables within a treatment period. The denominator for 
computation of percentages is the safety population within treatment arm. 
Adverse event incidence table will be provided by titration modality arm for all types of TEAEs: 
all TEAEs, all treatment emergent SAEs, all TEAEs leading to permanent treatment 
discontinuation and all TEAEs related to local tolerability at injection site and hypersensitivity. 
Death 
The following deaths summaries will be generated on the safety population: 
x 
Number (%) of patients who died by study period (TEAE, on-study, post-study*) and reasons for 
death summarized by allocated treatment arm 
x 
Death in nonrandomized patients or randomized and not treated patients 
x 
TEAE leading to death by primary SOC, HLGT, HLT and PT showing number (%) of patients 
sorted by internationally agreed order of SOC and alphabetic order of HLGT, HLT, and PT 
*Post-study deaths, if presented, will follow safety guideline instruction 
Injection site reaction and hypersensitivity reaction 
Number (%) of patients with events related to injection site reactions or hypersensitivity reaction 
will be provided separately 
Adverse event of special interest 
A listing of patients with symptomatic overdose with IMP/NIMP and increase of ALT will be 
provided separately. 
Patients with an SAE or AESI should be followed until resolution, stabilization, or death as 
appropriate. 
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Product technical complain (PTC) 
Information regarding PTC will be described. 
11.4.3.2.3  Vital signs and physical examination  
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
arm whatever the baseline level and according to baseline status. 
Change from baseline to Week 24 in body weight will be analyzed using the same approach as the 
one used to analyze FPG. 
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables 
Not applicable. 
11.4.5 Analyses of Patient Reported Outcomes (Health-related Quality of Life/health 
economics variables 
The analysis of PROs will be conducted on the ITT population 
PRO endpoints are described in Section 9.3.1 . 
For each questionnaire a descriptive summary at each visit (baseline, Week 12 and Week 24) and 
change from baseline at Week 12 and Week 24  (except for DTSQc) will be provided, excluding 
data obtained after rescue therapy initiation, including:  
• 
DTSQs total treatment satisfaction score (items 1, 4, 5, 6, 7 and 8), ‘perceived frequency 
of hyperglycemia’ (Item 2) and ‘perceived frequency of hypoqlycemia’ (Item 3) scores 
DTSQc total treatment satisfaction score (items 1, 4, 5, 6, 7 and 8), ‘perceived frequency 
of hyperglycemia’ (Item 2) and ‘perceived frequency of hypoqlycemia’ (Item 3) scores (at 
Week 12 and Week 24 only) 
• 
HABS subscale scores (confidence, anxiety and avoidance) 
The change in DTSQs and HABS scores from baseline to endpoint are analyzed using an MMRM 
model similar as model used for quantitative secondary efficacy endpoints.  
Average scores at Week 12 and at Week 24 in total treatment satisfaction score, hyperglycemia 
perception and hypoglycemia perception score from DTSQc will be analyzed using an ANCOVA 
model. This model will include fixed categorical effects of treatment arm, on randomization strata 
of screening HbA1c (<8.0%, 8.0%) and randomization strata of SU used at screening (yes/no) as 
well as continuous fixed covariates of corresponding baseline score from DTSQs.  
11.5 
INTERIM ANALYSIS 
No interim analysis will be performed during the study. 
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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 
HEALTH AUTHORITIES AND INSTITUTIONAL REVIEW BOARD/INDEPENDENT 
ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the Health Authorities (Competent Regulatory Authority) and 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 Health Authorities (Competent Regulatory Authority), as required by local 
regulation, in addition to the IRB/IEC before implementation, unless the change is necessary to 
eliminate an immediate hazard to the patients, in which case Health Authorities (Competent 
Regulatory Authority) and 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 and to the Health Authorities (Competent Regulatory Authority), as required by local 
regulation. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub-
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub-investigators shall be appointed and listed in a timely manner. The Sub-
investigators 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, serious adverse event (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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14 
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 Subinvestigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff / Subinvestigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub-investigators 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 Sub-investigator, 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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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC and/or notification/approval of Health Authorities (Competent Regulatory 
Authority) of an amendment, as required by local regulation, except where necessary to eliminate 
an immediate hazard(s) to clinical trial patients, or when the change(s) involves only logistical or 
administrative aspects of the trial. Any change agreed upon will be recorded in writing, the 
written amendment will be signed by the Investigator and by the Sponsor and the signed 
amendment will be filed with this clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In case of substantial amendment to the clinical trial protocol, approval from the Health 
Authorities (Competent Regulatory Authority) will be sought before implementation. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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16 
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