Clinical trial NCT02735044
Conditions: Type 1 Diabetes Mellitus
Sponsor: Sanofi
Start date: 2016-04-14; Completion date: 2018-12-20
Enrollment: 463 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

To compare the efficacy of a new formulation of insulin glargine (HOE901-U300) to Lantus in terms of change of HbA1c from baseline to endpoint (month 6) in children and adolescents with type 1 diabetes mellitus.

.

Secondary Objectives:

To compare HOE901-U300 and Lantus in terms of:

* Percentage of participants reaching target HbA1c and fasting plasma glucose (FPG).
* To assess the safety of HOE901-U300 including analysis of events of hypoglycemia, events of hyperglycemia with ketosis, and development of anti-insulin-antibodies.

Detailed description:
The study duration per participant was approximately 58 weeks that consisted of a 2 week screening period, a main 6-month comparative efficacy and safety treatment period, a 6-month comparative safety extension period, and a 4-week post treatment follow up period.

Arms: arm 1: HOE901-U300 (Insulin glargine 300 Units/milliliter \[U/mL\]) Subcutaneous(SC) injection once daily for 12 months. arm 2: Lantus (Insulin glargine 100 U/mL) SC injection once daily for 12 months.
Interventions: intervention 1: Insulin glargine,300 U/mL intervention 2: Insulin glargine (100 units /mL) intervention 3: Background therapy
Intervention descriptions: intervention 1: Subcutaneous injection in the morning or evening using a prefilled pen. Dose titration to achieve fasting self-monitored plasma glucose (SMPG) from 90 to 130 milligram/deciliter (mg/dL) (5.0 to 7.2 millimol per liter \[mmol/L\]) intervention 2: Subcutaneous injection in the morning or evening using a prefilled pen. Dose titration to achieve fasting SMPG from 90 to 130 mg/dL (5.0 to 7.2 mmol/L) intervention 3: Fast-acting mealtime insulin analogs

Protocol documents:
Prot_000.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: QSD-003152 VERSION N°3.0 (04-FEB-2016) 
Page 1
AMENDED CLINICAL TRIAL PROTOCOL 02 
COMPOUND: HOE901 
6-Month, Multicenter, Randomized, Open-label, 2-Arm, Parallel-group Study 
Comparing the Efficacy and Safety of a New Formulation of Insulin Glargine and 
Lantus® Injected Once Daily in Children and Adolescents age 6 - 17 years with 
Type 1 Diabetes Mellitus with a 6-month Safety Extension Period 
STUDY NUMBER: EFC13957 
STUDY NAME: EDITION JUNIOR 
VERSION DATE / STATUS: Approval date (23-Aug-2016) / Approved 
Protocol Amendment 02 
Version number: 1 (electronic 1.0) 
Date: 23-Aug-2016 
Amended Clinical Trial Protocol 01 
Version number: 1 (electronic 4.0) 
Date: 29-Jan-2016 
Protocol Amendment 01 
Version number: 1 (electronic 4.0) 
Date: 29-Jan-2016 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date: 16-Oct-2015 
EudraCT
2015-002084-42
IND Number(s) 
112400 
Version Number: 
1 
WHO universal trial number 
U1111-1168-4546 
Date: 
23-Aug-2016 
Total number of pages: 
109 
(electronic 5.0)
NCT Number: NCT02735044


Amended Clinical Trial Protocol 02  
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HOE901-EFC13957 -  insulin glargine 
Version number: 1 
 
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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 SUMMARY 
 
COMPOUND: HOE901- 
insulin glargine 
STUDY No: EFC13957 
STUDY NAME: EDITION JUNIOR 
TITLE 
6-Month, Multicenter, Randomized, Open-label, 2-Arm, Parallel-group Study 
Comparing the Efficacy and Safety of a New Formulation of Insulin Glargine and 
Lantus® Injected Once Daily in Children and Adolescents age 6 - 17 years with 
Type 1 Diabetes Mellitus with a 6-month Safety Extension Period 
INVESTIGATOR/TRIAL LOCATION 
Multinational, multicenter 
PHASE OF DEVELOPMENT 
3b 
STUDY OBJECTIVES 
 
Primary objective 
To compare the efficacy of a new formulation of insulin glargine (HOE901-U300) to 
Lantus in terms of change of glycated hemoglobin A1c (HbA1c) from baseline to 
endpoint (scheduled month 6) in children and adolescents with type 1 diabetes 
mellitus. 
Secondary objectives  
To compare HOE901-U300 and Lantus in terms of: 
• 
Percentage of patients reaching target HbA1c (<7.5%) at month 6 
overall and without any episode of severe and/or documented 
symptomatic hypoglycemia during last 3 months of the main 6-month 
randomized period; 
• 
Change from baseline to endpoint (month 6) in fasting plasma glucose 
(central laboratory); 
• 
Percent of patients reaching target fasting plasma glucose (FPG) value 
(≤130 mg/dL [7.2 mmol/L]) at month 6 overall and without any episode of 
severe and/or documented symptomatic hypoglycemia during the last 
3 months of the main 6-month randomized period; 
• 
Change in mean self-monitored plasma glucose (8-point SMPG profiles, 
24-hour mean plasma glucose, variability of 24-hour mean plasma 
glucose)  from baseline to month 6; 
To assess the safety of HOE901-U300 including analysis of events of 
hypoglycemia, events of hyperglycemia with ketosis and development of anti-
insulin-antibodies; 
To assess the extent of accumulation and metabolism of HOE901-U300 versus 
Lantus in this age group. 
STUDY DESIGN 
Open-label, 1:1 randomized, active-controlled, 2-arm parallel-group, multicenter 
international study comparing HOE901-U300 versus Lantus in children and 
adolescents with Type 1 diabetes mellitus (T1DM). 
Randomization will be stratified by age group (<12 years and ≥12 years) and by 
HbA1c value (<8.5% and ≥8.5%), both at the screening visit. The study will include 
a 2-week screening period, a 6-month efficacy and safety period followed by a  
6-month safety extension period and a 4-week post-treatment follow up period. 
Inclusion in the study is configured to ensure at least 30% of participants in the 
age range below 12 years. 
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STUDY POPULATION  
Main selection criteria 
Inclusion criteria  
•
Children and adolescents with T1DM for at least 1 year confirmed by
typical symptoms at diagnosis and/or by antibody testing (presence of
anti-GAD [glutamic acid decarboxylase] or anti-IA2 [islet antigen
2/tyrosine phosphatase] or anti-islet cell antibodies) and/or clinical
features (eg, history of ketoacidosis);
•
Signed written informed consent obtained from parent(s)/legal guardian
and written or oral assent obtained from patient.
Key exclusion criteria 
•
Age <6 years and ≥18 years at randomization;
•
Less than 1 year on insulin treatment prior to screening visit;
•
Less than 6 months on basal plus mealtime insulin and self-monitoring of
blood glucose prior to screening visit;
•
Patients using pre-mix insulins in the last 3 months before screening visit
or patients using human regular insulin as mealtime insulin in the last
3 months before screening visit;
•
Use of an insulin pump in the last 6 months before screening visit or
plans to switch to pump within the next 6 months after screening visit;
•
No willingness to inject insulin glargine (Lantus or HOE901-U300) once
daily;
•
HbA1c <7.5% or >11% at screening;
•
Initiation of any glucose-lowering medications in the last 3 months before
screening visit;
•
Hospitalization or care in the emergency ward for diabetic ketoacidosis
or history of severe hypoglycemia (as defined by need for glucagon or
intravenous [IV] glucose) and accompanied by seizure and/or
unconsciousness and/or coma in the last 3 months prior to screening
visit;
•
Postmenarchal girls not protected by highly-effective method(s) of birth
control and/or who are unwilling or unable to be tested for pregnancy.
Abstinence from sexual intercourse will be considered an acceptable
form of birth control;
•
Pregnant or breast-feeding adolescents or adolescents who intend to
become pregnant during the study period or who are at risk of getting
pregnant due to any psychosocial reason during the study period.
Total expected number of patients Approximately 450 patients will be randomized 
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STUDY TREATMENTS 
 
Investigational medicinal products 
 
Formulation 
Tested drug: HOE901-U300 
HOE901-U300 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 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 HOE901-U300 with other insulin products is not allowed nor dilution. 
Control drug: Lantus (Insulin glargine) 
Lantus will be supplied as a sterile, non-pyrogenic, clear, colorless solution in the 
marketed Lantus SoloStar prefilled (disposable) pen (insulin glargine 100 U/mL 
solution for subcutaneous injection).  
Each Lantus SoloStar contains in total 300 units of insulin glargine (3.0 mL of 
100 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 Lantus with other insulin products is not allowed nor dilution. 
Route of administration 
Tested drug: HOE901-U300 will be administered by subcutaneous (SC) 
injections once daily (self-administration or administration assisted by the 
parent/caregiver).  
Control drug: Lantus will be administered by SC injections once daily (self-
administration or administration assisted by the parent/caregiver). 
Dose regimen 
The same dose regimen will be used for HOE901-U300 and the comparator 
Lantus. 
Starting dose: The starting dose of the HOE901-U300 or Lantus will be the same 
(Unit for Unit) as the median dose (ie, the middle value out of the three values) of 
the total daily basal insulin doses in the last 3 days prior to the baseline visit, 
except if the patient was on more than once daily basal insulin products (eg, NPH 
insulin, insulin detemir), when the starting dose of HOE901-U300 or Lantus (U) 
should be reduced by approximately 20%. 
Dose titration: Dosing of insulin glargine given as HOE901-U300 or Lantus will be 
done based on self-measured, fasting, pre-breakfast plasma glucose levels (target 
range 90–130 mg/dL; 5.0–7.2 mmol/L) while avoiding hypoglycemia.   
After the end of study treatment patients on HOE901-U300 will have to switch from 
their daily HOE901-U300 dose to a non-study U100 basal insulin formulation by 
reducing the daily dose by 20% taking into account overall metabolic control. 
Non-investigational medicinal 
product(s)  
Formulation 
Patients in both treatment groups will continue with their fast-acting mealtime 
insulin analogue during the study. 
Solution for subcutaneous injection 
Route of administration 
Subcutaneous injection 
Dose regimen 
 
Dosing of the fast-acting mealtime insulin will be done based on self-measured, 
postprandial plasma glucose levels, target range for 2-hour post-prandial plasma 
glucose is <180 mg/dL (10.0 mmol/L) or, if clinically indicated, other individually 
determined goal. 
(electronic 
 
 
 
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Page 6 
ENDPOINTS 
 
Primary endpoint 
 HbA1c (change from baseline to endpoint [month 6/week 26]).                                  
Secondary endpoints 
• 
Percentage of patients with HbA1c values of <7.5%  at month 6 overall 
and without any episode of severe and/or documented  
(SMPG <54 mg/dL; 3.0 mmol/L) symptomatic hypoglycemia during the 
last 3 months of the main 6-month randomized period (from 
randomization date up to month 6 (Visit 14), regardless of study 
treatment discontinuation);  
• 
Change in FPG from baseline to month 6 (central laboratory); 
• 
Percentage of patients with FPG ≤130 mg/dL (7.2 mmol/L) at month 6 
overall and without any episode of severe and/or documented (SMPG 
<54 mg/dL; 3.0 mmol/L) symptomatic hypoglycemia during the last 
3 months of the main 6-month randomized period; 
• 
Change in 24-hour mean plasma glucose based on 8-point SMPG 
profiles from baseline to month 6; 
• 
Change in variability of 24-hour mean plasma glucose based on 8-point 
SMPG profiles from baseline to month 6; 
• 
Change in 8-point self-monitored plasma glucose (SMPG) profiles per 
time-point from baseline to month 6 (pre-prandial and 2 hour 
postprandial plasma glucose at breakfast, lunch and dinner, bedtime 
plasma glucose, nocturnal plasma glucose);  
Safety 
Hypoglycemia will be presented by hypoglycemia categories as defined in the 
publication American Diabetes Association (ADA) Workgroup on Hypoglycemia. In 
addition the composite category of severe and/or documented symptomatic 
hypoglycemia will be presented (documentation by SMPG <54 mg/dL; 3.0 mmol/L 
and SMPG ≤70 mg/dL; 3.9 mmol/L). 
Hyperglycemia (SMPG ≥252 mg/dL; 14 mmol/L) with ketosis (blood ketones 
≥1.5 mmol/L) will be presented. 
All adverse events, serious adverse events and adverse events of special interest 
will be collected from the time of informed consent signature and then at each visit 
until the end of the study. 
Physical examination including Tanner puberty stage, vital signs, body weight, 
height, body mass index (BMI) and safety laboratory data. 
Anti-insulin antibodies (AIA). 
(electronic 
 
 
 
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Page 7 
ASSESSMENT SCHEDULE 
 
 
 
 
Efficacy:  see Study Flowchart. 
Safety:  
see Study Flowchart. 
Pharmacokinetics (PK):  
Sparse sampling approach: 3 blood samples will be 
taken from all patients who consent to this assessment over a single day only after 
end of titration phase; during the period from Visit 13, Week 20 to Visit 14, 
Week 26 (see study flow chart). 
Anti-Insulin Antibodies: see study flow chart 
Early termination:  
In case of premature permanent Investigational Medicinal Product (IMP) 
discontinuation, all assessments normally planned for V18, Week 52 should be 
performed as soon as possible after last IMP administration. The patients will be 
asked to continue attending study visits and undergo assessments according to 
the schedule until the planned end of study treatment (month 12), including 
assessments normally scheduled for the 4-week post-treatment follow up period. 
For safety considerations, patients who wish to terminate participation in the study 
whatsoever, at the minimum should be assessed using the procedure normally 
planned for the post-treatment follow-up 1 visit (Visit 19). 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
The sample size was chosen to ensure sufficient power for the primary endpoint 
(change in HbA1c from baseline to endpoint).  
A sample size of 450 randomized patients (225 for HOE901-U300 and 225 for 
Lantus) will ensure that the upper bound of the two-sided 95% confidence interval 
(CI) for the adjusted mean difference between HOE901-U300 and Lantus would 
not exceed a non-inferiority margin of 0.3% HbA1c with 92% power. This 
calculation assumes a common standard deviation (SD) of 0.95%, with a one-
sided test at the 2.5% significant level and a true difference of zero in HbA1c 
between treatment groups. 
General aspects of the analyses: 
For efficacy analyses, the baseline is defined as the last available value obtained 
up to the date of randomization. 
Analysis population: 
The primary efficacy population is the intent-to-treat (ITT) population, which 
includes all randomized patients analyzed according to the treatment group 
allocated by randomization. 
The safety population is defined as all patients randomized and exposed to 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. 
Primary analysis: 
The primary efficacy variable (change in HbA1c from baseline to endpoint 
[month 6]), will be analyzed in the ITT population, using all post-baseline data 
available on the main 6-month randomized period (ITT estimand). A multiple 
imputation approach in two parts will be used where missing data from patients 
who do not adhere to IMP will be represented by the data from those patients in 
the same treatment group who also did not adhere to IMP but had the 
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Page 8 
measurement for the primary endpoint.  
The adjusted least squares mean change in HbA1c from baseline to month 6 for 
each treatment group (HOE901-U300, Lantus) will be estimated, as well as the 
between-group (HOE901-U300, Lantus) difference and the 95% CI for the 
adjusted mean. 
A stepwise closed testing approach will be used for the primary efficacy variable to 
assess non-inferiority and superiority sequentially.  
Step 1 will proceed to assess non-inferiority of HOE901-U300 versus Lantus. 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 endpoint between HOE901-U300 
and Lantus 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 HOE901-U300 and Lantus on ITT population is 
<0.3%. 
Only if non-inferiority of HOE901-U300 versus Lantus has been demonstrated, 
step 2 will be performed to test superiority of HOE901-U300 over Lantus. The 
superiority of HOE901-U300 over Lantus 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 endpoint between HOE901-U300 and Lantus on ITT population 
is <0 (zero). 
The tests for the primary endpoint (month 6) will be performed one-sided at level 
α = 0.025. 
A sensitivity analysis will be performed on change in HbA1c from baseline to 
month 6 on patients who complete the main 6-month on-treatment period in the 
ITT population (ie, patients who perform Visit 14 [Week 26] and who do not 
permanently discontinue treatment). 
In order to assess the impact of missing data, a penalized multiple imputation (MI) 
and a tipping point analysis will also be performed as sensitivity analyses. 
Analysis of secondary endpoints: 
Categorical efficacy parameters (responder rates) will be analyzed by using 
Cochran-Mantel-Haenszel (CMH) method with treatment as factors, stratified by 
randomization stratum of HbA1c (<8.5%, ≥8.5%) and by randomization stratum of 
age group (<12 years and ≥12 years) at screening. 
Secondary efficacy endpoints will be analyzed in the ITT population, using all 
available data on the 6-month randomized period (ITT estimand).  
A similar multiple imputation approach in two parts, as for the primary efficacy 
endpoint, will be used for change from baseline in FPG at Week 26. This analysis 
will be used descriptively. 
The other continuous secondary endpoints will be analyzed descriptively only. 
PK analyses: 
Blood samples will be collected to measure insulin glargine and its metabolites 
(M1 and M2) in plasma. PK analysis will be based on sparse sampling collected 
over a single day and will be done through a population PK approach. 
Safety analyses: 
Safety analyses will be descriptive using the safety population. Treatment 
emergent adverse events (TEAEs) are defined as AEs that developed or 
worsened or became serious during the period from the first dose administration of 
study treatment up to 2 days after the last administration. 
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Page 9 
Hypoglycemia will be analyzed for: 
• Incidence of patients (%) with at least one hypoglycemia; 
• Hypoglycemia episodes per patient year exposure. 
 
Analysis will be done: 
• By time of the day: anytime of the day, nocturnal (00:00 to 05:59), daytime 
(06:00 to 23:59) and by hour of the day; 
• By treatment periods: 6-month TEAE period, 12-month TEAE period, from 
first injection of IMP to end of week 8, from start of week 9 to month 6, monthly 
rates; 
• Hypoglycemia by HbA1c and age range and by Tanner puberty stage; 
• Hypoglycemia by sleep status. 
Hyperglycemia (SMPG ≥252 mg/dL; 14 mmol/L) with ketosis (blood ketones 
≥1.5 mmol/L) and AIA will be analyzed too. 
DURATION OF STUDY PERIOD 
(per patient)  
The study consists of: 
• a 2-week screening period; 
• a 6-month comparative efficacy and safety treatment period; 
• a 6-month comparative safety extension period; 
• a 4 week post-treatment follow up period, to evaluate insulin dose after switch-
back from the IMP to a commercially available basal insulin. 
In total the study duration will be approximately 58 weeks per patient. 
STUDY COMMITTEES 
Steering Committee:  
 Yes 
 No 
Safety Monitoring  
Committee:  
 Yes 
 No 
 
Ongoing safety surveillance will be performed by a blinded endpoint assessment 
committee consisting of experts in pediatric diabetology and endocrinology. The 
committee will be provided on a regular basis with tabulated overviews of 
hypoglycemia events, TEAEs and serious TEAEs. Additionally, the committee will 
assess antigenicity data (AIA data and potential clinical correlates [hypersensitivity 
events, indicators of insulin resistance]. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN 
 
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1.2 
STUDY FLOW CHART 
 
Screening 
(2 weeks) 
Treatment period (6 months) 
Extension period 
(6 months) 
Post treatment 
follow-up period 
(4 weeks) 
Visit: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 b 
End of 
treatment 
19 
Post  
treat- 
ment/ 
Follow-up 
1 
20 
Post 
treat- 
ment/ 
Follow-
up 2 
Visit window: 
Visit 3:  
±3 days vs. V1 
Visit 4 - 11: ±3 days vs. baseline 
Visit 12-18:  ±5 days vs. baseline 
Visit 19:  
+2 days vs. V18 
Visit 20:  
±5 days vs. V18 
Wk -2 
Wk-1 
 a 
Day 1 
Base- 
line 
Wk 
1 
  a 
Wk  
2  
a 
Wk 3 
  a 
Wk 4 
  a 
Wk 6 
  a 
Wk 
8 
  a 
Wk 
10  
a 
 
Wk 
12 
 
Wk16 
Mo 4 
  a  
Wk 
20 
 
    
Wk 
26 
Mo 6 
Wk 
32 
  a 
Wk 38 
 
Wk 45 
  a 
Wk 52 
Mo 12 
+ 48 
hours 
  a 
+ 4 
weeks 
  a 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history, demography, 
diabetes history, prior medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination c 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Vital signs d 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Body weight, height e 
X e 
 
X 
 
 
 
 
 
 
 
X e 
 
 
X e 
 
X e 
 
X e 
 
 
Tanner puberty stage f 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Dispensation of glucose meter, blood 
ketone meter & diary (and training at V1, 
V3 as needed and dispensation of 
corresponding supplies whenever needed) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispensation of urine container & training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Training on SMPG profiles, hypoglycemia 
(as needed) 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
Diet and lifestyle counseling (as needed) 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Dispensation of study medication (and 
training at V3) 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
 
 
 
Counting / collecting used and unused 
pens 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
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Page 12 
 
Screening 
(2 weeks) 
Treatment period (6 months) 
Extension period 
(6 months) 
Post treatment 
follow-up period 
(4 weeks) 
Visit: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 b 
End of 
treatment 
19 
Post  
treat- 
ment/ 
Follow-up 
1 
20 
Post 
treat- 
ment/ 
Follow-
up 2 
Visit window: 
Visit 3:  
±3 days vs. V1 
Visit 4 - 11: ±3 days vs. baseline 
Visit 12-18:  ±5 days vs. baseline 
Visit 19:  
+2 days vs. V18 
Visit 20:  
±5 days vs. V18 
Wk -2 
Wk-1 
 a 
Day 1 
Base- 
line 
Wk 
1 
  a 
Wk  
2  
a 
Wk 3 
  a 
Wk 4 
  a 
Wk 6 
  a 
Wk 
8 
  a 
Wk 
10  
a 
 
Wk 
12 
 
Wk16 
Mo 4 
  a  
Wk 
20 
 
    
Wk 
26 
Mo 6 
Wk 
32 
  a 
Wk 38 
 
Wk 45 
  a 
Wk 52 
Mo 12 
+ 48 
hours 
  a 
+ 4 
weeks 
  a 
Compliance Check (use of IMP and NIMP; 
glucose meter, ketone meter, diary, review 
of SMPG) 
 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Review of diary data 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IVRS/IWRS contact  
X g 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation and review of basal, 
prandial and corrective fast-acting insulin 
doses 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-monitoring of plasma glucose h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-monitoring of blood ketones i  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Central Laboratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c  
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
Fasting Plasma Glucose (FPG) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
C-peptide (fasting) 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Laboratory  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology j, Clinical Chemistry k 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
Anti-insulin antibody 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Hepatitis Serology l  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine analysis m 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Microalbuminuria and 
albumin/creatinine ratio n 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screening 
(2 weeks) 
Treatment period (6 months) 
Extension period 
(6 months) 
Post treatment 
follow-up period 
(4 weeks) 
Visit: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 b 
End of 
treatment 
19 
Post  
treat- 
ment/ 
Follow-up 
1 
20 
Post 
treat- 
ment/ 
Follow-
up 2 
Visit window: 
Visit 3:  
±3 days vs. V1 
Visit 4 - 11: ±3 days vs. baseline 
Visit 12-18:  ±5 days vs. baseline 
Visit 19:  
+2 days vs. V18 
Visit 20:  
±5 days vs. V18 
Wk -2 
Wk-1 
 a 
Day 1 
Base- 
line 
Wk 
1 
  a 
Wk  
2  
a 
Wk 3 
  a 
Wk 4 
  a 
Wk 6 
  a 
Wk 
8 
  a 
Wk 
10  
a 
 
Wk 
12 
 
Wk16 
Mo 4 
  a  
Wk 
20 
 
    
Wk 
26 
Mo 6 
Wk 
32 
  a 
Wk 38 
 
Wk 45 
  a 
Wk 52 
Mo 12 
+ 48 
hours 
  a 
+ 4 
weeks 
  a 
Pregnancy test (post menarchal girls) 
o; review of contraceptive measures 
X 
 
X 
 
 
 
 
 
 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Admission for PK sparse sampling p 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
Insulin dose after switch-back (basal and 
fast-acting) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Collection of diary and, if mandatory by 
local regulations, glucose meter &  blood 
ketone meter 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X q 
AE / SAE 
To be assessed and reported (if any) throughout the study (report SAE to the sponsor within 24 hours) 
X 
X 
Injection site reactions, hypersensitivity  
reactions 
To be assessed and reported (if any)  throughout the study 
X 
X 
Hypoglycemia recording 
To be assessed and reported (if any)  throughout the study 
X 
X 
a) 
 Mandatory telephone visit or optional clinical visit.  Additional, optional telephone visits to monitor and support the progress of insulin titration will be scheduled at the discretion of the investigator 
b) 
Or early termination visit. In case of premature and permanent IMP discontinuation, all assessments planned for V18 should be performed as soon as possible after last study treatment administration. The patient will be asked to attend all 
scheduled study visits and undergo study procedures until the planned end of treatment visit (or end of the 4-week post-treatment follow up period, whichever comes last). A post-treatment follow-up 1 safety phone call should be planned 
2 days (+2 days) after IMP discontinuation as well as post-treatment follow-up 2 safety phone call 4 weeks (±5 days) after IMP discontinuation 
c) 
The date of menarche will be captured if applicable 
d) 
At each on-site visit: Heart rate, blood pressure in sitting position 
e) 
Height at visits week -2 (screening), week 12, week 26  and during the extension period at visit week 38 and week 52 (or early IMP termination). BMI will be determined based on body weight and height. 
f) 
Tanner puberty stage until complete sexual maturity defined by Tanner stage 5 
g) 
IVRS/IWRS contact: before any blood sample is drawn because the patient number as allocated by IVRS/IWRS has to be reported on the laboratory requisition forms 
h) 
Self-monitored plasma glucose: 
Fasting plasma glucose: on at least 5 days in the week before each visit;  
It is recommended to perform fasting SMPG daily throughout the study. When up-titration of the IMP has been completed and fasting (pre-breakfast) SMPG is stable in the target range, the number of fasting SMPG checks can be reduced 
according to the investigator’s judgment, however at least 3 fasting (pre-breakfast) SMPG measurements per week should be done. On days when 8-point profiles are done, fasting SMPG will be considered as the second point of 
measurement, ie, the before breakfast time point. 
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8-point blood glucose profiles (starting with a measurement between 01:00 – 04:00 AM 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 week before the baseline visit, and the visits week 26 and week 52. Special attention should be paid that the nighttime SMPG value is recorded (1) 
SMPG during symptomatic hypoglycemia: whenever the patients feel hypoglycemic symptoms, plasma glucose should be measured by the patient (or others, if applicable), if possible. Patients should be instructed to measure plasma 
glucose levels prior to the administration of glucose or carbohydrate intake whenever symptomatic hypoglycemia is suspected, unless safety considerations necessitate immediate glucose/carbohydrate rescue prior to confirmation. Details 
of all hypoglycemia events will be reported on dedicated electronic Case Report Form (e-CRF) pages. 
Complementary SMPG: it is recommended to perform 4-6 SMPG daily at different times of the day and measure the nighttime SMPG once weekly for optimal control of glycemia and adjustment of the insulin regimen. Additional SMPG 
are recommended in association with exercise/sport (before start, during and after activity and at bedtime) and at sick days, menses. 
Tests using the control solution: It is recommended to perform tests with the control solution before first use of the study glucose meter, in cases when SMPG reading is considered incorrect or inconsistent with symptoms and whenever 
a new batch of test strips is used. 
i) 
Anytime SMPG ≥252 mg/dL (14 mmol/L) is measured in an unwell child or when persistent blood glucose values above ≥252 mg/dL (14 mmol/L) without substantial decline are present over a period of approximately 60-120 min after an 
extra dose of rapid-acting insulin, or during illness with fever and/or vomiting. Ketone readings are to be documented in the diary. 
j) 
Hematology: Erythrocytes, hemoglobin, hematocrit, leukocytes, differential blood count (neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelets 
k) 
Clinical chemistry: total bilirubin (in case of values above the normal range, differentiation in conjugated and non-conjugated bilirubin), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), 
creatinine, estimated glomerular filtration rate (eGFR) (Schwartz equation),  sodium, potassium, chloride,  calcium 
l) 
Hepatitis serology: Hepatitis B surface antigen (HbsAg) and Hepatitis C viral antibodies (HCAb); if HCAb positive: reflex test for Hepatitis C virus (HCV) RNA  
m) Urine analysis: pH, glucose, ketones, leucocytes, blood/hemoglobin, protein 
n) 
Microalbuminuria, albumin/creatinine ratio: in first morning urine sample. Container to be dispensed at Visit 1 
o) 
For post-menarchal girls; serum pregnancy test for screening (central laboratory); urine pregnancy test (at study site) for subsequent monitoring; review of contraceptive measures at each on-site visit 
p) 
PK sparse sampling will be collected in patients who provided dedicated consent over one day after the end of titration phase during the period from visit 13, week 20 to visit 14, week 26. The sample times will depend on the existing 
dosing regimen:  
- Participants with dose administered in the evening (~ 20:00)  on the day before the date of the visit: sample schedule: 12 h, 16 h and 20 h post-dose (which will be around 08:00, 12:00, 16:00 on day of visit) 
- Participants with dose administered in the morning (~ 08:00)  on the day of the visit: sample schedule: pre-dose, 4 h, and 8 h post-dose (which will be around 08:00, 12:00, 16:00 on visit day) 
q) 
At last study visit (if performed as an on-site visit) or shortly thereafter 
Note: Telephone counseling will be available at any time as needed. 
 
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2 
TABLE OF CONTENTS 
 
AMENDED CLINICAL TRIAL PROTOCOL 02 ..............................................................................................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 ..........................................................................................................21 
4 
INTRODUCTION AND RATIONALE.............................................................................................23 
5 
STUDY OBJECTIVES ...................................................................................................................27 
5.1 
PRIMARY.......................................................................................................................................27 
5.2 
SECONDARY ................................................................................................................................27 
6 
STUDY DESIGN ............................................................................................................................28 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................28 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................28 
6.2.1 
Duration of study participation for each patient .............................................................................28 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................28 
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 current knowledge of Sanofi compound......................................31 
7.2.3 
Additional exclusion criteria during or at the end of screening phase before randomization ........31 
8 
STUDY TREATMENTS .................................................................................................................32 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS.............................................................................32 
8.1.1 
Formulations ..................................................................................................................................32 
8.1.2 
Injection devices and training for injection devices........................................................................32 
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8.1.2.1 
Injection devices.............................................................................................................................32 
8.1.3 
Dosage schedule ...........................................................................................................................33 
8.1.4 
Starting dose..................................................................................................................................34 
8.1.5 
Dose adjustment ............................................................................................................................34 
8.1.6 
Switch-back to commercial basal insulin .......................................................................................36 
8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT......................................................................37 
8.2.1 
Dosage schedule ...........................................................................................................................37 
8.2.2 
Starting dose..................................................................................................................................37 
8.2.3 
Dose adjustment ............................................................................................................................37 
8.3 
TITRATION OVERVIEW AND EVALUATION OF PATIENTS NOT MEETING GLYCEMIC 
GOALS...........................................................................................................................................38 
8.4 
BLINDING PROCEDURES............................................................................................................39 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................39 
8.6 
PACKAGING AND LABELING ......................................................................................................40 
8.7 
STORAGE CONDITIONS AND SHELF LIFE................................................................................41 
8.8 
RESPONSIBILITIES ......................................................................................................................41 
8.8.1 
Treatment accountability and compliance......................................................................................41 
8.8.2 
Return and/or destruction of treatments ........................................................................................42 
8.9 
CONCOMITANT MEDICATION.....................................................................................................42 
8.9.1 
Concomitant Diabetes Therapy .....................................................................................................42 
8.9.2 
Prohibited concomitant therapy .....................................................................................................43 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................44 
9.1 
EFFICACY .....................................................................................................................................44 
9.1.1 
Primary endpoint............................................................................................................................44 
9.1.1.1 
HbA1c measurement .....................................................................................................................44 
9.1.2 
Secondary endpoints .....................................................................................................................45 
9.1.2.1 
Fasting Plasma Glucose ................................................................................................................45 
9.1.2.2 
Self-measured plasma glucose (SMPG)........................................................................................45 
9.1.2.3 
Dose of basal and mealtime insulin ...............................................................................................47 
9.2 
SAFETY ENDPOINTS ...................................................................................................................47 
9.2.1 
Hypoglycemia.................................................................................................................................48 
9.2.2 
Hyperglycemia with ketosis............................................................................................................49 
9.2.3 
Adverse events ..............................................................................................................................49 
9.2.4 
Laboratory safety variables............................................................................................................50 
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9.2.5 
Physical examination and Tanner puberty stage...........................................................................51 
9.2.6 
Body Weight and Height ................................................................................................................51 
9.2.7 
Vital signs.......................................................................................................................................51 
9.2.8 
Immunogenicity..............................................................................................................................52 
9.2.9 
Blinded external endpoint assessment committee ........................................................................52 
9.3 
OTHER ENDPOINTS.....................................................................................................................53 
9.3.1 
Pharmacokinetics sparse sampling ...............................................................................................53 
9.4 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................53 
10 
STUDY PROCEDURES ................................................................................................................55 
10.1 
VISIT SCHEDULE..........................................................................................................................55 
10.1.1 
Screening period............................................................................................................................56 
10.1.1.1 Screening visit (Visit 1, Week - 2)..................................................................................................56 
10.1.1.2 Telephone visit 2 (week -1)............................................................................................................58 
10.1.2 
Open-label randomized treatment phase (Day 1 to Week 52) ......................................................59 
10.1.2.1 Baseline visit (Visit 3, Day 1) .........................................................................................................60 
10.1.2.2 Phone call visits: Visit 4-10 (Week 1-10), Visit 12 (Week 16), Visit 15 (Week 32) and Visit 
17 (Week 45)..................................................................................................................................62 
10.1.2.3 On-site Visits: Visit 11 (Week 12); Visit 13 (Week 20); Visit 14 (Week 26 – main study 
endpoint visit); Visit 16 (Week 38) .................................................................................................63 
10.1.2.4 End of Treatment Visit (Visit 18, Week 52) or Early Treatment Discontinuation Visit ...................65 
10.1.3 
Post- treatment follow up period (the 4 weeks [± 5 days] following Visit 18).................................66 
10.1.3.1 Post-treatment Follow up Visit 1 (Visit 19; two days [+2 days] after Visit 18) and Post-
treatment Follow up Visit 2 (Visit 20 – End of Study Visit -  four weeks  [± 5 days] after Visit 
18) ..................................................................................................................................................66 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................67 
10.2.1 
Source data verification requirements for patients not randomized ..............................................68 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................68 
10.3.1 
Temporary treatment discontinuation with investigational medicinal products..............................68 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product ...............................69 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................69 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................69 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................70 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................71 
10.4.1 
Definitions of adverse events.........................................................................................................71 
10.4.1.1 Adverse event ................................................................................................................................71 
10.4.1.2 Serious adverse event ...................................................................................................................71 
10.4.1.3 Adverse event of special interest...................................................................................................72 
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10.4.2 
General guidelines for reporting adverse events ...........................................................................73 
10.4.3 
Instructions for reporting serious adverse events ..........................................................................73 
10.4.4 
Guidelines for reporting adverse events of special interest...........................................................74 
10.4.5 
Guidelines for management of specific laboratory abnormalities ..................................................74 
10.4.6 
Summary of adverse event and hypoglycemia reporting instructions ...........................................74 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................76 
10.6 
SAFETY INSTRUCTIONS .............................................................................................................76 
10.6.1 
Hypoglycemia instructions .............................................................................................................76 
10.6.2 
Hyperglycemia with ketosis instructions ........................................................................................77 
10.6.3 
Local tolerability at injection site and hypersensitivity reactions....................................................77 
10.6.4 
Follow-up of laboratory abnormalities............................................................................................77 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................77 
11 
STATISTICAL CONSIDERATIONS..............................................................................................78 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................78 
11.1.1 
Justification of the non-inferiority margin .......................................................................................78 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................78 
11.3 
ANALYSIS POPULATIONS...........................................................................................................80 
11.3.1 
Efficacy populations .......................................................................................................................80 
11.3.1.1 Intent–to-treat population ...............................................................................................................80 
11.3.2 
Safety population ...........................................................................................................................80 
11.3.3 
PK population.................................................................................................................................80 
11.4 
STATISTICAL METHODS .............................................................................................................81 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................81 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................81 
11.4.1.2 Daily insulin doses .........................................................................................................................81 
11.4.1.3 Compliance ....................................................................................................................................82 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................82 
11.4.2.1 Analysis of primary efficacy endpoint.............................................................................................82 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................85 
11.4.2.3 Multiplicity considerations ..............................................................................................................85 
11.4.3 
Analyses of safety data..................................................................................................................86 
11.4.3.1 Hypoglycemia.................................................................................................................................86 
11.4.3.2 Hyperglycemia with ketosis............................................................................................................87 
11.4.3.3 Adverse events ..............................................................................................................................87 
11.4.3.4 Laboratory safety variables............................................................................................................88 
11.4.3.5 Vital signs and physical examination .............................................................................................88 
11.4.3.6 Analyses of AIA variables ..............................................................................................................89 
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Page 19 
11.4.4 
Analyses of pharmacokinetic variables..........................................................................................89 
11.5 
INTERIM ANALYSIS......................................................................................................................89 
11.6 
DATABASE LOCK .........................................................................................................................89 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................90 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................90 
12.2 
INFORMED CONSENT .................................................................................................................90 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............91 
13 
STUDY MONITORING...................................................................................................................92 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS .........................................................................92 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................92 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................93 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................93 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................93 
14 
ADDITIONAL REQUIREMENTS...................................................................................................94 
14.1 
CURRICULUM VITAE....................................................................................................................94 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................94 
14.3 
CONFIDENTIALITY .......................................................................................................................94 
14.4 
PROPERTY RIGHTS.....................................................................................................................95 
14.5 
DATA PROTECTION.....................................................................................................................95 
14.6 
INSURANCE COMPENSATION....................................................................................................96 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................96 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................97 
14.8.1 
By the Sponsor...............................................................................................................................97 
14.8.2 
By the Investigator .........................................................................................................................97 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................97 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................98 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................99 
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16 
BIBLIOGRAPHIC REFERENCES...............................................................................................100 
17 
APPENDICES..............................................................................................................................101 
APPENDIX A 
TANNER PUBERTY STAGE CLASSIFICATION..............................................................102 
APPENDIX B 
CRITERIA TO REDUCE REPRODUCTIVE RISK.............................................................103 
APPENDIX C GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI....................................................................................................104 
APPENDIX D BACK-UP PLAN FOR SAE AND AESI REPORTING PROCESS WHEN THE E-CRF 
SYSTEM FAILS ...........................................................................................................................109 
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3 
LIST OF ABBREVIATIONS 
 
ADA: 
American Diabetes Association 
AESI: 
adverse event of special interest 
AIA: 
anti-insulin antibodies 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
BMI: 
body mass index 
CI: 
confidence interval 
CRF: 
case report form 
CSR: 
clinical study report 
DBP: 
diastolic blood pressure 
DKA: 
diabetic ketoacidosis 
DRF: 
discrepancy resolution form 
ECG: 
electocardiogram 
e-CRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
FDA: 
Food and Drug Administration 
FPG: 
fasting plasma glucose 
GCP: 
good clinical practrice 
HbA1c: 
glycated hemoglobin A1c 
HBsAg: 
hepatitis B surface antigen 
HCAb: 
hepatitis C viral antibodies 
HCV: 
hepatitis C virus 
HLGT: 
high level group term 
HLT: 
high level term 
HR: 
heart rate 
ICH: 
International Conference on Harmonization 
IEC: 
independent ethics committee 
IMP: 
investigational medicinal product 
IRB: 
institutional review board 
ITT: 
intent-to-treat 
IV: 
intravenous 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
MI: 
multiple imputation 
NGSP: 
national glycohemoglobin standardization program 
NIMP: 
non-investigational medicinal product 
PCSA: 
potentiallly clinically significant abnormality 
PD: 
pharmacodynamics 
PK: 
pharmacokinetics 
PT: 
preferred term 
SBP: 
systolic blood pressure 
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SC.: 
subcutaneous 
SE: 
standard error 
SMPG: 
self-measured plasma glucose 
SOC: 
system organ class 
T1DM: 
type 1 Diabetes Mellitus 
T2DM: 
type 2 Diabetes Mellitus 
TEAE: 
treatment emergent adverse event 
ULN: 
upper limit of normal range 
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4 
INTRODUCTION AND RATIONALE 
Insulin glargine U100 (HOE901) is 21A-Glycine-30Ba -L-arginine-30Bb-L-Arginine-human 
insulin, a recombinant analog of human insulin providing a 24-hour basal insulin supply after a 
single-dose subcutaneous (SC) injection.  Insulin glargine U100 has been marketed as Lantus® for 
approximately 15 years. Its efficacy and safety are well-known through extensive data collection 
involving over 200 000 patients in clinical studies, including randomized, controlled clinical trials 
and the results of postmarketing surveillance arising from approximately 66.9 million patient-
years of clinical experience. Further information on Lantus, including important clinical trials 
performed pre- and postregistration, can be found in the national product label or in the Product 
Information (2) and Investigator´s Brochure HOE901 (3). 
Insulin glargine U100 (Lantus) is approved for a once daily injection for the treatment of diabetes 
in adults and pediatric (age range 6 to 15 years; in the EU also in preschoolers 1–6 years of age) 
patients with type 1 diabetes mellitus (T1DM) and in adults with type 2 diabetes mellitus 
(T2DM). 
HOE901-U300 is a new formulation of insulin glargine. It has the same composition as the 
marketed insulin glargine 100 U/mL formulation with adjustment of 3-times the amount of Active 
Pharmaceutical Ingredient (API) and corresponding Zinc content. Toujeo was approved in the US 
on February 25, 2015 and in the European Union on April 12, 2015 for the treatment of adults 
with diabetes mellitus. Review of the regulatory submission documents is ongoing in other 
countries worldwide. 
Insulin glargine has the same metabolism regardless of the concentration of the formulation, 
notably the formation of 21A-Gly-human insulin (M1 metabolite) as the predominant circulating 
metabolite. The difference between HOE901-U300 and Lantus rests in the 
pharmacokinetics/pharmacodynamics (PK/PD) profile which shows slower and more prolonged 
absorption of HOE901-U300 resulting in a flatter time-concentration profile. 
Based on the results of Phase 1 studies with HOE901-U300 in healthy subjects and adults with 
T1DM (PKD10086, PKD11627 and TDR11626), it was anticipated that compared to Lantus, the 
prolonged and flatter profile of the glucose-lowering activity of HOE901-U300 (up to 36 hours) 
could result in more constant glycemic control within a 24-hour injection interval, in turn, 
resulting in less circadian fluctuation in blood glucose levels and lower risk of hypoglycemia. 
In Phase 3 clinical studies in a broad range of adult patient population with T1DM and T2DM, 
HOE901-U300 has shown comparable efficacy, safety and tolerability to Lantus with different 
pre-treatment regimens and dose requirements of insulin. In patients with T2DM, HOE901-U300 
was consistently associated with a lower risk of hypoglycemia as compared with Lantus, as shown 
for severe and/or confirmed hypoglycemia. In the study in T1DM (EFC12456) there was no 
difference between the treatment groups for percentages of patients reporting hypoglycemia or the 
event rates per patient year. In the study the assessment of the hypoglycemia risk associated with 
the basal insulin may have been confounded by the concomitant use of fast-acting insulin. 
Further details on HOE901-U300 can be found in the Investigator’s Brochure HOE901. 
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Since Lantus is approved in the T1DM pediatric population 6 to 18 years of age, it is anticipated 
that HOE901-U300 may also be used in this population. This study is planned to generate 
evidence of efficacy and safety of HOE901-U300 in children and adolescents 6-17 years of age 
with T1DM requiring insulin treatment. 
The purpose of this multicenter, randomized, open-label, 2-arm parallel-group study in children 
and adolescents is to compare the efficacy and safety of HOE901-U300 with that of Lantus, both 
given once-daily by SC injection. Patients with type 1 diabetes and glycated hemoglobin A1c 
(HbA1c) in the range of 7.5% to 11% on a basal plus fast-acting insulin regimen are eligible for 
the study. Patients with hospitalization for diabetic ketoacidosis (DKA) or history of severe 
hypoglycemia (as defined by need for glucagon or intravenous [IV] glucose) during the previous 
3 months, are excluded from the study. 
Patients will be randomized (1:1) to receive HOE901-U300 or Lantus. 
Patients will be stratified by their HbA1c (<8.5%; ≥8.5%) and age group (<12 years; ≥12 years) at 
the time of screening. Inclusion in the study is configured to ensure at least 30% of participants in 
the age range below 12 years. The primary efficacy analysis will test non-inferiority of  
HOE901-U300 compared to Lantus in terms of change of HbA1c from baseline to endpoint 
(month 6; non-inferiority margin 0.3% HbA1c units).  
Secondary analyses will be performed to evaluate the effects of the flat insulin profile over at least 
24 hours, which should result in more sustained glycemic control within predefined blood glucose 
margins. The analyses will be based on fasting plasma glucose (FPG, central laboratory), on self-
monitored plasma glucose measurements (SMPG; eg, 8-point glucose profiles), hypoglycemia 
reports and insulin doses. 
A thorough hypoglycemia analysis will be performed. Evaluations will include incidence of 
hypoglycemia (number of patients with at least one hypoglycemia) and hypoglycemia episodes 
per patient year. Hypoglycemia episodes will be evaluated overall and by time of the day, 
(ie, daytime, nocturnal, overall, distribution over the 24-hour period) and by study periods. The 
American Diabetes Association (ADA) definitions will be applied to define the hypoglycemia 
categories (4, 5). All confirmed hypoglycemia categories will be also evaluated for the more 
stringent SMPG threshold of <54 mg/dL (3.0 mmol/L). In addition, composite categories 
including the clinically important categories of severe hypoglycemia and/or symptomatic 
hypoglycemia documented by SMPG <54 mg/dL (3.0 mmol/L) and ≤70 mg/dL (3.9 mmol/L) will 
be evaluated. Other safety evaluation will include the comparison of clinical treatment emergent 
adverse events (TEAEs), hyperglycemia with ketosis, hypersensitivity reactions and injection site 
reactions. Laboratory safety will include the standard hematology and biochemistry and the 
determination of anti-insulin antibodies (AIA) and assessments of effects on weight. 
PK of insulin glargine 100 U/mL and metabolites were evaluated in adults (study TDR11626) and 
in children 1–6 years of age (EFC11202, PRESCHOOL) with T1DM. The principal 
pharmacologically active entity in serum was the insulin glargine metabolite M1 in both 
populations. Insulin glargine parent compound and metabolite M2 Ctrough were below limit of 
quantification (<0.2 ng/mL) in the vast majority of patients. No PK data exists on insulin glargine 
HOE901-U300 in pediatrics and adolescents 6 to 18 years of age. In this study, serum 
concentration of insulin glargine and its metabolites M1 and M2 will be determined at various 
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time points over a single day according to a defined sparse sampling scheme to evaluate the time 
course of accumulation and the metabolism of insulin glargine given as HOE901-U300 or Lantus. 
The blood samples will be taken after the end of titration phase, during the period from visit 13, 
week 20 to visit 14, week 26) from all participants who provided consent for PK data collection. 
The study consists of a 2-week screening period and a treatment period of 6 months, followed by 
a comparative on-treatment 6-month safety extension period and a 4-week post-treatment follow-
up period.  
HOE901-U300 or Lantus will be injected subcutaneously once daily, either in the morning or in 
the evening. Efforts will be made to maintain the same dosing time (hh:mm) during the whole 
treatment period so that the interval between once daily injections of the investigational medicinal 
product (IMP) will be kept at or close to 24 hours. Patients will continue with their mealtime fast-
acting insulin analogue.  
During the 6-month treatment period the basal insulin dose will be titrated using a titration 
schedule to reach the target fasting/pre-prandial plasma glucose in the range of 90 to 130 mg/dL 
(5.0 to 7.2 mmol/L), bedtime / nocturnal plasma glucose in the target range of 90–150 mg/dL 
(5.0 and 8.3 mmol/L) (6), avoiding hypoglycemia. Mealtime insulin will be adjusted to achieve a 
target 2-hour postprandial plasma glucose <180 mg/dL (10.0 mmol/L). After reaching the target 
range, the insulin dose will be adjusted depending on the prevailing plasma glucose to maintain 
the glycemic control over the remaining study duration. Patients will be encouraged to measure 
and record frequent SMPG values on a daily basis at different times of the day and in line with 
recommendations by the International Society for Pediatric and Adolescent Diabetes (ISPAD) (1). 
Patients will be instructed to measure and record their blood ketones if SMPG is ≥252 mg/dL 
(≥14 mmol/L) while being unwell (eg, feeling sick or nauseated) or when persistent blood glucose 
values ≥252 mg/dL (14 mmol/L) without substantial decline are present over a period of 
approximately 60-120 min after an extra dose of rapid-acting insulin analogue, or during 
illness with fever and/or vomiting. Ketone readings 1.5 mmol/L or more and concomitant 
SMPG ≥252 mg/dL (14 mmol/L) will be considered as alert for development of diabetic 
ketoacidosis and the investigator will be contacted immediately. Patients who have completed the 
6-month treatment period will continue their study treatment during the 6-month comparative 
safety extension period to evaluate long-term safety and maintenance of efficacy. 
After end of study treatment (Month 12) patients will be monitored after switch-back to 
commercial basal insulin during the 4-week post-treatment follow up period. Patients who 
prematurely and permanently discontinue study treatment will be asked to continue attending 
study visits and undergo assessments according to the schedule until the planned end of study 
treatment (Month 12). For patients who prematurely and permanently discontinue study treatment 
during the main 6-month treatment period, as a minimum visit at Week 26/Visit 14 (assessments 
of primary and secondary efficacy endpoints) should be conducted. 
The number of visits to the study site (7 out of 20 visits planned) is kept at a minimum in order to 
minimize the impact on the daily activities of the adolescents and their caregivers. Instead, 
monitoring of glycemic control including self-monitored plasma glucose, hypoglycemia events, 
titration of the basal insulin, dosing of study and mealtime insulin is done during phone-call visits. 
If deemed necessary by the investigator or by the patient/caregiver, on-site visits may be arranged 
any time. 
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The overall benefit-risk assessment does not raise any concern for this study, because there is no 
reason to suppose that HOE901-U300 would pose a greater risk or confer worse efficacy 
outcomes than in the adult population or than Lantus in the population consisting of children and 
adolescents with T1DM. In this study, HOE901-U300 will be administered using the Toujeo 
SoloStar® prefilled (disposable) pen. Its accuracy has been determined to be in accordance with 
respective standards. The safety of patients in this study, including hypoglycemia events, will be 
closely followed within the framework of clinical trial. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To compare the efficacy of a new formulation of insulin glargine (HOE901-U300) to Lantus in 
terms of change of HbA1c from baseline to endpoint (month 6) in children and adolescents with 
type 1 diabetes mellitus. 
5.2 
SECONDARY 
• To compare HOE901-U300 and Lantus in terms of  
- 
Percentage of patients reaching target HbA1c (<7.5%)  at month 6 overall and without 
any episode of severe and/or documented symptomatic hypoglycemia during last 
3 months of the main 6-month randomized period; 
- 
Change from baseline to endpoint (month 6) in fasting plasma glucose (central 
laboratory); 
- 
Percent of patients reaching target FPG value (≤130 mg/dL [7.2 mmol/L]) at month 6 
overall and without any episode of severe and/or documented symptomatic 
hypoglycemia during the last 3 months of the main 6-month randomized period; 
- 
Change in mean self-monitored plasma glucose (8-point SMPG profiles, 24-hour mean 
plasma glucose, variability of 24-hour mean plasma glucose) from baseline to 
month 6; 
• To assess the safety of HOE901-U300 including analysis of events of hypoglycemia, 
events of hyperglycemia with ketosis and development of anti-insulin-antibodies; 
• To assess the extent of accumulation and metabolism of HOE901-U300 versus Lantus in 
this age group. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is an open-label, 1:1 randomized, active-controlled, 2-arm parallel-group, multicenter 
international, phase 3b study comparing HOE901-U300 versus Lantus in children and adolescents 
with T1DM. Patients will continue their fast-acting mealtime insulin analogue during the study. 
Randomization will be stratified by age group (<12 years and ≥12 years) and by HbA1c  
(<8.5% and ≥8.5%) at screening. Inclusion in the study is configured to ensure at least 30% of 
participants in the age range below 12 years.  
PK sparse sampling: all participants who will give assent (and will have additional dedicated 
consent form signed by their parent) will provide 3 blood samples over a single day in the period 
between Visit 13 (week 20) and Visit 14 (week 26), inclusive, see Section 9.3.1. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The study consists of: 
• A 2-week screening period; 
• A 6-month comparative efficacy and safety treatment period; 
• A 6-month comparative safety extension period; 
• A 4-week post-treatment follow up period 
In case of premature permanent discontinuation of study treatment, patients will be asked to 
continue attending study visits and undergo assessments according to the schedule until the 
planned end of study treatment (Month 12), including assessments normally scheduled for the  
4-week post-treatment follow up period. As a minimum, visit at Week 26/Visit 14 (assessments of 
primary and secondary efficacy endpoints) should be conducted. For safety considerations, 
patients/parents who withdraw consent for further participation in the study, at the minimum 
should be contacted 2 days after last intake of the IMP. 
In total the study duration per patient will be approximately 58 weeks (2 weeks of screening + 
52 weeks of treatment + 4 weeks of post-treatment follow up). 
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. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Children and adolescents with T1DM for at least 1 year confirmed by typical symptoms at 
diagnosis and/or by antibody testing (presence of anti-GAD [glutamic acid decarboxylase] 
or anti-IA2 [islet antigen 2/tyrosine phosphatase] or anti-islet cell antibodies) and/or 
clinical features (eg, history of ketoacidosis); 
I 02. Signed written informed consent obtained from parent(s)/legal guardian1 (hereinafter the 
“parent”) and written or oral assent obtained from patient. 
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 3 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. Age <6 and ≥18 years at randomization; 
E 02. Less than 1 year on insulin treatment prior to screening visit; 
E 03. Less than 6 months on basal plus mealtime insulin and self-monitoring of blood glucose 
prior to screening visit;  
E 04. Patients using pre-mix insulins in the last 3 months before screening visit or patients using 
human regular insulin as mealtime insulin in the last 3 months before screening visit; 
E 05. Use of an insulin pump in the last 6 months before screening visit or plans to switch to 
pump within the next 6 months after screening visit; 
E 06. Any contraindication to use of insulin glargine as defined in the national product label; 
E 07. No willingness to inject insulin glargine (Lantus or HOE901-U300) once daily; 
E 08. HbA1c <7.5% or >11% at screening; 
                                                 
1 "Legal guardian" means an individual or judicial or other body authorised under applicable law to consent 
on behalf of a prospective patient to the patient's participation in the procedure(s) involved in the 
research. In this document “parent” will be used as a synonym for “legal guardian” 
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E 09. Hospitalization or care in the emergency ward for diabetic ketoacidosis or history of severe 
hypoglycemia (as defined by need for glucagon or IV glucose) and accompanied by 
seizure and/or unconsciousness and/or coma in the last 3 months prior to screening visit; 
E 10. Initiation of any glucose-lowering agents in the last 3 months before screening visit; 
E 11. End stage renal disease (creatinine clearance <15 mL/min/1.73m2 or on renal replacement 
treatment); 
E 12. Hemoglobinopathy or hemolytic anemia, transfusion of blood or plasma products within 
3 months prior to screening visit; 
E 13. History of drug or alcohol abuse within 6 months prior to the time of screening; 
E 14. Patients with severe or unstable, clinically relevant non-diabetes disorders making 
implementation of the study protocol or interpretation of the results of the study difficult or 
patients with short life expectancy or any other medical condition that might interfere with 
the evaluation of study medication according to investigator’s medical judgment; 
E 15. Active liver disease or alanine aminotransferase (ALT) or Aspartate aminotransferase 
(AST)  >3 times upper limit of normal or total bilirubin >1.5 times upper limit of normal 
(except in case of documented Gilbert’s syndrome) at screening;  
E 16. Positive test for hepatitis B surface antigen and/or infection with hepatitis C virus at 
screening; 
E 17. Use of investigational drug(s) within 1 month or 5 half-lives, whichever is longer prior to 
the screening visit;  
E 18. 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 19. Likelihood of requiring treatment during the study period with drugs not permitted by the 
study protocol; 
E 20. Mental condition rendering the patient or parent unable to understand the nature, scope and 
possible consequences of the study, including blood glucose monitoring requirements 
including 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; 
E 21. Parents/patients not willing to undergo all study assessments and treatments, including 
home blood glucose monitoring, multiple daily insulin injections, and visits, as dictated by 
the protocol (if a telephone is not available patients may undergo all visits in person); 
E 22. Patients/parents not willing to be treated with basal/bolus insulin therapy for the duration 
of the study. Patients/parents must be willing to use a single injection of insulin glargine as 
their sole basal insulin during the study as assigned by the randomization process. They 
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must agree to use rapid acting insulin as their bolus insulin for the duration of study 
treatment; 
E 23. Adolescents who will reach the legal age of maturity during the study period if continuity 
of care at the study site cannot be ensured due to transition from pediatric to adult health 
care; 
E 24. Parent unable to read and write; 
E 25. Parent is related to or an employee of sanofi or sponsor representatives or member of the 
investigator’s staff;  
E 26. Postmenarchal girls not protected by highly-effective method(s) of birth control (as defined 
in Appendix B) and/or who are unwilling or unable to be tested for pregnancy. Abstinence 
from sexual intercourse will be considered an acceptable form of birth control; 
E 27. Pregnant or breast-feeding adolescents or adolescents who intend to become pregnant 
during the study period or who are at risk of getting pregnant due to any psychosocial 
reason during the study period. 
7.2.2 Exclusion criteria related to the current knowledge of Sanofi compound 
E 28. History of hypersensitivity to metacresol or other excipient of Lantus or HOE901-U300. 
7.2.3 Additional exclusion criteria during or at the end of screening phase before 
randomization 
E 29. Patients or parents who withdraw consent during the screening period (patient who is not 
willing to continue or fails to return). 
E 30. Patients/parents who cannot demonstrate the proper use of injection pens, diary or glucose 
meter before randomization or who were not compliant to the fasting SMPG measurement 
schedule. 
A patient must not be randomized more than once. 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. New informed consent has to be signed by the parent before re-screening (and new 
assent obtained from the patient). 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCTS 
The IMP is insulin glargine. It will be provided either as HOE901-U300 (tested drug) or as Lantus 
(control drug). 
8.1.1 Formulations 
Tested drug: HOE901-U300 
HOE901-U300 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 
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 HOE901-U300 with other insulins is not allowed nor dilution. 
Control drug: Lantus (Insulin glargine) 
Lantus will be supplied as a sterile, non-pyrogenic, clear, colorless solution in the marketed 
Lantus SoloStar prefilled (disposable) pen (insulin glargine 100 U/mL solution for subcutaneous 
injection).  
Each Lantus SoloStar contains in total 300 units of insulin glargine (3.0 mL of 100 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 Lantus with other insulins is not allowed nor dilution. 
8.1.2 Injection devices and training for injection devices 
8.1.2.1 Injection devices 
Disposable injection devices (prefilled study drug pens) with needles are provided to each patient 
for the injection of HOE901-U300 or Lantus specifically labeled for use in the study. 
The following commercial pen needles will be provided for use with the disposable injection pen 
devices:  
• BD Ultra Fine Needles 32 G x 4 mm  
• BD Ultra Fine Needles 31 G x 5 mm 
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If deemed appropriate by the investigator, other types of needles approved for use with the 
SoloStar pen may be used. 
Handling procedures of the disposable pen and needles and administration technique is provided 
in specific manuals (see Pen leaflet). The patients (and/or parents) are trained on the use of the 
study drug disposable pen and needles by the study staff and provided with an instruction leaflet 
at Visit 3. For the duration of the treatment, the participants will be required to use the same type 
of study drug disposable pens and needles. 
Pen-device issues (malfunctions) associated with the IMP pen that are not resolved by further 
guidance/review of instructions or troubleshooting with the pen during the visit (on site visit or 
phone visit), must be reported to the sponsor by  means of a product technical complaint (PTC) 
form. (This procedure is described in a separate manual.) The pen associated with the event 
should be retrieved and sent together with the form to the manufacturing site for technical 
investigation. 
Injection pens should never be shared with others. 
8.1.2.1.1 Injection pen for HOE901-U300 
Patients randomized to HOE901-U300 will be supplied with the appropriate number of disposable 
pens for insulin glargine 300 U/mL and needles according to the dose range. 
Each pen contains a cartridge with a total 450 units of insulin glargine. Doses can be set in steps 
of 1 unit. If a dose of HOE901-U300 greater than 80 units is required, it will be given as two or 
more consecutive SC (subcutaneous) injections at the same time with the daily dose split in equal 
or close to equal doses. Splitting the doses into a morning and evening injection is not allowed. 
8.1.2.1.2 Injection pen for Lantus 
Patients randomized to Lantus will be supplied with the appropriate number of disposable pens for 
insulin glargine 100 U/mL and needles according to the dose range. 
Each pen contains a cartridge with a total 300 units of insulin glargine. Doses can be set in steps 
of 1 unit. If a dose of Lantus greater than 80 units is required, it will be given as two or more 
consecutive SC injections at the same time with the daily dose split in equal or close to equal 
doses. Splitting the doses into a morning and evening injection is not allowed. 
8.1.3 Dosage schedule 
The study medication, HOE901-U300 or Lantus, will be injected by deep subcutaneous injection 
(either self-administered or injected by the parent) in any of the following areas: buttocks, thighs, 
abdomen, or upper arms. Changes to another area of injection will be done periodically and will 
be consistent with the habits of the individual patient. Injection sites (ie, the very place of 
injection within the area of injection) will be rotated within that area from injection to injection 
(what may include rotating the sides [left, right] of the body) to reduce the risk of injection site 
reactions. The injection areas for IMP and non-investigational medicinal product (NIMP) should 
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be different so that any injection site reactions can be attributed specifically either to IMP 
(HOE901-U300 or Lantus) or NIMP (fast-acting insulin analogue). Injection site reactions 
associated with administration of the IMP or NIMP, if any, will be reported as Adverse Events 
(see Section 10.4.1 and Section 10.6.3) and information on localization and insulin (IMP or 
NIMP) is required. 
The IMP will be administered once daily either in the morning or in the evening. It is expected 
that patients taking their pre-study basal insulin once daily in the morning will continue with the 
morning regimen of the IMP during the study as well as patients taking their pre-study basal 
insulin once daily in the evening will continue with the evening regimen. At Visit 3 (baseline) 
patients receiving more than 1 daily injection of basal insulin will change to once daily injection 
either in the morning or in the evening, at the discretion of the patient/parent/investigator. Once 
fixed at randomization, the time of day of injection with the IMP (ie, either in the morning or in 
the evening) will remain the same throughout the whole study treatment duration. Efforts will be 
made to maintain the same dosing time (hh:mm) during the whole treatment period so that the 
interval between once daily injections of the IMP will be kept at or close to 24 hours. Patients will 
continue with their mealtime fast-acting insulin analogue which is not to be changed during the 
study (see Section 8.2).  
8.1.4 Starting dose 
The median (ie, the middle value out of the three values) of the total daily basal insulin doses in 
the last 3 days prior to the baseline visit will be used for the calculation of the starting dose. With 
the exception of those on more than once daily basal insulin products (eg, NPH insulin, insulin 
detemir), patients will switch 1:1 (Unit for Unit) from their daily basal insulin dose to HOE901-
U300 or Lantus.  In patients who switch from more than once daily basal insulin products, the 
starting dose of HOE901-U300 or Lantus (U) should be reduced by approximately 20%.  If 
deemed necessary by the investigator the first dose of the IMP may be administered at a reduced 
dose. See also Section 10.1.2.1 
8.1.5 Dose adjustment 
Doses of HOE901-U300 and Lantus will be titrated to achieve glycemic targets of fasting SMPG 
without hypoglycemia. 
The same dosing schedule will be applied for Lantus and HOE901-U300. Changes in the Lantus 
or HOE901-U300 dose are based on fasting SMPG measurements using the glucometer provided 
for this study according to the following schedule (Table 1). Other pre-prandial (pre-lunch, pre-
dinner) SMPG measurements will be taken into account, too. 
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The recommended target range for fasting, pre-prandial plasma glucose is 90 to 130 mg/dL (5.0 to 
7.2 mmol/L). 
Table 1 - IMP dose titration schedule 
Median* fasting (pre-breakfast) SMPG 
Current basal insulin 
dose 
Dose adjustment of 
HOE901-U300 or Lantus 
Above target range: 
• >180 mg/dL (10.0 mmol/L)  
and no evidence of severe hypoglycemia 
<15 U/day 
≥15 U/day 
+ 2 U 
+ 4 U 
Above target range: 
• >130 to 180 mg/dL 
(7.2 mmol/L to 10.0 mmol/L)  
and no evidence of severe hypoglycemia 
<15 U/day 
≥15 U/day 
+ 1 U 
+ 2 U 
In target range: 
• 90 to 130 mg/dL  (5.0 to 7.2 mmol/L) 
and no evidence of severe hypoglycemia 
 
No change of basal insulin dose 
Below target range: 
• <90 mg/dL (5.0 mmol/L) 
<15 U/day 
≥15 U/day 
- 1 U 
- 2 U 
In case of hypoglycemia: 
In case relevant hypoglycemia is reported (without 
adequate explanation, eg unexpected exercise) 
 
In case of severe hypoglycemia (neurological 
symptoms, 3rd party assistance required) 
 
 
<15 U/day 
≥15 U/day 
Doses may be reduced at any time 
- 1 U 
- 2 U 
 
In addition to dose reduction, upward 
titration may be stopped for 1 week. 
* Median = the middle value of fasting (pre-breakfast) SMPG out of the three values from last 3 days including the current day 
Good clinical judgment is to be exercised while titrating the basal insulin dose. Adjustment of the 
basal insulin dose should be done once per week. 
When implementing the insulin titration dose, a dose increase may be split into 2 incremental dose 
steps every 3-4 days, rather than implementing the entire dose increase at one time, if it was 
concluded by the investigator or medically qualified designee to be in the best interest of the 
patient to do so. Dose titration should be done no more frequently than every 3-4 days. 
The dose of Lantus or HOE901-U300 will be increased until the patient reaches the target fasting 
SMPG. Best efforts should be made to complete up-titration of either basal insulin by 6 to 
12 weeks. Thereafter, until the end of the study, the dose will be adjusted as necessary to maintain 
the glycemic control. 
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It is recommended to attain and maintain bedtime and nocturnal plasma glucose in the target 
range of 90 to 150 mg/dL (5.0 to 8.3 mmol/L), avoiding hypoglycemia. 
If needed, additional unscheduled contacts (phone, on-site visit) should be made available for 
patients/parents to discuss dose adjustments in-between the scheduled visits already outlined in 
the protocol. 
Additionally, adherence to the titration rules will be monitored by the sponsor. Non-compliance to 
the titration schedule will be raised to the attention of the investigator for explanation or 
correction. If applicable, reasons justifying deviations from the protocol-defined schedule 
(eg, temporarily increased glycemic target due to hypoglycemia unawareness) have to be 
documented in the patient’s file. 
Fasting SMPG will be measured by the patient/parent before breakfast or any administration of 
insulin. 
Patients who experienced a non-severe hypoglycemia as a result of inadequate calculation of dose 
of mealtime insulin analogue against the carbohydrate content of a meal or due to a missed meal, 
unusual exercise or alcohol use will not have their insulin glargine (IMP) dose decreased and 
whenever appropriate will be counseled on the correction of those behaviors. 
It may be prudent to temporarily increase glycemic targets for a patient if, for example, 
hypoglycemia unawareness or frequent episodes of hypoglycemia occur. In such situation new 
targets and the rationale behind should be documented in the patient file. 
Sound clinical judgment is to be exercised while titrating doses of the IMP. Investigators may 
adjust or stop titration, or temporarily reduce dose if they believe further titration would be 
hazardous at that time; however, the rationale of deviating from the adjustment schedule should 
be documented in the patient file. 
Patients and/or parents will be familiarized with the titration schedule so that they will be able to 
monitor and comply with the titration with the assistance of the investigator or medically qualified 
designee. During contacts (phone or on-site visits) with the study site, all dose adjustments should 
be discussed between the patient (and/or parent) and appropriate site personnel and be 
documented in the source document. 
8.1.6 Switch-back to commercial basal insulin 
Upon discontinuation of the study treatment, either scheduled or premature, patients must resume 
treatment with commercially available basal insulin. It is suggested that patients receiving Lantus 
will transition to commercial 100 U/mL formulation of basal insulin at 1:1 (Unit for Unit) rate 
(total daily basal insulin dose). Since with HOE901-U300 a slightly higher dose is needed to 
achieve comparable levels of glycemia, the total daily dose of replacement 100 U/mL insulin 
formulation should be reduced by 20% versus the last HOE901-U300 dose in order to reduce the 
risk of hypoglycemia in the initial period post transition. Further adjustments should be guided by 
SMPG and close glucose monitoring should be ensured during the initial weeks after the 
transition. 
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8.2 
NON-INVESTIGATIONAL MEDICINAL PRODUCT 
Mandatory additional insulin therapy is a fast-acting mealtime insulin analogue (glulisine, aspart 
or lispro) which is considered a Non-Investigational Medicinal Product (NIMP). Regular human 
insulin must not be used during the study. 
8.2.1 Dosage schedule 
Patients in both treatment groups will continue with their fast-acting mealtime insulin analogue 
during the study. The cost of the mealtime insulin analogue may be reimbursed if not covered by 
health insurance and if allowed by local regulations. 
The area of injection for the fast-acting mealtime insulin analogue should be different from that of 
IMP (insulin glargine) so that any injection site reaction can be attributed specifically either to the 
fast-acting mealtime insulin or to IMP. As with IMP, site of mealtime insulin injections will be 
rotated within the injection area and areas will be changed periodically. Injection site reactions 
associated with administration of the IMP or NIMP, if any, will be reported as Adverse Events 
(see Section 10.4.1 and Section 10.6.3) and information on localization and insulin (IMP or 
NIMP) is required. 
8.2.2 Starting dose 
At baseline, when changing over from the pre-study basal insulin to the study basal insulin, doses 
of the fast-acting mealtime insulin analogue may remain the same.  
8.2.3 Dose adjustment 
Titration of mealtime insulin will occur at the investigator’s discretion informed by instructions in 
the national product label and under consideration of the following general guidance, while 
avoiding hypoglycemia: 
• While basal insulin doses are increased, fast-acting insulin doses may be reduced to avoid 
hypoglycemia particularly during daytime. The need for corrective doses may also be 
reduced. 
• The dose of the mealtime insulin analogue (glulisine, lispro or aspart) is to be titrated 
based on SMPG data, including 2-hour postprandial plasma glucose results and the size or 
carbohydrate content of the meal. A scheme consistent with local guidelines and practices 
may be applied, eg, carbohydrate counting and a correction/supplemental scale for glucose 
out of goal range based on pre-meal SMPG. The scheme will be documented in the 
patient’s file. 
• The titration goal is a 2-hour postprandial SMPG of <180 mg/dL (10.0 mmol/L) while 
avoiding hypoglycemia. For the purpose of this protocol, 2 hours postprandial is defined 
as 2 hours after the start of the meal. If clinically indicated and if in line with local 
treatment guidelines, other individual goal for postprandial SMPG may be determined for 
a given patient; such individual goal needs to be documented in the patient’s file.  
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The injection of the fast-acting mealtime insulin analogue in relation to meals will be done 
according to the individual habits of the patient, preferably prior to meal or snack. Occasional 
postprandial injection soon after meal intake may be done if deemed necessary and if allowed by 
the national product label. 
Dietary modifications (eg, snacks) will be made by the investigator, dietician or other medically 
qualified person based on his/her best judgment. 
After the end of the study treatment, doses of mealtime insulin may remain similar, however, if 
the study drug is replaced by NPH insulin, the potential for additive effects (eg, between morning 
NPH and lunchtime mealtime insulin) due to the peaked kinetics of the NPH, need to be taken 
into account. 
8.3 
TITRATION OVERVIEW AND EVALUATION OF PATIENTS NOT MEETING GLYCEMIC 
GOALS 
The progress of titration will be regularly assessed by the sponsor personnel supported by a 
dedicated web-based tool, taking into account SMPG, insulin doses and hypoglycemia events 
which have been documented in the diary by the patients. Observed deviations from the titration 
schedule or unexpected trends will be communicated to the investigator. In addition, a central 
laboratory alert is set up to inform about inadequate glycemic control in terms of HbA1c 
exceeding the predefined level. The threshold value of HbA1c is defined as 8.5% from Visit 11 
(Week 12) onwards. 
In case of HbA1c above the target values and/or SMPG are not improving as expected in spite of 
successive IMP dose titration, the investigator should ensure that no reasonable explanation exists 
for insufficient glucose control and in particular that: 
• Pre-breakfast SMPG was actually measured in fasting condition (ie, after at least 8 hours 
fasting) 
• SMPG are correctly categorized in the diary 
• Compliance to treatment is appropriate: 
- 
IMP dose is adjusted according to the dosing schedule  
- 
NIMP dose is properly adjusted, including correction doses for pre-prandial glucose 
values above goal 
• There is no inter-current disease which may jeopardize glycemic control (eg, infectious 
disease) 
• Compliance to diet and lifestyle is appropriate, in particular, dosage adjustment for 
changes in carbohydrate content of the meal and SMPG 
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• 
If any of the above can reasonably explain the insufficient glycemic control, the 
investigator should undertake appropriate action, ie,: 
- 
Titrate the dose of IMP and/or NIMP 
- 
Set up adequate investigation and treatment of inter-current disease (to be reported 
in adverse event (AE)/serious adverse event (SAE)/concomitant medication parts of 
the e-CRF, 
- 
Stress the absolute need to be compliant to treatment, including the importance of 
consistency in meals and insulin dosing, particularly during this time of poor 
glycemic control, and compliance to lifestyle recommendations, 
- 
Consider additional monitoring of night time glucose, 
- 
Organize a specific interview with a specialist pediatric dietitian (or healthcare 
professional with documented experience in childhood diabetes) in particular with 
attention to awareness of the carbohydrate content of the meal and covering snacks 
with a dose of fast-acting mealtime insulin analogue, 
- 
Schedule HbA1c assessment at the next visit. 
8.4 
BLINDING PROCEDURES 
Administration of all forms of insulin during the trial is to be open-label, and no attempt will be 
made to blind administration to investigators, patients and sponsor’s and/or Clinical Research 
Organization local monitoring teams and auditors. 
Despite the open-label administration of study insulin, assessment of outcomes, where possible, 
will be based on objectively collected data, which are assessments for HbA1c (primary endpoint) 
and FPG by a central laboratory blinded to study treatment groups.  
The global sponsor study team will remain blinded with regards to the treatment arm of individual 
patients throughout the study (eg, patient’s or cumulative tables or listings [such as AE or SAE 
listings] rendered accessible to facilitate data review will not bear study treatment identification). 
The members of the blinded endpoint assessment committee will review data in a blinded manner. 
Personnel involved in medical review of individual patients’ data will have access to the treatment 
arm of patients whose events warranted CIOMS generation since CIOMS reports will include 
study treatment identification. 
8.5 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
Patients are randomized to receive during the 6-month treatment period and also during the  
6-month extension period either HOE901-U300 or Lantus once daily in an open-label manner. 
The randomization ratio is 1:1. The randomization is stratified by HbA1c at screening 
(<8.5 versus ≥8.5%) and by age group at screening (<12 years versus ≥12 years).  
Inclusion in the study is configured to ensure at least 30% of participants in the age range below 
12 years. The randomized treatment kit number list is generated centrally by Sanofi. The IMPs are 
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packaged in accordance with this list. The Trial Supply Operations Manager provides the 
treatment kit number list, and the Study Biostatistician provides the randomization scheme 
(including stratification) 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 groups to the patients. 
The IMPs (HOE901-U300 or Lantus) are provided in open-label boxes and are identified with 
treatment kit numbers. 
At the screening visit the investigator or designee has to contact the IVRS/IWRS center to receive 
the patient number. The patient identification (patient number) is composed of 12-digit number 
containing the 3-digit country code, the 4-digit center code and the 5-digit patient chronological 
number. If a patient who had previously failed screening is approached for re-screening, a new 
informed consent form must be signed by the parent (and assent obtained from the patient).  In 
such case, a new patient number will be assigned by IWRS/IVRS. 
On Visit 3 (Day 1), the IVRS/IWRS is contacted for randomization and for the first treatment 
kit(s) allocation. For each randomized patient, the IVRS/IWRS will allocate a treatment kit using 
their treatment kit number and a quantity of kit(s) to be dispensed corresponding to the same 
treatment group as assigned at randomization. After Visit 3 (Day 1) the IVRS/IWRS is contacted 
again each time a new treatment kit(s) allocation is necessary that is at Visit 11 (Week 12), at 
Visit 13 (Week 20), at Visit 14 (Week 26) and at Visit 16 (Week 38). IVRS/IWRS will be again 
contacted at Visit 18 (Week 52 or early discontinuation) for notification of the end of study 
treatment. 
A randomized patient is defined as a patient who has been allocated to a randomized treatment by 
the IVRS/IWRS regardless whether the treatment kit was used or not. A patient cannot be 
randomized more than once in the study. A patient who needs to be moved to another site will 
have his/her randomization number assigned at the new site. 
8.6 
PACKAGING AND LABELING 
The respective number of the study treatment will be packaged under the responsibility of Sanofi 
according to good manufacturing practice and local regulatory requirement. Lantus will be 
supplied in boxes of 2 disposable pens for insulin glargine 100 U/mL and HOE901-U300 will be 
supplied in boxes of 2 disposable pens for insulin glargine 300 U/mL. 
The appropriate number of kits will be dispensed to cover up to the next dispensing visit. Storage 
conditions and use-by-end date are part of the label text. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. Treatment labels will 
indicate the treatment number used for treatment allocation. The patient number, visit number and 
box number will be entered manually by the site staff on the treatment box label prior to 
dispensing. 
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8.7 
STORAGE CONDITIONS AND SHELF LIFE 
Investigators or other authorized persons (eg, pharmacists) are responsible for storing IMP in a 
secure and safe place in accordance with local regulations, labeling, specifications, policies and 
procedures. 
Control of IMP storage conditions, especially control of temperature (eg, refrigerated storage) and 
information on in-use stability and instructions for handling the Sanofi compound should be 
managed according to the rules provided by the Sponsor and are provided to study participants in 
the instruction for use leaflet together with the IMP injection pens. 
The expiry date is mentioned on the IMPs labels, and storage conditions are written on the IMPs 
labels and in the instruction leaflet. 
8.8 
RESPONSIBILITIES 
The investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All 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. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.8.1 Treatment accountability and compliance 
Returned and dispensed IMP will be documented into the Treatment Log Form. Investigator or 
delegate has to visually check the filling status of the cartridges in the pens in the returned packs 
and compare to dosing records documented in the patients’ diaries. Discrepancies have to be 
addressed to the patient for clarification of real treatment administration. The investigator or 
designee completes the appropriate treatment log form based on the unused, used and in-use IMP 
(study drug pens) returned. 
The monitor will check the e-CRF data by comparing them with patient’s diary entries, treatment 
log forms and unused treatment kits. 
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For the mandatory background fast-acting insulin analogue (NIMP) provided by the sponsor, a 
treatment log form will be completed and reconciliation will be performed.  
For NIMP not provided by the sponsor, the following information will be captured in standard site 
documents and records: Study identification, patient identification (number or name/ initials), 
NIMP trade name, batch, start date, end date. 
8.8.2 Return and/or destruction of treatments 
Patients have to return all the used, in-use and unused IMP at each on-site visit including final 
assessment on-treatment visit (Visit 18 - either scheduled at Week 52 or in case of permanent 
premature discontinuation) (see Section 1.2). 
All partially used and 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. 
8.9 
CONCOMITANT MEDICATION 
A concomitant medication is any treatment, including vaccines, received by the patient 
concomitantly to the IMP. 
Treatments in addition to the study treatment and NIMP 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 treatments, 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. 
8.9.1 Concomitant Diabetes Therapy 
See Section 8.2.  
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8.9.2 Prohibited concomitant therapy 
The following drugs are not permitted during the study until the End of treatment visit (Visit 18 – 
Week 52 or early treatment discontinuation): 
• Antihyperglycemic treatments other than the mandatory fast-acting mealtime insulin 
analogue (See Section 8.2), except the short-term use (ie, maximum 10 days) eg, during 
hospitalization, etc. 
• Any basal insulin other than the IMPs, following randomization, except the short-term use 
(ie, maximum 10 days) eg, during hospitalization, etc.  
• Insulin pump therapy 
• Systemic glucocorticoid use for more than 10 days. Topical, inhaled or local 
(ie, formulations without major systemic effect lasting for more than 10 days) applications 
are allowed, regardless of duration of use. 
• Weight loss drugs 
• Any investigational study drug other than the IMP for this study 
The need for use of prohibited therapy will result in the patient’s withdrawal from the study 
treatment. 
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 
All biological efficacy and safety analysis will be performed by a Central Laboratory. Detailed 
information on sample drawing, management and analysis will be provided in a specific manual. 
9.1 
EFFICACY 
The baseline value for efficacy variables will be the last available value obtained up to the date of 
randomization. 
Observation periods for efficacy variables 
• The main 6-month on-treatment period for efficacy variables is defined as the time from 
the first dose of IMP up to month 6 (visit 14) or, in case of premature treatment 
discontinuation, up to:  
- 
7 days after the last dose of IMP for HbA1c,  
- 
2 days after the last dose of IMP for hypoglycemia, 
- 
1 day after the last dose of IMP for FPG and SMPG value. 
• The main 6-month randomized period for efficacy variables is defined from randomization 
date up to month 6 (Visit 14), regardless of study treatment discontinuation. 
• The 12-month on-treatment period for efficacy variables is defined as the time from the 
first dose of IMP up to: 
- 
7 days after the last dose of IMP for HbA1c,  
- 
2 days after the last dose of IMP for hypoglycemia, 
- 
1 day after the last dose of IMP for FPG and SMPG value. 
9.1.1 Primary endpoint 
HbA1c (change from baseline to endpoint [Month 6/Week 26]). 
9.1.1.1 HbA1c measurement 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified level I 
National Glycohemoglobin Standardization Program (NGSP) at central laboratory. 
HbA1c is assayed at screening (Visit 1, Week-2); at baseline (Visit 3; Day 1); at Visit 11 
(Week 12); at Visit 14 (Week 26 primary endpoint assessment visit); at Visit 16 (Week 38) and at 
End of treatment Visit 18 (Week 52 and, if applicable, early treatment discontinuation). 
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9.1.2 Secondary endpoints 
• Percentage of patients with HbA1c values of <7.5%  at month 6 overall and without any 
episode of severe and/or documented (SMPG <54 mg/dL; 3.0 mmol/L) symptomatic 
hypoglycemia during the last 3 months of the main 6-month randomized period (from 
randomization date up to month 6 (Visit 14), regardless of study treatment 
discontinuation);  
• Change in FPG from baseline to month 6 (central laboratory); 
• Percentage of patients with fasting plasma glucose (FPG) ≤130 mg/dL (7.2 mmol/L) 
at month 6 overall and without any episode of severe and/or documented  
(SMPG <54 mg/dL; 3.0 mmol/L) symptomatic hypoglycemia during the last 3 months of 
the main 6-month randomized period; 
• Change in 24-hour mean plasma glucose based on 8-point SMPG profiles from baseline to 
month 6; 
• Change in variability of 24-hour mean plasma glucose based on 8-point SMPG profiles 
from baseline to month 6; 
• Change in 8-point self-monitored plasma glucose (SMPG) profiles per time-point from 
baseline to month 6 (pre-prandial and 2-hour postprandial plasma glucose at breakfast, 
lunch and dinner, bedtime plasma glucose, nocturnal plasma glucose);  
9.1.2.1 Fasting Plasma Glucose 
Fasting plasma glucose is measured at a central laboratory.  
Blood samples for FPG measurement are taken at baseline (Visit 3; Day 1), at Visit 14 (Week 26), 
and at End of treatment Visit 18 (Week 52 and, if applicable, early treatment discontinuation). 
9.1.2.2 Self-measured plasma glucose (SMPG) 
Glucose meter, patient diary and training  
All the patients/parents are supplied with a glucose meter, the corresponding supplies (lancets, test 
strips, control solution, etc.) and with diaries at Visit 1 (Week -2) in order to perform self-
measurement of plasma glucose, reporting hypoglycemic symptoms and record IMP/NIMP doses. 
It is recommended to perform tests with the control solution before first use of the study glucose 
meter, in cases when SMPG reading is considered incorrect or inconsistent with symptoms and 
whenever a new batch of test strips is used. If SMPG ≥252 mg/dL (14 mmol/L) is measured, 
measurement of blood ketones may be needed, please see detailed instructions in Section 10.6.2. 
During the study, all SMPG have to be done using the sponsor-provided glucose meter. The 
readings are to be transferred to the diary. 
Patients/parents will be instructed on the proper use of the glucose meter and the diary including 
education around hypoglycemia symptoms (see Section 9.2.1) and management  
(see Section 10.6.1) at screening (Visit 1, Week-2); at baseline (Visit 3; Day 1) and the training 
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will be repeated as often as necessary at the study visits. The diary, blood glucose meter and blood 
ketone meter need to be brought to the study site at each on-site visit. 
SMPG measurements include the following: 
Fasting SMPG 
The fasting (pre-breakfast) SMPG will be measured on at least 5 days in the week before each 
visit. It is recommended to perform fasting SMPG daily throughout the study. When up-titration 
has been completed and fasting (pre-breakfast) SMPG is stable in the target range, the number of 
fasting SMPG checks can be reduced according to the investigator’s judgment, however at least 
3 fasting (pre-breakfast) SMPG measurements per week should be performed.  
During the screening period compliance to the fasting SMPG measurement schedule will be used 
to assess eligibility for entry in the randomized treatment period.   
8-point SMPG Profiles 
Eight-point blood glucose profiles should be measured at the following 8 time-points: between 
01:00 and 04:00 AM at night; before and 2 hours after breakfast; before and 2 hours after lunch; 
before and 2 hours after dinner; at bedtime). Two hours post meal is defined as 2 hours after the 
start of the meal. 
Patients are required to have 8-point SMPG profiles performed on at least one day in the week 
before the baseline visit, and the visits week 26 and week 52 (end of treatment). Special attention 
should be paid that the nighttime SMPG value (between 01:00 and 04:00 AM) is recorded. 
On days when 8-point profiles are done, fasting SMPG will be considered as the second point of 
measurement, ie, “before breakfast” time point after the first point measurement at 01:00 – 04:00 
AM at night.  
SMPG during episodes of symptomatic hypoglycemia 
Whenever the patient feels hypoglycemic symptoms, plasma glucose should be measured by the 
patient/parent (or others, if applicable), if possible. Patients/parents should be instructed to 
measure plasma glucose levels prior to the administration of glucose or carbohydrate intake 
whenever symptomatic hypoglycemia is suspected (see Section 10.6.1), unless safety 
considerations necessitate immediate glucose/carbohydrate rescue prior to confirmation.  
Complementary SMPG 
Patients are encouraged to continue with their usual pattern of SMPG measurements on top of 
protocol-mandated profiles. It is recommended to perform 4-6 SMPG daily at different times of 
the day and measure the nighttime SMPG once weekly for optimal control of glycemia and 
adjustment of the insulin regimen. Additional SMPG are recommended in association with 
exercise (before start of exercise, when need arises during exercise, after exercise and at bedtime) 
and, if deemed appropriate by the investigator, at sick days or menses (1, 7).  
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9.1.2.3 Dose of basal and mealtime insulin 
Patients will record their basal insulin and mealtime insulin dosing data (time and dose), including 
corrective doses, in the diary daily during the screening period and during the treatment period up 
to Visit 11 (Week 12); at least over one week before each visit during the remainder of the 
treatment period until the End of Treatment visit (Visit 18 - Week 52 or early treatment 
discontinuation); over the first week of the post-treatment follow up period and on at least 2 
consecutive days per week during the remainder of the follow up period.  
9.2 
SAFETY ENDPOINTS  
The safety endpoints to be assessed are: 
 
• Hypoglycemia (see Section 9.2.1), 
• Hyperglycemia with ketosis (see Section 9.2.2) 
• AEs (including injection site reactions and hypersensitivity reactions), SAEs and Adverse 
event of special interest (AESI) (see Section 10.4.1), 
• Safety laboratory values (see Section 9.2.4), 
• Anti-insulin Antibodies (AIA) (see Section 9.2.8), 
• Physical examination (see Section 9.2.5),  
• Vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP] and heart rate 
[HR]) (see Section 9.2.7), 
• Body weight (see Section 9.2.6). 
The baseline value for safety endpoints will be the last available value prior to the first dose of 
IMP. 
Observation period of safety endpoints 
The observation period of safety data will be divided as follows: 
• The pre-treatment period is defined as the time between the date of the informed consent 
and the first injection of open-label IMP, 
• The main 6-month TEAE period is defined as the time from the first injection of open-
label IMP up to Month 6/ Week 26 (visit 14) or up to 2 days after the last injection of IMP, 
whichever comes earlier, 
• The 12-month TEAE period is defined as the time from the first injection of open-label 
IMP up to 2 days after the last injection of IMP, 
• The post-treatment period is defined as the time starting 3 days after last injection of open-
label IMP (after the TEAE period). 
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9.2.1 Hypoglycemia 
Hypoglycemia events will be categorized as follows using the criteria published by the ADA (4, 5) 
and ISPAD (1): 
• Severe hypoglycemia 
Severe hypoglycemia is defined as the child/adolescent having altered mental status and 
cannot assist in their care, is semiconscious or unconscious, or in coma ± convulsions and 
may require parenteral therapy (glucagon or glucose) (8). 
Note that “cannot assist in their care” means that the severity of symptoms prevents self-
treatment by a child/adolescent who is otherwise capable of managing his or her episodes 
of hypoglycemia. Assisting a patient out of kindness, when assistance is not required, 
should not be considered a “severe hypoglycemia” incident. 
Plasma glucose concentrations may not be available during an event, but neurological 
recovery following the return of plasma glucose to normal is considered sufficient 
evidence that the event was induced by a low plasma glucose concentration. 
Any hypoglycemic event which leads to unconsciousness, coma, or seizure must be 
reported as an SAE.  In addition, any hypoglycemic event, which at investigator discretion, 
qualifies as serious adverse event must also be reported as an SAE. 
• 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 could be: 
cold sweatiness, pallor, pounding heart, tremor/trembling, headache, nausea, difficulty 
concentrating, blurred or altered vision, slurred speech, difficulty hearing, unsteady gait, 
altered judgment and confusion, irritability, erratic behavior, nightmares, inconsolable 
crying, seizures, unconsciousness, coma. 
• 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 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. 
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• Pseudo-hypoglycemia 
Pseudo-hypoglycemia is an event during which the child/adolescent with diabetes reports 
any of the typical symptoms of hypoglycemia, but with a measured plasma glucose 
concentration greater than 70 mg/dL (3.9 mmol/L); symptoms are relieved with a 
countermeasure. 
In addition the composite category of severe and/or documented (SMPG <54 mg/dL; 
3.0 mmol/L and ≤70 mg/dL; 3.9 mmol/L) symptomatic hypoglycemia will be presented. 
All documented hypoglycemia categories will be also evaluated for the more stringent 
SMPG threshold of <54 mg/dL (3.0 mmol/L). Details of all hypoglycemia events will be 
reported on dedicated e-CRF pages. 
Instructions on hypoglycemia collecting and reporting are described in Section 10.6.1. 
All hypoglycemia events reported by investigator as severe and/or reported as serious 
adverse events will be independently reviewed by an external expert pediatrician 
specialized in diabetology blinded to treatment arm (see Section 9.2.9). 
9.2.2 Hyperglycemia with ketosis 
If SMPG is ≥252 mg/dL (≥14 mmol/L) in an unwell child (eg, feeling sick or nauseated) or when 
persistent blood glucose values ≥252 mg/dL (14 mmol/L) without substantial decline are present 
over a period of approximately 60-120 min after an extra dose of rapid-acting insulin analogue, or 
when a patient is ill with fever and/or vomiting, capillary blood ketones will be measured using a 
meter provided by the sponsor. Hyperglycemia with ketosis is defined as self-measured plasma 
glucose ≥252 mg/dL (14 mmol/L) with accompanying self-measured blood ketones ≥1.5 mmol/L. 
Instructions on collecting and reporting events of hyperglycemia with ketosis are described in 
Section 10.6.2. 
9.2.3 Adverse events 
Adverse events, serious adverse events and adverse events of special interest will be collected 
from the time of informed consent signature and then at each visit until the end of the study. 
Refer to Section 10.4, Section 10.5 and Section 10.6 for details. 
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9.2.4 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including hematology, clinical chemistry) 
and urinalysis. Samples will be collected for central laboratory in accordance with the study 
schedule and values will be analyzed after conversion into standard international units.  
The following laboratory safety variables will be analyzed: 
• Hematology: erythrocytes, hemoglobin, hematocrit, leukocytes, differential blood count 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils) and platelets at screening 
(Visit 1, Week -2); Visit 14 (Week 26) and End of treatment Visit 18 (Week 52 and, if 
applicable, early treatment discontinuation); 
• Clinical chemistry: total bilirubin (in case of values above the normal range, 
differentiation in conjugated and non-conjugated bilirubin), AST (Aspartate 
aminotransferase), ALT (Alanine aminotransferase), ALP (Alkaline phosphatase ), 
creatinine, estimated glomerular filtration rate (eGFR) (Schwartz equation) (9), sodium, 
potassium, calcium, chloride at screening (Visit 1, Week -2); Visit 14 (Week 26) and End 
of treatment Visit 18 (Week 52 and, if applicable, early treatment discontinuation); 
• C-peptide (Visit 3, Day 1); 
• Urine (for analysis including pH, glucose, ketones, leucocytes, blood/hemoglobin, protein) 
will be collected at screening (Visit 1, Week -2) and End of treatment Visit 18 (Week 52 
and, if applicable, early treatment discontinuation); 
• Urine albumin/creatinine ratio assessment and microalbuminuria (to be done on first 
morning urine sample) will be performed at baseline (Visit 3, Day 1); 
• Serum pregnancy test (at screening [Visit 1, Week -2]) and urine pregnancy test (at study 
site; each onsite visit thereafter) in post-menarchal girls; 
• In addition, hepatitis B surface antigen (HBsAg) and Hepatitis C viral antibodies (HCAb) 
(and reflex test for Hepatitis C virus RNA in case of positive HCAb) laboratory data will 
also be collected only at screening visit (Visit 1, Week -2) for identifying patients with 
exclusion criteria or safety consideration. 
Note: Any abnormal laboratory value estimated as clinically significant by the investigator should 
be immediately rechecked (whenever possible using the central laboratory) for confirmation 
before making a decision of permanent discontinuation of IMP for the concerned patient. Any 
confirmed laboratory abnormality estimated as clinically significant by the investigator must be 
reported as an AE/SAE as applicable. Please also refer to Section 10.4.1. 
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9.2.5 Physical examination and Tanner puberty stage 
Physical examination is performed at screening (Visit 1, Week -2); at baseline (Visit 3, Day 1), at 
Visit 14 (Week 26) and at End of treatment Visit 18 (Week 52 and, if applicable, early treatment 
discontinuation). The date of menarche will be captured if applicable.  
Tanner puberty stage is assessed at baseline (Visit 3, Day 1), Visit 14 (Week 26) and Visit 18 
(Week 52 [and at early treatment discontinuation visit if the previous assessment did not occur 
within the previous 3 months]) (see Section 1.2). Once the adult stage is determined, defined by 
Tanner stage 5 (see Appendix A), no further assessments will be performed. 
9.2.6 Body Weight and Height 
The same scale should be used throughout the study, and calibrated on a regular basis as 
recommended by the manufacturer. 
Body weight should be obtained with the patient wearing undergarments or very light clothing 
and no shoes, and with an empty bladder. The floor surface on which the scale rests must be hard 
and should not be carpeted or covered with other soft material. The weight is read and recorded in 
the e-CRF and Source Data. Self-reported weights are not acceptable; patients/parents must not 
read the scales themselves. 
Body weight is measured at screening (Visit 1, Week -2), baseline (Visit 3, Day 1), Visit 11 
(Week 12), Visit 14 (Week 26), Visit 16 (Week 38) and End of treatment Visit 18 (Week 52 and, 
if applicable, early treatment discontinuation). Height is measured at screening (Visit 1, Week -2), 
at Visit 11 (Week 12), Visit 14 (Week 26), Visit 16 (Week 38) and End of treatment Visit 18 
(Week 52 and, if applicable, early treatment discontinuation). Body mass index (BMI) will be 
determined based on body weight and height. 
9.2.7 Vital signs 
Vital signs include: systolic and diastolic blood pressure (mmHg) and heart rate (beats per minute: 
bpm). They are assessed at screening (Visit 1, Week- 2) and at each on-site visit thereafter 
(see Section 1.2). Blood pressure (mmHg) should be measured on right arm when the patient has 
been sitting quietly for 5 minutes, and is seated with his or her back supported, feet on the floor 
and right arm supported, cubital fossa at heart level. Measurement should be taken under 
standardized conditions, approximately at the same time of the day, with the same device 
(regularly recalibrated according to manufacturers´ instructions) using the cuff appropriate to the 
size of the patient’s upper right arm and the values are to be recorded in the e-CRF. Both systolic 
blood pressure (SBP) and diastolic blood pressure (DBP) should be recorded. The preferred 
method of blood pressure measurement is auscultation. 
Heart rate (bpm) will be measured at the time of the measurement of blood pressure and also is to 
be reported in the e-CRF.   
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9.2.8 Immunogenicity 
Anti-insulin antibodies (AIA) will be determined at a centralized laboratory using a validated anti-
insulin antibody immunogenicity assay.  
Blood samples for immunogenicity tests will be collected prior the first administration of 
HOE901-U300 or Lantus (during the baseline visit [Visit 3]) and at Visit 11 (Week 12), Visit 14 
(Week 26) and End of treatment Visit 18 (Week 52 and, if applicable, early treatment 
discontinuation). The samples should be taken prior to administration of the basal insulin 
(applicable to patients who have their basal insulin injection in the morning) and at least four 
hours after last dosing of the fast-acting mealtime insulin analogue (insulin glulisin, insulin lispro, 
insulin aspart). 
Detailed procedure of sample preparation, storage and shipment will be described in the specific 
laboratory manual. Two (2.0) ml blood volume is to be collected for each anti-insulin antibody 
sample. 
The AIA endpoints will be detailed in the Statistical Analysis Plan. 
9.2.9 Blinded external endpoint assessment committee 
Ongoing safety surveillance will be performed by a blinded external endpoint assessment 
committee consisting of experts in pediatric diabetology and endocrinology:  
• The ISPAD definition of severe hypoglycemia is broad and includes a subjective element: 
‘The child has altered mental status and cannot assist in his own care’, and determining 
whether an episode fulfils the definition can be challenging, especially in young children. 
Therefore, all reported episodes of severe hypoglycemia will be reviewed in a blinded 
manner by the external safety monitoring group, in order to determine whether the 
episodes fulfilled the criteria for severe hypoglycemia. For this purpose the experts will be 
provided on a regular basis with a tabulated overview of hypoglycemia events. 
To monitor general safety of the study participants, the committee will be provided on a regular 
basis with tabulated overviews of TEAEs, serious TEAEs. 
The committee will also assess the antigenicity data (AIA data and potential clinical correlates 
[hypersensitivity events, indicators of insulin-resistance]). 
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9.3 
OTHER ENDPOINTS 
9.3.1 Pharmacokinetics sparse sampling 
The concentration of Insulin glargine and its metabolites (M1 and M2) in plasma will be 
measured using a validated LC-MS (Liquid Chromatograph Ion Spray Mass Spectroscopy) assay 
with an LLOQ (Lower Limit of Quantitation) of 0.2 ng/mL. One (1) mL of blood should be 
collected at each PK sampling time according to the below schedule. 
PK sparse sampling will be proposed to all randomized patients and will be collected over a single 
day in those participants who consent to this assessment after the end of titration phase during the 
period when only minor adjustments of the basal insulin dose are done to maintain the glycemic 
control (ie, no sooner than at Visit 13, Week 20, but no later than at Visit 14, Week 26,). All 
participants who provided an assent and whose parents signed the specific informed consent form 
(see Section 12.2), will provide 3 blood samples. Patients will be offered to stay at the study site 
throughout the day when the procedure is performed and meals will be provided to patients. The 
day of the PK sparse sampling procedure within the authorized window will be agreed between 
patient/parent and investigator. The sample times will depend on the existing basal insulin dosing 
regimen: 
• Patients with IMP dose administered in the evening (~8:00 PM) on the day before the date 
of the visit: patients can have breakfast (including mealtime insulin injection) at home and 
come to the study site in the morning to have blood samplings at around 8:00AM, 12:00 
PM, 04:00 PM (what corresponds with samplings 12 h, 16 h and 20 h after the last basal 
insulin injection). Sample times can be within ±1 h. 
• Patients with IMP dose administered in the morning (~8:00 AM) on the day of the visit: 
patients will come to the study site in the morning in fasting condition not having injected 
their basal and mealtime insulin to have blood samplings at around 8:00AM, 12:00 PM, 
04:00 PM (what corresponds with pre-dose sampling [to be done within 1 h before time of 
dosing] and 4 h and 8 h post dose sampling). Sample times can be within ±1 h. 
9.4 
APPROPRIATENESS OF MEASUREMENTS  
The primary efficacy endpoint of this study is change of HbA1c from baseline to endpoint 
(Week 26/Month 6). HbA1c reflects the average glycemia over 2-3 months and has strong 
predictive value for diabetes complications. It is accepted by regulatory agencies as an appropriate 
primary endpoint to support a claim based on glycemic control. Twenty six weeks duration of 
study treatment is considered to be sufficient for achieving steady state conditions with  
HOE901-U300 or Lantus enabling an adequate assessment of time-dependent changes in HbA1c 
and the concomitant risk of hypoglycemia. 
Analysis of responders (HbA1c) is set up to compare both formulations in terms of rate of patients 
achieving and/or maintaining optimal long-term glucose control confirmed by target HbA1c 
<7.5% at month 6 overall as well as not compromised by severe and or documented  
(SMPG <54 mg/dL; 3.0 mmol/L) symptomatic hypoglycemia during the last 3 months of the main 
6-month treatment period. 
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Fasting plasma glucose (FPG): change from baseline to Month 6/Week 26 and rate (%) of patients 
reaching target FPG at month 6 without hypoglycemia. Change in FPG is an acceptable secondary 
efficacy endpoint by regulatory agencies.    
Studies have demonstrated that frequent SMPG measurements correlate with decreased HbA1c. 
Thus it is recommended that regardless of mandatory SMPG measurements patients regularly 
perform 4-6 SMPG at different times of the day (7). 
Incidence of patients with nocturnal hypoglycemia: one of the limiting factors in achieving 
desired glycemic control in patients treated with insulins, including basal insulins, is a risk of 
hypoglycemia, especially nocturnal hypoglycemia. Even distribution of the glucose lowering 
activity over the 24 hour injection intervals following once daily administration of HOE901-U300, 
as demonstrated in phase 1 studies, is expected to reduce the rate of hypoglycemia, including 
nocturnal hypoglycemia. Lower risk of nocturnal hypoglycemia may result in better adherence to 
antidiabetic therapy and increase chances of reaching glycemia targets resulting in reduced risk / 
delayed onset of chronic complications of diabetes. Two nocturnal hypoglycemia categories will 
be taken into account for analysis: defined by the time of the day (between 00:00 and 05:59 a.m.) 
and defined by sleep status (waking up the patient after going to bed in the evening and before 
getting up in the morning). 
Safety will be evaluated by standard clinical and laboratory measurements including assessment 
of parameters of interest for a glucose lowering injectable peptide such as injection site reactions 
and hypersensitivity reactions. A special attention will be paid to the most prominent limiting 
factor in achieving optimal glycemic control, ie, hypoglycemia. Hypoglycemia (incidence and rate) 
will be assessed according to categories defined by the ADA (4) and (5). Documented 
hypoglycemia categories will be assessed using two plasma glucose thresholds: <54 mg/dL 
(3.0 mmol/L) and ≤70 mg/dL (3.9 mmol/L).  
In established T1DM the estimated incidence of DKA is 1-10% per patient per year (10); DKA is 
a special safety concern in the pediatric population. Incidences of hyperglycemia with ketosis 
(defined as self-measured plasma glucose ≥252 mg/dL [14 mmol/L] with accompanying self-
measured blood ketones ≥1.5 mmol/L), which may indicate the risk of developing DKA, will be 
assessed. 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and comprehensive list of procedures/assessments is presented in the “Study 
Flow Chart” in Section 1.2.  
This is an outpatient study and consists of 7 on-site visits and 13 phone-call visits. Phone-call 
visits can alternatively be performed as on-site visits. Additional contacts (phone, on-site visit) 
will be made available for patients’ in-between the scheduled visits as needed. Patients should be 
accompanied by parent/legal guardian2 during each scheduled visit/contact. In case a patient does 
not show up for a visit or cannot be reached for a phone visit, the investigator has to make three 
phone call attempts and send a certified letter in order to locate the patient. 
All on site visits should take place in the morning at approximately the same time. The patient has 
to be in fasting condition for the following on-site visits: Visit 3 (baseline), Visit 11 (Week 12), 
Visit 14 (Week 26) and End of treatment Visit 18 (Week 52 and, if applicable, early treatment 
discontinuation); timing of fasting on-site visits should be agreed with patients/parents to reduce 
risk of hypoglycemia and to prevent non-compliance with fasting requirements due to extension 
of fasting period if such visit is scheduled relatively late as compared to the patient’s daily routine. 
The fasting condition is defined as an overnight fast of at least 8 hours that consisted of no food or 
liquid intake, other than water. IMP and NIMP should be administered after the fasting blood 
sample is drawn for all laboratory tests at the study site at visits where such sampling is scheduled. 
Note: If the patient is not fasting at Visit 3 (baseline), a new appointment should be given to the 
patient for the following day if possible, with instruction to be fasted. If the patient is not fasting 
at the remaining visits specified above, the planned study procedures/assessments except 
collection of blood for central laboratory may be performed and a new appointment should be 
given to the patient for the following day if possible, with instruction to be fasted. 
Nutritional and lifestyle advice will be provided by a specialist pediatric dietitian (or healthcare 
professional with documented experience in childhood diabetes) as needed by the patients/parents 
and when deemed appropriate according to the investigator’s judgment.  
Visit window: Visit 3 (baseline) will take place 14 ± 3 days after Visit 1 (screening); from Visit 4 
(Week 1) to Visit 11 (Week 12; inclusive), a timeframe of ± 3 days is acceptable and from 
Visit 12 (Week 16) up to Visit 18 (Week 52), a time frame of ± 5 days is acceptable using the day 
of Visit 3 (Day 1, baseline) as reference (if one visit date is changed, the next visit should take 
place according to the original schedule). During the post-treatment follow-up period, for Visit 19 
(Follow-up 1 visit) a time frame of +2 day is acceptable and for Visit 20 (Follow-up 2 visit) a time 
                                                 
2 "Legal guardian" means an individual or judicial or other body authorised under applicable law to consent 
on behalf of a prospective patient to the patient's participation in the procedure(s) involved in the 
research. In this document “parent” will be used as a synonym for “legal guardian” 
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frame of ± 5 days is acceptable using the day of Visit 18 (scheduled at Week 52 or early treatment 
discontinuation, as applicable) as reference. 
Starting from the time when the informed consent has been obtained, AEs/SAEs will be recorded 
at each visit. Hypoglycemia will also be recorded all along the study. Appropriate e-CRF pages 
(visit-specific pages and whenever applicable also non visit-specific pages such as adverse event, 
hypoglycemia, medication pages) need to be completed during the patient’s visit or shortly 
thereafter, except SAE or AESI which have to be reported within 24 hours. E-CRF reporting 
instructions and timelines are described in a separate document. 
10.1.1 Screening period 
Patients meeting all the inclusion criteria are candidates for the screening phase. 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 1 (Week -2).  
As an exception, if any of the laboratory parameters required for assessment of eligibility are not 
available by the date of scheduled baseline (V3) visit (eg, lost specimen, non-assessable sample, 
etc.), a retest can be performed and the screening period can be extended by one additional week. 
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 
form signed and new assent obtained and allocation of a new patient number. In case of 
adolescents who will reach the legal age of maturity during the study and are subject to transition 
from pediatric to adult health care, before the patient can be screened, the investigator has to 
ensure that the patient may continue to attend planned study visits and undergo study procedures 
at the study site according to the protocol until the planned last study visit. 
10.1.1.1 Screening visit (Visit 1, Week - 2) 
The patient should come to the study site in the morning. 
The following procedures/assessments will be performed and recorded at this visit: 
• Informed consent/assent: 
- 
The patient and the parent(s) will receive verbal information concerning the aims and 
methods of the study, its constraints and risks and the study duration. Message to 
patients will be adapted to their individual level of comprehension. Written 
information will be provided to the parent(s) and, if applicable, written assent will be 
provided to the patient. Written informed consent form must be signed by the parent 
and investigator prior to any investigations. Written assent (when applicable) also must 
be signed by the patient and investigator prior to any investigations. Younger children 
for whom the written assent does not apply may only be screened if oral assent has 
been obtained in presence of an impartial witness (see Section 12.2). 
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• Assessment of Inclusion/Exclusion criteria; whenever available, laboratory reports 
confirming presence of antibodies indicative of T1DM will be documented in source 
documents; 
• IVRS/IWRS contact: 
- 
IVRS/IWRS will be contacted for notification of screening and patient number 
allocation (see 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. 
• Demography, diabetes and medical/surgical history, allergy history, alcohol and smoking 
habits:  
- 
Demography data such as birth date, gender and race will be collected.  
- 
Collection of diabetes history will include documentation of duration of diabetes, 
antibody status and C-peptide at diagnosis (provide a copy of results if available), 
basal and mealtime insulin regimen, and history of acute and microvascular 
complications. 
- 
Medical/surgical history including patient’s allergy history and patient’s family allergy 
history will be recorded. Data for alcohol habits during the last 6 months before 
screening visit and smoking habit will be collected. 
• Previous (within the previous 3 months) and concomitant medication history (other than 
insulin), including doses and regimen, 
• Physical examination; the date of menarche, if applicable, will be captured, 
• Body weight and height; see Section 9.2.6, 
• Vital signs (SBP and DBP, HR); see Section 9.2.7, 
• Central laboratory testing: blood and urine sample is collected for all scheduled central 
laboratory tests, including: 
- 
HbA1c, 
- 
Safety laboratory test for hematology, serum chemistry and urinalysis, 
- 
HbsAg and HCAb tests (including confirmatory sample for Hepatitis C RNA in case 
of positive result of the HCAb screening sample), 
- 
Serum pregnancy test in post-menarchal girls, 
• Information on acceptable measures preventing pregnancy (see Appendix B) to 
postmenarchal girls and their parents and documentation; 
• Dispensation of blood glucose meter (including related material) and instruction on the 
proper use, including recommendations concerning tests with the control solution 
(see Section 9.1.2.2), 
• Explanation of symptoms suggestive of hypoglycemia, and instruction on the management 
of episodes of hypoglycemia (see Section 10.6.1), 
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• Dispensation of a blood ketone meter (including related material) and instruction on the 
proper use (see Section 10.6.2), education around prevention of hyperglycemia, 
• Nutritional and lifestyle advice (as needed), 
• Dispensation of a patient diary. Study patients will be given detailed instruction on use of 
the diary including what information need to be reported. The diary includes sections for 
time and dose of basal and mealtime insulin injections, time, value and attribution of 
scheduled and unscheduled SMPG, time and value of self-measured blood ketones, details 
of hypoglycemia. 
• Instruction on SMPG schedule (see Section 9.1.2.2), 
• Dispensation of urine container and instruct them how to collect at home in the morning of 
patients’ first morning urine and to bring the urine sample to the site at randomization visit 
(Visit 3). 
An appointment is given to the patient/parent for the next two visits: phone-call visit 2 (Week -1) 
and baseline visit (Day 1). The patient is to come to the study site for the baseline visit (Visit 3, 
Day 1) 14 days ± 3 days after the date of Visit 1 in fasting condition. The patient/parent is 
instructed to bring container with patient’s first morning urine, the glucose meter, the ketone 
meter, the diary and patient’s current anti-diabetic medications. 
10.1.1.2 Telephone visit 2 (week -1) 
Approximately one week after the screening visit the patient/parent 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. This visit is a mandatory 
telephone visit, but can optionally be performed as a clinical visit.  
During the phone call the following points have to be addressed with the patient/parent: 
• Did you/your child experience any new medical event, disease or symptom since the last 
visit? (Please pay attention to any possible hypoglycemic event or symptom). 
• Did you/your child experience any change in a preexisting medical event or disease or 
symptom since the last visit? 
• Did you/your child change or add any concomitant medication since the last visit? What 
are the actual basal and fast-acting mealtime insulin analogue doses? 
• Do you/your child feel comfortable in handling the diary, glucose meter and ketone meter 
or do you need any more explanation? 
• The patient/parent is asked about fasting SMPG values and, if available, other SMPG 
values from the last week (if SMPG ≥252 mg/dL [14 mmol/L] was measured when the 
child was unwell or when persistent blood glucose values ≥252 mg/dL (14 mmol/L) 
without substantial decline were present over a period of approximately 60-120 min after 
injection of an extra dose of rapid-acting insulin analogue, or when the patient was ill with 
fever and/or vomiting, check if blood ketones were measured, too). 
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Further following procedures will be performed: 
• Review of Inclusion/Exclusion criteria. 
• If based on the glycemic data, adjustment of insulin doses is needed, the investigator 
instructs patients/parents on the new insulin doses. 
• The patients/parents are reminded to measure required SMPG and if applicable blood 
ketones and complete the diary. 
• Diary data available in the e-CRF are reviewed (basal insulin dose, NIMP dose, SMPG 
values (see Section 9.1.2.2), hypoglycemia events, blood ketone values  
(see Section 10.6.2). 
• Change of concomitant medications is documented in the e-CRF. 
• AE/SAE if any are reported. 
Furthermore, an appointment for the baseline visit (V3, Day 1) in fasting condition at study site in 
one week is confirmed with the patient/parent. The patient/parent is reminded to bring container 
with patient’s first morning urine, the glucose meter, the ketone meter, the diary and patient’s 
current anti-diabetic medications. The patient/parent will be reminded not to inject any insulin in 
the morning of the visit.  
If a patient is found ineligible and thus considered a screen failure, the patient must not enter the 
randomized treatment phase and IVRS/IWRS has to be contacted as soon as possible in order to 
register the patient as a screening failure. 
10.1.2 Open-label randomized treatment phase (Day 1 to Week 52) 
The open-label randomized treatment phase consists of two periods: the main 6-month treatment 
period spanning from baseline (Visit 3 [Day 1]) to the primary endpoint assessment (Visit 14 
[Week 26]) and the on-treatment safety extension period starting after the primary endpoint visit 
and lasting until the end of treatment visit (Visit 18, Week 52). 
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 phase. 
At Visit 3 (Day 1), patients/parents must demonstrate competence in the unaided use of the 
injection device, including dose setting and the proper use of glucose meter, ketone meter and the 
diary before randomization may occur. 
Training will be repeated as often as deemed necessary by study site staff during the treatment 
period. 
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10.1.2.1 Baseline visit (Visit 3, Day 1) 
At this visit, the patient must return to the investigation site in the morning in fasting condition. 
Patients who inject their pre-study basal insulin in the morning (either as once daily or more than 
once daily regimen) will come to the study site without having injected the morning dose of basal 
insulin. 
Patients accompanied by parent will come with the blood glucose meter, ketone meter, the diary, 
current anti-diabetic medications and with the first-morning urine sample of the same day. 
The following procedures/assessments will be performed and recorded at this visit: 
• Review of all inclusion/exclusion criteria 
• Determination of the starting dose of the IMP 
• IVRS/IWRS contact 
Call IVRS/IWRS for randomization, investigational medicinal product starting dose has to be 
established before contacting IVRS/IWRS (see Section 8.1.4).  
The IMP (either HOE901-U300 or Lantus) will be given at an individually titrated dose by SC 
injection once daily either in the morning or in the evening at the same time every day. It is 
expected that patients taking their pre-study basal insulin once daily in the morning will continue 
with the morning regimen of the IMP during the study as well as patients taking their pre-study 
basal insulin once daily in the evening will continue with the evening regimen. At Visit 3 
(baseline) patients receiving more than one daily injection of their pre-study basal insulin will 
change to once daily injection either in the morning or in the evening, at the discretion of the 
patient/parent/investigator. Patients will stick with either morning or evening injections 
throughout the whole study treatment duration. The dosing interval between once daily injections 
of the IMP should be kept close to 24 hours as much as possible. Patients will continue with their 
mealtime fast-acting insulin analogue which is not to be changed during the study.  
Patients switching from more than once daily basal insulin regimen, who wish to adopt a once 
daily evening administration schedule, will not use any basal insulin in the morning of the 
baseline visit and start HOE901-U300 or Lantus injection in the evening of the baseline visit. For 
those patients who wish to adopt a once daily morning administration schedule, the first 
administration of the IMP will take place at the end of the baseline visit, after scheduled 
laboratory samples have been drawn, at a reduced dose (approximately -20% of the calculated 
starting dose [see Section 8.1.4] or at the discretion of the investigator) taking into account 
changeover from more than once daily to the once daily regimen with the previous injection in the 
evening the day before. 
• Blood sampling for: 
- 
HbA1c 
- 
FPG 
- 
C-peptide 
- 
Anti-insulin antibody 
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• Collect urine sample for albumin/creatinine ratio 
• Urine pregnancy test (postmenarchal girls) 
• Review of measures preventing pregnancy (see Appendix B) (postmenarchal girls) 
• Physical examination including determination of Tanner puberty stage (see Section 9.2.5) 
• Body weight 
• Vital signs (SBP and DBP [in sitting position], HR) 
• Review of diary data reported by the patient in the diary (basal insulin dose, NIMP dose, 
SMPG values (see Section 9.1.2.2), hypoglycemia events, blood ketone values 
(see Section 10.6.2)  
• Collect and report in the e-CRF AE/SAE if any 
• Record in the e-CRF names of basal and mealtime insulins 
• Document in the e-CRF new or change in concomitant medication, if any 
• Patient/parent training and education on self-injection devices, diary, blood glucose meter 
and blood ketones meter 
• Diet and lifestyle counseling (as needed) 
• Dispense boxes with prefilled disposable pens with the study drug  
• Dispense glucose meter-related and ketone meter-related material (lancets, control solution, 
test strips, etc.) as needed 
• Explanation of study treatment administration 
- 
Fixing of time point of once daily administration (see Section 8.1.3) 
- 
Explanation of dose titration (see Section 8.1.5) 
Instruction to document details of problems experienced with the IMP injection device 
(see Section 8.1.2.1) 
Telephone visit within 1 week ± 3 days after baseline (Visit 4) is to be appointed with the 
patient/parent and the schedule of subsequent telephone visits is reviewed. Remind the patient to 
perform scheduled SMPG (see Section 9.1.2.2) and blood ketones measurements whenever 
applicable (see Section 10.6.2). 
Instruct the patient to bring the glucose meter, the ketone meter, the diary, the used and in use 
IMP and their current fast-acting mealtime insulin analogue for each visit to the study site 
(scheduled or unscheduled).  
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10.1.2.2 Phone call visits: Visit 4-10 (Week 1-10), Visit 12 (Week 16), Visit 15 (Week 32) and 
Visit 17 (Week 45) 
The patient/parent 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. A phone call visit can 
be performed as a clinical visit if such need is expressed by the patient/parent (eg, need for 
nutritional and lifestyle advice) or for other reasons as deemed appropriate by the investigator. 
During the phone call, answers to the following questions are to be obtained from the 
patient/parent: 
• Did you experience any new medical event, disease or symptom since the last visit (please 
pay attention to any potential hypoglycemic events, potential allergic or injection site 
reaction)? 
• Did you experience SMPG ≥252 mg/dL [14 mmol/L] while you were unwell (eg, you felt 
sick or nauseated; you had abdominal pain) or did you have persistent blood glucose 
values ≥252 mg/dL (14 mmol/L) without substantial decline over a period of 
approximately 60-120 min after injection of an extra dose of your rapid-acting insulin 
analogue or were you ill with fever and/or vomiting? If yes, did you measure and record 
the level of blood ketones? 
• Did you experience any changes in a pre-existing medical condition, disease or symptom 
since the last visit? 
• Did you experience any problems using the IMP injection device?  
• Did you adjust IMP since last visit? What are your actual IMP and mealtime insulin doses?  
• Did you change or start any concomitant medication since the last visit? 
• Do you feel comfortable in handling the diary, glucose meter and ketone meter or do you 
need any more explanation? 
• Data entered by the patient in the diary are reviewed. 
The phone visits will also include: 
• Diary data available in the e-CRF are reviewed (IMP and NIMP dose, SMPG values 
(see Section 9.1.2.2), hypoglycemia events, blood ketone values (see Section 10.6.2). 
• IMP treatment kit number(s) are documented in the e-CRF. 
• Change in concomitant medications, if any, is documented in the e-CRF. 
• Documentation and reporting of AE/SAE, PTC associated with the IMP pen if any. 
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The patient/parent will be instructed to: 
• Perform required SMPG measurements (see Section 9.1.2.2), and ketones measurement 
whenever SMPG is ≥252 mg/dL (14 mmol/L) while feeling unwell (eg, sick, nauseated, 
abdominal pain) or when persistent blood glucose values ≥252 mg/dL (14 mmol/L) 
without substantial decline are present over a period of approximately 60-120 min after 
injection of an extra dose of rapid-acting insulin analogue or when being ill with fever 
and/or vomiting, 
• Complete daily the diary 
• Inject (self-injection by the patient or injection by the parent) once daily IMP at the dose 
prescribed by the investigator,  
• Contact the site in case of occurrence of adverse event or problem with the IMP injection 
device and return to the site as deemed appropriate. 
Give an appointment to the patient/parent for subsequent visits (on-site visit or phone call visit) 
and remind them to come for on-site visits in fasting condition (except on-site Visit 13 [Week 20] 
and Visit 16 [Week 38], when fasting is not required) not having injected the basal insulin for at 
least 8 hours and holding mealtime insulin, and to bring the glucose meter, ketone meter, the diary, 
the used, in use and unused IMP and their current fast-acting mealtime insulin analogue. 
10.1.2.3 On-site Visits: Visit 11 (Week 12); Visit 13 (Week 20); Visit 14 (Week 26 – main 
study endpoint visit); Visit 16 (Week 38) 
The patient (accompanied by the parent) must return to the investigation site in the morning of 
each on-site visit after randomization in fasting condition (except on-site Visit 13 [Week 20] and 
Visit 16 [Week 38] when fasting is not needed). 
The following procedures/assessments will be performed and recorded at each on-site visit: 
• Counting and collecting used and unused study drug disposable pens 
• Review of data entered in the diary with the patient/parent (IMP and NIMP dose, SMPG 
values [see Section 9.1.2.2], hypoglycemia events, blood ketone values  
[see Section 10.6.2]) 
• Compliance check (IMP and NIMP dosing; SMPG; ketones measurements) and re-training 
as needed 
• IMP treatment kit number(s) are documented in the e-CRF 
• Ask for new or change in concomitant medications and document change in the e-CRF, if 
any  
• Collect and report in the e-CRF AE/SAE, if any, including injection site reactions and 
possible allergic reactions as well as PTC associated with the IMP pen if any 
• Nutritional and lifestyle advice by a specialist pediatric dietitian (or healthcare 
professional with documented experience in childhood diabetes): anytime when needed by 
the patient/parent and when deemed appropriate by the investigator 
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• IVRS/IWRS contact for allocation of treatment kit and dispensation of treatment kit 
• Dispensation of glucose meter-related and ketone meter-related material (lancets, control 
solution, test strips, etc.) as needed 
• Body weight and height (except Visit 13 [Week 20]) 
• Vital signs (SBP and DBP [in sitting position], HR) 
• Physical examination (Visit 14 [Week 26] only) 
• Determination of Tanner puberty stage (Visit 14 [Week 26] only), (see Section 9.2.5) 
• Review of measures preventing pregnancy (see Appendix B) in postmenarchal girls 
• Blood sample for Central Laboratory assessments (except Visit 13 [Week 20]) 
(see Section 9.2.4) 
Note: particular attention needs to be paid to ensure availability of the primary and secondary 
efficacy laboratory parameters (ie, HbA1c and FPG) scheduled for the main study endpoint 
visit (Visit 14 [Week 26]). If for instance the patient is not fasting, the blood sample will not 
be collected and a new appointment has to be given to the patient for the following day if 
possible, with instruction to be fasted. If the sample is not analyzable or the result is not 
available (eg, sample lost during shipment), an appointment needs to be given in order to 
perform a retest sample as soon as possible. 
• Urine pregnancy test (post-menarchal girls) 
• PK sparse sampling (optional). PK sparse sampling will take place after the end of titration 
phase, on the day of the on-site Visit 13, Week 20 or on the day of Visit 14, Week 26 or 
additional admission may be appointed according to patient/parent and investigator’s 
preference during the period between these visits. See Section 9.3.1. 
Education on self-injection, the use of glucose meter, ketone meter, diary will be repeated when 
necessary throughout the study. 
During the on-treatment safety extension period when on-site visits are planned every 3 months, 
instruct the patients/parents to contact their investigators in case of occurrence of any AE and 
symptomatic hypoglycemia, missing the IMP dose, changing the dose or adding/changing any 
concomitant medication.  
The patient/parent is reminded to perform scheduled SMPG measurements (see Section 9.1.2.2) 
and blood ketones measurements whenever applicable (see Section 10.6.2) and to complete the 
diary daily. 
Upon completion of each on-site visit, an appointment for the next visit (on-site visit or phone call 
visit) will be made. Patients are instructed to come at next on-site visit in fasting condition (except 
Visit 13 [Week 20] and Visit 16 [Week 38] when fasting is not needed) not having injected basal 
insulin within 8 hours prior to the visit and holding mealtime insulin until after blood is drawn for 
all laboratory tests, and to bring the glucose meter, ketone meter, the diary, the used and unused 
IMP and their current fast-acting mealtime insulin analogue. 
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10.1.2.4 End of Treatment Visit (Visit 18, Week 52) or Early Treatment Discontinuation Visit 
The following procedures/assessments will be performed and recorded at this visit: 
• Counting and collecting used and unused study drug disposable pens 
• Review of data entered in the diary with the patient/parent (IMP and NIMP dose, SMPG 
values [see Section 9.1.2.2], hypoglycemia events, blood ketone values  
[see Section 10.6.2]) 
• Document in the e-CRF IMP treatment kit number(s) 
• Ask for new or change in concomitant medications and document change in the e-CRF, if 
any  
• Collect and report in the e-CRF AE/SAE, if any, including injection site reactions and 
possible allergic reactions as well as PTC associated with the IMP pen if any. 
• Nutritional and lifestyle advice by a specialist pediatric dietitian (or healthcare 
professional with documented experience in childhood diabetes): if needed by the 
patient/parent and if deemed appropriate by the investigator 
• IVRS/IWRS contact for notification of end of open-label treatment period  
• Body weight and height 
• Vital signs (SBP and DBP [in sitting position], HR) 
• Physical examination 
• Determination of Tanner puberty stage (see Section 9.2.5) 
• Blood and urine sample for Central Laboratory assessments (see Section 9.2.4) 
• Urine pregnancy test (post-menarchal girls) 
• Determination of the dose of a commercial basal insulin and mealtime insulin 
As this visit ends the study on-treatment period, no more study medication will be dispensed and 
the investigator has to ensure that the patient continues with commercially available basal insulin 
as well as with mealtime insulin therapy. The choice of basal and mealtime insulin is at the 
discretion of the investigator/treating physician.  
• Although decisions for transition dosing are ultimately those of the treating physician, it is 
suggested that a transition to an alternate form of basal insulin will be made by reducing 
the total daily dose of glargine by 20% for patients changing over from HOE901-U300 
whereas patients receiving Lantus as the IMP will transition to a commercial basal insulin 
at the suggested 1:1 ratio (see Section 8.1.6). 
Further adjustments of the insulin therapy during the 4-week post-treatment follow up period will 
be at discretion of the investigator/treating physician and will be documented in the e-CRF. 
An appointment for the telephone Post-treatment Follow Up Visit 1 (Visit 19; two days [+2 days] 
later), and for the telephone Post-treatment Follow Up Visit 2 (Visit 20 – last study visit; four 
weeks ± 5 days after Visit 18) is given to the patient. 
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Patients who prematurely discontinue from the study treatment will be asked to attend all 
scheduled study visits and undergo study procedures until the planned end of treatment visit (or 
end of the 4-week post-treatment follow up period, whichever comes last); as a minimum, visit at 
Week 26/Visit 14 (assessments of primary and secondary efficacy endpoints) should be conducted. 
Such patients will not attend visit 19 and/or 20 if scheduled dates of these visits coincide with any 
of the scheduled visits until the planned end of study treatment (Week 52). During the planned 
end of treatment visit (Week 52) procedures related to the study drug normally scheduled for the 
End of treatment visit (eg, IVRS/IWRS contact for notification of end of treatment; collection of 
IMP pens, etc.) and already performed at the Early Treatment Discontinuation Visit will not be 
performed.   
10.1.3 Post- treatment follow up period (the 4 weeks [± 5 days] following Visit 18) 
After completion of the open-label randomized treatment phase, either scheduled or premature, 
patients enter the 4-week post-treatment follow up period where safety and insulin treatment data 
will be collected. The cost of the basal insulin as well as the mealtime insulin used during the  
4-week post-treatment follow up period may be reimbursed if not covered by health insurance and 
if allowed by local regulations. During this period patients will perform SMPG measurements 
(see Section 9.1.2.2) and blood ketones measurements whenever applicable (see Section 10.6.2) 
and will record in the diary basal and mealtime insulin dosing data (see Section 9.1.2.3) as well as 
adverse events and hypoglycemia events, if any.  
10.1.3.1 Post-treatment Follow up Visit 1 (Visit 19; two days [+2 days] after Visit 18) and 
Post-treatment Follow up Visit 2 (Visit 20 – End of Study Visit -  four weeks  
[± 5 days] after Visit 18) 
The patient/parent 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. A phone call visit can 
optionally be performed as a clinical visit. 
During the phone call, answers to the following questions are to be obtained from the 
patient/parent: 
• Did you experience any new medical event, disease or symptom since the last visit (please 
pay attention to any potential hypoglycemic events, potential allergic or injection site 
reaction)? 
• Did you experience SMPG ≥252 mg/dL [14 mmol/L] while you were unwell (eg, you felt 
sick or nauseated; you had abdominal pain) or did you have persistent blood glucose 
values ≥252 mg/dL (14 mmol/L) without substantial decline over a period of 
approximately 60-120 min after injection of an extra dose of your rapid-acting insulin 
analogue, or were you ill with fever and/or vomiting? If yes, did you measure and record 
the level of blood ketones? 
• Did you experience any changes in a pre-existing medical condition, disease or symptom 
since the last visit? 
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• Did you document your basal insulin and fast-acting insulin doses since the previous visit 
in the diary (see Section 9.1.2.3)?  
• Data entered by the patient in the diary are reviewed (basal and mealtime insulin dose, 
SMPG values [see Section 9.1.2.2], hypoglycemia events, blood ketone values 
[see Section 10.6.2]). 
The visits will also include: 
• Record in the e-CRF names of commercial basal and mealtime insulins 
• Document in the e-CRF AE/SAE, if any  
• Arrange return of the diary and, if mandatory by local regulations, glucose meter and 
blood ketone meter (in case of premature treatment discontinuation the devices will be 
collected during the planned end of treatment visit – Week 52 [or at the end of the 4-week 
post-treatment follow up period, whichever comes last]). 
10.2 
DEFINITION OF SOURCE DATA 
Evaluations that are reported in the e-CRF must be supported by appropriately signed identified 
source documentation related but not limited to the following: 
• Agreement and signature of informed consent form provided by the parent mentioning the 
study identification, as well as written assent or documentation of oral assent obtained 
from the patient as applicable, 
• Patient and parent identification, patient’s last participation in a clinical trial, medical 
history, associated diseases, and data related to the studied pathology, 
• Previous and concomitant medication (including basal and mealtime insulin), 
• IVRS/IWRS confirmation notifications by fax or e-mail (screening, screen failure, 
randomization, treatment reallocation, treatment/study discontinuation, treatment 
replacement if applicable, etc.),  
• Study identification, 
• Treatment kit number of IMP, 
• Dates and doses of study medication administration (IMP and NIMP), 
• Names of preparations and administration regimen of basal and mealtime insulin before 
and after study treatment, 
• Dates of visits and assessments including the examination report, 
• Vital signs, height, body weight, Tanner puberty stage signed and dated, 
• Date and time of blood samples for PK analysis, 
• Central laboratory reports and original report received at site, 
• Adverse events and follow-up, 
• In case of SAE, the site should file in the source documents at least copies of the 
hospitalization reports and any relevant examination reports documenting the follow-up of 
the SAE, 
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• Date of premature study discontinuation (if any) and reason, 
• All relevant information collected during the investigator’s call following hypoglycemic 
event or following patient’s reporting of symptoms suggesting such event, 
Source documentation may be found in the following: 
• Patient’s medical records (eg, discharge notes) 
• Nursing notes 
• Dietician’s notes 
• Physician’s notes, 
• Patient’s diary 
• Laboratory reports 
10.2.1 Source data verification requirements for patients not randomized 
For patients not randomized, the source data that must be checked include the patient's and 
parent’s identification details, the informed consent signed by the parent, written assent or 
documentation of oral assent obtained from the patient as applicable, 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.  
10.3.1 Temporary treatment discontinuation with investigational medicinal products 
Temporary treatment discontinuation may be considered by the investigator because of suspected 
AEs. Re-initiation 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 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, ie, any day without IMP administration, patients are 
asked to report in their diary for IMP a dose 0 units for each of these days. Investigator will check 
patients´ diaries and ensure all days corresponding to a temporary treatment discontinuation are 
appropriately captured in the database. Additionally, the investigator must record in the e-CRF 
any non-study basal insulin administered as a replacement for IMP during those periods 
(see Section 8.9).  
Temporary treatment (IMP) discontinuation decided by the investigator corresponds to one or 
more dose not administered to the patient. 
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10.3.2 Permanent treatment discontinuation with investigational medicinal product 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the investigator or the patient/parent 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/their parents 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. Particular attention should be paid whether or not treatment 
discontinuation was associated with an adverse event or hypoglycemia and, if applicable, 
corresponding event has to be reported in the e-CRF. 
The following will lead to permanent treatment discontinuation: 
• Patient’s own request or patient’s parent request, ie, withdrawal of the consent for 
treatment 
• If, in the investigator's opinion, continuation with the administration of IMP would be 
detrimental to the patient's well-being, 
• Specific request of the Sponsor. 
• Intercurrent condition that requires discontinuation of IMP: eg, laboratory abnormalities 
(see decision tree and general guidance for the follow up of laboratory abnormalities in 
Appendix C),  
• The need to initiate the prohibited therapy (see Section 8.9.2) 
• Pregnancy in all cases 
• If, in the investigator's opinion, a female patient undertakes behavior deemed to be at risk 
of getting pregnant or decides to attempt to become pregnant. 
Any abnormal laboratory value or electrocardiogram (ECG) parameter 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 
As soon as possible after the premature and permanent discontinuation of study treatment, the 
patients will be assessed using the procedure normally planned for the last day of the treatment 
period (Visit 18, Week 52, see Section 10.1.2.4). The patients will be asked to continue attending 
study visits and undergo assessments according to the schedule until the planned end of study 
treatment (Month 12), including assessments normally scheduled for the 4-week post-treatment 
follow up period to evaluate insulin dose after switch-back to a non-study therapy during the 
initial four weeks after change over from the study treatment. As a minimum, visit at 
Week 26/Visit 14 (assessments of primary and secondary efficacy endpoints) should be conducted. 
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All cases of permanent treatment discontinuation should be recorded by the investigator in the 
appropriate pages of the e-CRF when considered as confirmed. IVRS/IWRS will be notified when 
a patient prematurely discontinues treatment. 
10.3.5 Procedure and consequence for patient withdrawal from study   
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. Withdrawal of consent for treatment should be distinguished 
from withdrawal of consent for follow-up visits and from withdrawal of consent for non-patient 
contact follow-up, eg, medical records check. Patients and their parents will be told that they are 
free to withdraw from the study at any time without any adverse effect on their care. However, if 
they no longer wish to take the IMP, they will be encouraged to remain in the study and attend the 
remaining visits or, at the minimum, attend Visit 14 at Week 26. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. Patients who do not wish to continue in the study after the premature and 
permanent discontinuation of study treatment should be assessed as soon as possible after IMP 
discontinuation using the procedures normally planned for the End of Treatment visit (Visit 18, 
see Section 10.1.2.4). 
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 study site for the End of Treatment visit, unless the patient 
withdraws the consent for follow-up, the investigator should make the best effort to re-contact the 
patient/parent (eg, contacting patient’s parents or other member of family whose contact details 
were collected at the beginning of the study, or private physician, reviewing available registries or 
health care databases), and to determine his/her health status, including at least his/her vital status. 
These contacts attempts must be documented in the patient’s records (eg, times and dates of 
attempted telephone contact, receipt for sending a registered letter). 
Patients who withdraw (and/or their parents) 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 (and/or the parent) should withdraw consent in writing and, if 
the patient or the parent refuses or is physically unavailable, the site should document and sign the 
reason for the patient’s or parent’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. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study. Their 
inclusion and treatment numbers must not be reused.  
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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. 
10.4.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
• Is a medically important event 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive: 
- 
Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm  
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc),  
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc). 
- 
Development of drug dependence or drug abuse 
- 
ALT >3 x ULN (upper limit of normal range) + total bilirubin >2 x ULN or 
asymptomatic ALT increase >10 x ULN 
- 
Suicide attempt or any event suggestive of suicidality 
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- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling) 
- 
Bullous cutaneous eruptions 
- 
Cancers diagnosed during the study or aggravated during the study, including in-situ 
malignancies  
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study. 
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. 
The AESIs are listed below: 
• Symptomatic overdose with IMP/NIMP 
- 
A symptomatic overdose (accidental or intentional) with the IMP/NIMP is an event 
suspected by the investigator or spontaneously notified by the patient/parent (not based 
on systematic drug accountability) and defined as follows: 
- 
any IMP or fast-acting mealtime insulin analogue (NIMP) dose administration 
which, in the investigator’s opinion based on clinical judgment is considered 
significantly greater than the prescribed dose of insulin and which results in 
symptomatic hypoglycemia, ie, an event accompanied by clinical symptoms that 
are considered to result from low blood glucose regardless whether or not plasma 
glucose was determined. The event is treated with oral carbohydrate, glucagon or 
IV glucose.  
- 
Symptomatic overdose with IMP/NIMP (non-serious as well as serious) will be 
recorded on the standard AE form as “symptomatic overdose with IMP (or NIMP) 
accidental (or intentional)” and as hypoglycemia on the Hypoglycemia form. AE 
Safety Complementary form has to be completed, if serious. 
Of note, asymptomatic overdose (ie, an event defined as above but which does not result 
in clinical symptoms regardless whether or not plasma glucose was determined) has to be 
reported as a standard AE as “asymptomatic overdose with IMP (or NIMP) accidental (or 
intentional)”. For asymptomatic IMP/NIMP overdoses events with a measured plasma 
glucose concentration ≤70 mg/dL (3.9 mmol/L), corresponding hypoglycemia has to be 
reported on Hypoglycemia form, too. 
• ALT increase as outlined in flowchart in Appendix C. 
• Pregnancy 
- 
Pregnancy will be recorded as an AE in all cases. It will be qualified as an SAE only if 
it fulfills SAE criteria. 
- 
In the event of pregnancy, study treatment should be discontinued and the sponsor 
informed immediately (ie, within 24 hours).   
- 
Follow-up of the pregnancy will be mandatory until the outcome has been determined. 
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10.4.2 General guidelines for reporting adverse events 
• All AEs, regardless of seriousness or relationship to IMP/NIMP, spanning from the 
signature of the informed consent form until the end of the study as defined by the 
protocol for that patient, are to be recorded on the corresponding page(s) or screen(s) of 
the e-CRF. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or NIMPs or by the study procedure(s).   
• Whenever an event resulted from another, separate event (eg, arm fracture secondary to 
fall), both should be reported separately. 
• The investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by the Sponsor. 
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study as defined by the protocol for that patient. 
• Laboratory, vital signs or ECG abnormalities are to be recorded as AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
10.4.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the investigator or any designees must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the investigator within the e-CRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to the Sponsor. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
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medications, patient status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
A back-up plan (using a paper Case Report Form [CRF] process) is available and should be used 
when the e-CRF system does not work (see Appendix D). 
• 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 (see Section 10.4.3), even if not fulfilling a seriousness criterion, using the 
corresponding screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 2. 
10.4.5 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
Appendix C.  
The following laboratory abnormalities should be monitored, documented, and managed 
according to the related flow chart in protocol appendices.  
• Neutropenia 
• Thrombocytopenia 
• Increase in ALT 
• Acute renal failure 
• Suspicion of rhabdomyolysis 
10.4.6 Summary of adverse event and hypoglycemia reporting instructions 
See Table 2. 
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Table 2 - Summary of adverse event and hypoglycemia reporting instructions 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this category 
AE 
form 
AE Safety 
Complementary 
Form 
Hypoglycemia 
Form 
Other specific 
forms 
Adverse Event  
(non-SAE, non-AESI) 
Routine 
Any AE that is not SAE, AESI or hypoglycemia 
Yes 
No 
No 
No 
Hypoglycemia  
(non-SAE; non-AESI) 
Routine 
Any hypoglycemia that is not SAE or AESI 
No 
No 
Yes 
No 
Serious Adverse Event (non-AESI; non-
hypoglycemia) 
Expedited  
(within 24 hours) 
Any AE meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
No 
No 
Serious hypoglycemia  
(non-AESI) 
Expedited  
(within 24 hours) 
Any hypoglycemia meeting seriousness criterion per 
Section 10.4.1.2 
Yes 
Yes 
Yes 
No 
Adverse Event of Special Interest  
(non-SAE) 
Expedited 
(within 24 hours) 
Symptomatic overdose  
(see Section 10.4.1.3) 
Yes 
No 
Yes 
No 
 
ALT increase1 
Yes 
No 
No 
Yes 
 
 
Pregnancy 
No 
No 
No 
Yes 
Symptomatic overdose 
 (see Section 10.4.1.3) 
Yes 
Yes 2 
Yes 
No 
ALT increase1 
Yes 
Yes 
No 
Yes 
Adverse Event of Special Interest  
(serious) 
Expedited  
(within 24 hours) 
Pregnancy 
Yes 
Yes 
No 
Yes 
Laboratory, vital sign, or ECG abnormality 
recorded as AE (non- SAE, non-AESI) 
Routine 
Neutropenia, Thrombocytopenia, Acute renal failure, 
Rhabdomyolysis, Hyperglycemia with ketosis, Other 
Yes 
No 
No 
No 
           Footnote: 
1 See criteria defined in Appendix C 
2 Corresponding to the overdose adverse event and to the related severe hypoglycemia event 
 
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10.5 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, the Sponsor will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, Institutional review boards/ Independent ethics committees 
(IRBs/IECs) as appropriate and to the investigators.    
• All SAEs that are expected and at least reasonably related to the IMP to the regulatory 
authorities, according to local regulations. 
In this study, some AEs considered related to the underlying condition (eg, blood glucose 
increased) will not be considered unexpected as given in the Investigator’s Brochure.  
Any other AE not listed as an expected event in the Investigator’s Brochure or in this protocol 
will be considered unexpected. 
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report (CSR). 
10.6 
SAFETY INSTRUCTIONS 
10.6.1 Hypoglycemia instructions 
Symptoms suggestive of hypoglycemia will be explained to patients/parents as well as situations 
posing the patient at high risk of hypoglycemia. Patients/parents will be instructed to measure 
finger stick plasma glucose levels with the study-provided glucose meter 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. 
Additional information related to the hypoglycemic event will be collected in the diary as soon 
after the event as possible. Following severe events, patients/parents will contact the sites as soon 
as possible to review the details and decide on any necessary measures to be taken. 
Patients will report in the diary the occurrence of symptoms suggesting hypoglycemia with or 
without SMPG values. Patients with SMPG value ≤70 mg/dL (3.9 mmol/L) will document in the 
diary whether it was symptomatic or asymptomatic. If symptomatic, appropriate hypoglycemic 
symptoms will be reported. In all cases, patients/parents will document whether severity of 
symptoms warranted assistance in the patient’s care. 
All hypoglycemia episodes will be documented by the study site on the “hypoglycemia specific 
form” in the e-CRF. This includes all symptomatic hypoglycemia events and asymptomatic 
hypoglycemia. Hypoglycemia events fulfilling the criteria of an SAE including all hypoglycemia 
events associated with coma, seizure or unconsciousness will be documented on the 
“hypoglycemia specific form” and as SAE on the “Adverse Event” form (category “Serious 
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Hypoglycemia”) with corresponding complementary forms (AE Safety Complementary Form) in 
the e-CRF (see Table 2, Summary of adverse event and hypoglycemia reporting instructions). 
For instructions concerning symptomatic hypoglycemia event resulting from an overdose with the 
IMP/NIMP, see Section 10.4.1.3 and Table 2. 
Categories of hypoglycemia which will be assessed are described in Section 9.2.1. 
10.6.2 Hyperglycemia with ketosis instructions 
Testing of capillary ketones must be performed using the meter provided by the sponsor: 
• When SMPG is ≥252 mg/dL (≥14 mmol/L) in an unwell child (eg, feeling sick or 
nauseated; persistent polyuria, abdominal pains, rapid breathing) 
• When SMPG persists at ≥252 mg/dL (≥14 mmol/L) without substantial decline over a 
period of approximately 60-120 minutes after injection of an extra dose of rapid-acting 
insulin analogue 
• During illness with fever and/or vomiting 
Ketone readings 1.5 mmol/L or more and concomitant SMPG ≥252 mg/dL (14 mmol/L) will be 
considered as alert for development of diabetic ketoacidosis and the investigator will be contacted 
immediately. The event will be reported as AE or – if respective criteria are met – as SAE 
(see Section 10.4.1.2). Self-measured ketones values will be documented in the diary. 
10.6.3 Local tolerability at injection site and hypersensitivity reactions 
If the investigator or the patient/parent recognizes any signs of local intolerability at the site of 
IMP or NIMP injection or hypersensitivity reactions, the event should be recorded in the adverse 
event page in the e-CRF. For local reactions at IMP/NIMP injection site, the event verbatim will 
include localization and, if known, the insulin (IMP or NIMP) associated with the reaction. 
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. Severe injection 
site reactions should be photographed if possible. 
10.6.4 Follow-up of laboratory abnormalities 
Decision trees for the management of specific laboratory abnormalities are provided in 
Appendix C. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final CSR. 
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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 Month 6/Week 26. 
A sample size of 450 randomized patients (225 for HOE901-U300 and 225 for Lantus) will 
ensure that the upper bound of the two-sided 95% confidence interval (CI) for the adjusted mean 
difference between HOE901-U300 and Lantus would not exceed a non-inferiority margin of 0.3% 
HbA1c with 92% power. This calculation assumes a common standard deviation (SD) of 0.95%, 
with a one-sided test at the 2.5% significant level and a true difference of zero in HbA1c between 
treatment groups. 
Calculations were made using nQuery Advisor® Software Version 7.0. 
11.1.1 Justification of the non-inferiority margin 
Previous randomized studies in Type 1 diabetes involving Lantus were considered for the 
justification of the choice of non-inferiority margin: in studies of similar duration, with HbA1C as 
the primary endpoint, and designed to show superiority of Lantus versus NPH human insulin, the 
sample size calculation was based on a mean expected difference between treatment groups 
ranging between 0.5% and 0.7%. In study 4010 (a 30-week randomized study comparing Lantus 
and NPH in combination with insulin lispro), superiority of Lantus over NPH was shown, with an 
estimated difference in HbA1C change between Lantus and NPH of -0.53% (95%CI: -0.93, -
0.13).  To be in line with recommendations by regulatory agencies (11, 12) and considering that 
the non-inferiority margin must be less than the effect of Lantus versus NPH, and that the 
experimental treatment (HOE901-U300) is requested to preserve a notable fraction of the effect 
considered as clinically relevant, a non-inferiority margin of 0.3% was considered appropriate, 
corresponding to preservation of around 50% of a difference ranging between 0.5% and 0.7%. 
11.2 
DISPOSITION OF PATIENTS 
The total number of patients for each of the following categories will be presented. 
• Screened: all patients who originally met inclusion criteria and signed the informed 
consent form;  
• Screen failure patients and reason for screen failure; 
• 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; 
• Safety population (Section 11.3.2), presented as treated; 
• The intent-to-treat (ITT) population (Section 11.3.1.1 analyzed as randomized); 
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• The randomization strata (Age group at screening visit [<12 years and ≥12 years] and 
screening HbA1c categories [<8.5%, ≥8.5%]) assigned by IVRS/IWRS will be 
summarized. The discrepancy between the strata assigned by IVRS/IWRS and the 
information reported on e-CRF will be listed for all randomized patients; 
• Completed populations (presented as randomized):  
- 
Patients who have completed the main 6-month on-treatment period (who have 
performed Visit 14 (Month 6/ Week 26)) and who did not permanently discontinue 
treatment; 
- 
Patients who completed the main 6-month randomized period (patients who have 
performed visit 14); 
- 
Patients who have completed the 12-month on-treatment period (who have performed 
Visit 18 (Month 12/ Week 52)) and who did not permanently discontinue treatment; 
- 
Patients who completed the 12-month randomized period (patients who have 
performed visit 18); 
• Patients who permanently discontinued the IMP during the main 6-month treatment 
period, and the reasons for permanent treatment discontinuation; 
• Patients who did not complete the main 6-month randomized period; 
• Patients who discontinued the main 6-month randomized period by main reason for study 
discontinuation; 
• Patients who permanently discontinued the IMP during the 12-month treatment period, 
and the reasons for permanent treatment discontinuation; 
• Patients who did not complete the 12-month randomized period; 
• Patients who discontinued the 12-month study by main reason for randomized 
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. 
Patients with the following deviations will be identified and described in separate listings: 
• Treated but not randomized, 
• Randomized but not treated, 
• Randomized but not treated as randomized. 
A list of patients prematurely discontinued from the treatment, along with reasons for 
discontinuation, will be provided. 
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. 
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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, analyzed according to the treatment group allocated by randomization. 
11.3.2 Safety population 
The safety population is defined as all randomized patients who did actually receive at least one 
dose of IMP, regardless of the amount of 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: 
• If a patient is dispensed IMP and is lost to follow-up without any documented evidence 
whether or not the patient took  IMP, the patient will be considered exposed and included 
in the safety population. 
• Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized. 
In addition:  
• Non randomized but treated patients will not be part of the safety population, but their 
safety data will be presented separately.  
• 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 PK population 
All patients who provided at least one PK measurement and who do not have major deviation 
regarding administration of IMP will be included in the PK population. 
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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 
also be summarized categorically by numbers and percentages for each of the following 
categories and cumulatively according to these categories: 
• up to 2 weeks; 
• >2 to 4 weeks; 
• >4 to 8 weeks; 
• >8 to 12 weeks; 
• >12 to 16 weeks; 
• >16 to 20 weeks; 
• >20 to 25 weeks; 
• >25 to 26 weeks; 
• >26 to 38 weeks; 
• >38 to 51 weeks; 
• >51 to 52 weeks; 
• >52 weeks. 
The exposure parameters will be provided for the main 6-month on-treatment period and for the 
12-month on-treatment period, respectively. 
11.4.1.2 Daily insulin doses 
The daily insulin doses (basal, mealtime, total) will be described at each visit, as well as the 
changes from baseline. 
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11.4.1.3 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol.  No imputation will be made for patients with 
missing or incomplete data.  
Treatment compliance percentage will be summarized descriptively (N, Mean, SD, Median, Min, 
and Max). The percentage of patients with compliance <80% will be summarized. 
11.4.2 Analyses of efficacy endpoints 
Efficacy analyses will be performed on the ITT population. 
All efficacy parameters will be summarized by treatment group for each visit and at endpoint for 
the main 6-month randomized period and the 12-month randomized period respectively. 
11.4.2.1 Analysis of primary efficacy endpoint 
11.4.2.1.1 Primary analysis 
The primary efficacy variable (change in HbA1c from baseline to Month 6 in % as defined in 
Section 9.1.1) will be analyzed for non-inferiority assessment, in the ITT population using all 
post-baseline HbA1c data available up to Month 6, regardless of study treatment discontinuation 
(analysis on the main 6-month randomized period (defined in Section 9.1), ITT estimand).  
A multiple imputation approach will be used where missing data from patients who do not adhere 
to IMP will be represented by the data from those patients in the same administration treatment 
group who also do not adhere to IMP but have the measurement for the primary endpoint. Details 
of the proposed multiple imputation analysis in two parts, are provided below: 
1. Missing data in patients who prematurely discontinued IMP during the main 6-month 
treatment period will be imputed using a model estimated solely from data observed in 
other patients who prematurely discontinue IMP during the main 6-month treatment period 
and have change in HbA1c available at Week 26. Due to the anticipated small number of 
these latter patients, a basic imputation model will be built, including only the 
administration treatment group as predictor. Missing data will be imputed using the 
regression method. 
2. Missing data in patients who complete the main 6-month on-treatment period will be 
imputed separately, using a model estimated from data observed in other patients who 
complete the main 6-month on-treatment period and have change in HbA1c available at 
Week 26. The imputation model will include the administration treatment group, the 
randomization stratum of age group at screening visit (<12 years and ≥12 years), the 
continuous fixed covariates of baseline HbA1c value, as well as the change from baseline 
in HbA1c observed at Week 12. Since in general, the missing pattern will not be 
monotone, a two-step approach will be used: 
- 
Step 1: the Markov Chain Monte Carlo (MCMC) method will be used in conjunction 
with the IMPUTE=MONOTONE option to create an imputed data set with a 
monotone missing pattern. 
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- 
Step 2: using the monotone data set from step 1, missing data will be imputed using 
the regression method. 
Missing values will be imputed 1,000 times. Completed datasets from the two parts detailed above 
will be combined into a single dataset. Each completed dataset will be analyzed using an analysis 
of covariance (ANCOVA) of change from baseline to Week 26 in HbA1c, including the fixed 
categorical effects of administration treatment group, randomization strata, as well as the 
continuous fixed covariates of baseline value. The final results will be obtained by combining the 
least squares means and least squares mean differences from these 1,000 analyses, using Rubin’s 
formula.  
This model will provide baseline adjusted least squares (LS) means estimates at Month 6 for both 
treatment groups, as well as, the differences of these estimates, with their corresponding standard 
errors (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: 
• Step 1: to assess non-inferiority of HOE901-U300 versus Lantus, the upper bound of the 
two-sided 95% CI (Confidence Interval) for the difference in the mean change in HbA1c 
from baseline to endpoint (Month 6) between HOE901-U300 and Lantus on ITT 
population will be compared with the predefined non-inferiority margin of 0.3%. Non-
inferiority will be demonstrated if this upper bound is <0.3%.  
• Step 2: only if the previous step of the hierarchical procedure has been demonstrated, 
superiority of HOE901-U300 over Lantus in HbA1c change from baseline to endpoint 
(Month 6) will be assessed. Superiority of HOE901-U300 over Lantus 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 Month 6 between HOE901-U300 and Lantus is <0. 
The tests for the primary endpoint (Month 6) will be performed one-sided at level α = 0.025. 
11.4.2.1.2 Key sensitivity analysis 
A sensitivity analysis will be performed on the change in HbA1c from baseline to Month 6 on 
patients who complete the main 6-month on-treatment period in the ITT population, (ie, patients 
who perform Visit 14 [Week 26] and who do not permanently discontinue treatment). A similar 
multiple imputation approach as described for primary analysis part 2 will be used (ie, for missing 
data in patients who complete the main 6-month on-treatment period). 
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 (MI) 
In order to assess the impact of missing data, the change in HbA1c from baseline to Month 6 in % 
using HbA1c values during the randomized 6-month period (all post baseline available data), will 
be analyzed in the ITT population using a multiple imputation approach to account for missing 
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data at any time points (including missing baseline, Week 12 and Month 6) followed by the 
testing of treatment arms using an analysis of covariance (ANCOVA) model. 
Missing data will be imputed 1,000 times to generate 1,000 complete data sets with the MI SAS 
procedure. For each simulation leading to negative imputed value, another value will be redrawn 
for imputation using MINIMUM option of multiple imputation SAS procedure. Since in general, 
the missing pattern will not be monotone, a two-step approach will be used: 
• Step 1: the Markov Chain Monte Carlo (MCMC) method will be used in conjunction with 
the IMPUTE=MONOTONE option to create an imputed data set with a monotone missing 
pattern 
• 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 12 and Month 6.  
The imputation model for step 2 will include 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 26 in the HOE901-U300 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 Lantus 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 26. 
The 1,000 complete data sets will then be analyzed using an analysis of covariance (ANCOVA) 
model including the fixed categorical effects of randomization stratum of age group at screening 
visit (<12 years and ≥12 years), treatment group, 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 1,000 analyses using Rubin’s formulae.  
This procedure will provide baseline adjusted least-squares means estimates at Week 26 for both 
treatment groups, as well as, the differences of these estimates, with their corresponding SEs and 
95% CIs. 
Tipping point analysis  
In order to assess the impact of missing data, a tipping-point analysis based on the pattern mixture 
model approach will also be performed. A specific illustration on the value of the minimum 
penality leading to a non-rejection of the null hypothesis will be provided (13). 
The tipping point analysis will be conducted by multiply imputing missing HbA1c values with a 
delta adjustment in the HOE901-U300 arm. In the tipping point analysis, missing HbA1c values at 
Week 26 will be imputed and a delta (HbA1c increase) will be added to each imputed value in the 
HOE901-U300 arm in the ITT population. 
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To investigate how the conclusions depend on the adopted values of delta, the testing will be 
repeated over a range of plausible values for delta. Results will be then summarized using graphs. 
Further pattern mixture models could be explored depending on the observed missing data pattern 
in the HOE901-U300 arm. 
11.4.2.2 Analyses of secondary efficacy endpoints 
Secondary efficacy endpoints are described in Section 9.1.2. 
All secondary efficacy endpoints will be analyzed and summarized on the main 6-month 
randomized period using the ITT population (ITT estimand). 
Secondary efficacy endpoints will be analyzed in the ITT population, using all available data on 
the 6-month randomized period (ITT estimand).  
A similar multiple imputation approach in two parts, as described above for the primary efficacy 
endpoint, adding randomization stratum of screening HbA1c (<8.5%; ≥8.5%) only in part 2 
imputation model (ie, for missing data in patients who complete the main 6-month on-treatment 
period), will be used for change from baseline in FPG at Week 26. This analysis will be used 
descriptively. 
The other continuous secondary endpoints will be analyzed descriptively only. 
Categorical efficacy parameters will be analyzed by using Cochran-Mantel-Haenszel (CMH) 
method with treatment as factors, stratified by randomization stratum of HbA1c (<8.5%, ≥8.5%) 
and by randomization stratum of age group (<12 years and ≥12 years) at screening. 95 % 
confidence interval for the treatment difference or ratios will be provided for descriptive purpose 
only. 
All secondary endpoints will be evaluated at end of treatment of the whole study (Week 52), for 
descriptive purpose, using the same statistical methods as described above. 
11.4.2.3 Multiplicity considerations 
To control the type I error, a hierarchical step-down testing procedure will be applied. 
• Step 1: non-inferiority comparison of the mean change from baseline to Month 6/ Week 26  
in HbA1c with HOE901-U300 compared to Lantus 
• Step 2: only if non-inferiority is demonstrated, superiority of HOE901-U300 over Lantus 
of the mean change from baseline to Month 6/ Week 26  in HbA1c will be assessed 
The other secondary efficacy variables will be analyzed for exploratory purpose only. 
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11.4.3 Analyses of safety data 
Safety endpoints are described in Section 9.2. 
The summary of safety results will be presented by treatment group for the main 6-month TEAE 
period in the 6-month CSR and for the 12-month TEAE period (as defined in Section 9.2) in the 
12-month CSR. 
All safety analyses will be performed on the Safety population using the following common rule: 
• The baseline value is defined generally as the last available value prior to the first injection 
of IMP. 
The following definitions will be applied to laboratory parameters, vital signs and ECG: 
• 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 clinical 
laboratory tests and vital signs.  
• PCSA criteria will determine which patients had at least one PCSA during the TEAE 
periods, taking into account all evaluations performed during the TEAE periods, including 
unscheduled or repeated evaluations.  The number of all such patients will be the 
numerator for the PCSA percentage during the TEAE periods. 
11.4.3.1 Hypoglycemia 
Incidence of patients with at least one hypoglycemia event will be presented by type of event and 
treatment group, during the TEAE periods.  
Number and rate of hypoglycemia event per patient-year will be summarized by type of event and 
treatment group, during the TEAE periods. 
Incidence of patients with at least one hypoglycemia event and number of hypoglycemia events 
per patient-year will be also presented by treatment period (titration phase, maintenance phase, 
over 26 weeks of treatment and over 52 weeks of treatment). 
Hypoglycemia episodes of the categories defined in Section 9.2.1 will be analyzed: 
• by diurnal distribution (0:00-23:59); 
• by time of the day: 
- 
nocturnal hypoglycemia (defined by time of the day): any hypoglycemia that occurs 
between 00:00 and 05:59 a.m. hours, regardless whether patient was awake or woke up 
because of the event; 
- 
daytime hypoglycemia (defined by time of the day): any hypoglycemia that occurs 
between 6:00 a.m. to 23:59; 
- 
nocturnal hypoglycemia (defined by sleep status):  any hypoglycemia waking-up the 
patient from sleep after having gone to bed in the evening and before getting up in the 
morning (ie, before the morning determination of fasting pre-breakfast SMPG and 
before administration of insulin (IMP or NIMP); 
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• by treatment periods: 6-month TEAE period, 12-month TEAE period, from first injection 
of IMP to end of week 8, from start of week 9 to month 6, monthly rates; 
• by HbA1c, by age range and by Tanner puberty stage. 
11.4.3.2 Hyperglycemia with ketosis 
Incidence of patients with at least one hyperglycemia with ketosis event will be presented by type 
of event and treatment group, during the TEAE periods.  
Number and rate of hyperglycemia with ketosis event per patient-year will be summarized by type 
of event and treatment group, during the TEAE periods. 
Incidence of patients with at least one hyperglycemia with ketosis event and number of 
hyperglycemia with ketosis events per patient-year will be also presented by treatment period 
(titration phase, maintenance phase, over 26 weeks of treatment and over 52 weeks of treatment). 
11.4.3.3 Adverse events 
All adverse events will be coded to a “Preferred Term” (PT) and “High Level Group Term” 
(HLGT), “High Level Term” (HLT) and primary “System Organ Class” (SOC) using the version 
of MedDRA currently in use by the sponsor at the time of database lock.  
Adverse event incidence tables will present by SOC (sorted by internationally agreed order), 
HLGT, HLT and PT sorted in alphabetical order for each treatment group, the number (n) and 
percentage (%) of patients experiencing an AE.  Multiple occurrences of the same event in the 
same patient will be counted only once in the tables within a treatment phase. The denominator 
for computation of percentages is the safety population within each treatment group. 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment emergent SAEs, all TEAEs leading to permanent treatment discontinuation 
and all TEAEs related to local tolerability at injection site and hypersensitivity. 
Death 
The following deaths summaries will be generated on the safety population: 
• Number (%) of patients who died by study period (TEAE periods, on-study, post-study) 
and reasons for death summarized by treatment received 
• Death in nonrandomized patients or randomized and not treated patients 
TEAE leading to death (death as an outcome on the AE e-CRF page as reported by the 
investigator) 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.  
Injection site reaction and hypersensitivity reaction 
Number (%) of patients with events related to injection site reactions or hypersensitivity reaction 
will be provided separately. 
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Adverse event of special interest 
A listing of patients with symptomatic overdose with IMP/NIMP and increase of ALT will be 
provided separately. 
11.4.3.4 Laboratory safety variables 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post baseline time point, last on-
treatment) by treatment group for the TEAE periods. 
The incidence of PCSAs at any time during the TEAE periods will be summarized by biological 
function and treatment group whatever the baseline level and according to the following baseline 
status categories:  
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For parameter for which no PCSA criterion is defined, similar table(s) using the normal range is 
provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, ALP, and total bilirubin are used to assess possible 
drug induced liver toxicity. The proportion of patients with PCSA values at any post-baseline visit 
by baseline status will be displayed by treatment group for each parameter.  
Listing of possible Hy’s Law cases identified will be provided by treatment group (eg, patients 
with any elevated ALT ≥3xULN, and associated with an increase in bilirubin  >2xULN (ULN) 
with: ALT, AST, ALP, Total bilirubin  and the following complementary parameters (if 
available): Conjugated Bilirubin and Prothrombin Time / INR ,CPK, serum creatinine, complete 
blood count. 
11.4.3.5 Vital signs and physical examination 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital signs variables (values and changes from baseline) including body weight, 
height, BMI, will be calculated for each visit or study assessment (baseline, each post baseline 
time point, last on-treatment) by treatment group for the TEAE periods. The Tanner puberty stage 
data will be summarized too. 
The incidence of PCSAs at any time during the TEAE periods will be summarized by treatment 
group whatever the baseline level and according to baseline status. 
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11.4.3.6 Analyses of AIA variables 
The analyses of AIA data are performed based on the safety population. 
AIA analyses will be detailed in the Statistical Analysis Plan. 
11.4.4 Analyses of pharmacokinetic variables 
PK data analysis will be performed using a population PK approach. Details of such analysis will 
be documented in a separate analysis plan. 
11.5 
INTERIM ANALYSIS 
Not applicable. 
This controlled open-label study will not to be terminated early with a positive claim for efficacy 
or safety. The primary analysis of the efficacy and safety will be performed on the data collected 
during the 6-month comparative treatment period. The timing of this analysis is when the last 
randomized patient has completed the 6-month comparative treatment period. The results of the 
primary analysis are not used to change the conduct of the ongoing study in any aspect. 
11.6 
DATABASE LOCK 
It is planned to lock the database approximately 4 weeks after Last Patient Last Visit of the 
comparative treatment phase (6 months). 
It is further planned to lock the database approximately 4 weeks after Last Patient Last Visit of the 
safety extension phase (extension by further 6 months). 
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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 sub-investigator, 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 International Conference on Harmonization (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, should fully inform the patient (and the parent[s]) of all pertinent aspects of the 
clinical trial including the written information given 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 informed consent form should be signed, 
name filled in and personally dated by the patient’s parent(s) or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion.  Local law 
must be observed in deciding whether 1 or both parents consent is required.  If only 1 parent signs 
the consent form, where both signatures are required, the investigator must document the reason 
for only 1 parent signature. 
In addition, participants will assent as detailed below or will follow the Ethics Committee 
(IRB/IEC) approved standard practice for pediatric participants at each participating center. 
Patients who can read the assent form will do so before writing their name and dating and signing 
the form. 
Patients who cannot read will have the assent form read to them in presence of an impartial 
witness, who will sign and date the assent form to confirm that assent was given. Such patients, if 
only are able to write, will also be offered to sign and date the form. 
The informed consent form and the assent form used by the investigator for obtaining the Parent´s 
informed consent and Patient´s assent must be reviewed and approved by the Sponsor prior to 
submission to the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. 
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The same rules apply to the consent for optional PK blood sampling, including assent process 
with the patient. 
Prior to collection of blood for PK evaluations, the optional PK informed consent form (written) 
must be signed, name filled in, and personally dated by the parent(s), and by the person who 
conducted the informed consent discussion. A copy of the signed and dated written optional 
informed consent form will be provided to the parent. The optional PK assent form must be 
obtained from the patient prior to collection of blood for PK evaluations, according to the rules 
applicable to the main study assent. 
The main study informed consent form and the optional PK informed consent forms as well as 
corresponding assents used by the investigator for obtaining the parent’s informed consent as well 
as the patient's assent must be reviewed and approved by the Sponsor prior to submission to the 
appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with  IRB/IEC 
composition. 
In relation with the population of patients exposed in the trial ie, pediatric/minor patients, the 
IRB/IEC should ensure proper advice from specialist with pediatrics expertise (competent in the 
area of clinical, ethical and psychosocial problems in the field of pediatrics) according to national 
regulations. This should be documented. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, assent, 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. 
IMP will not be released at the study site and the investigator will not start the study before the 
written and dated approval/favorable opinion is received by the investigator and the Sponsor. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATORS 
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 e-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 e-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 assent/parent informed consent form, patient recruitment and follow-up, SAE 
documentation and reporting, AESI documentation and reporting, AE documentation, IMP 
allocation, patient compliance with the IMP regimen, IMP accountability, concomitant therapy 
use and quality of data. 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the e-CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the e-CRF. The informed 
consent form will include a statement by which the parent allows the Sponsor’s duly authorized 
personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records of the patient which support the data on the e-CRFs (eg, patient's medical 
file, patient’s diary entries, 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 e-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. In case of a 
need to use back-up plan for SAE and other investigator Expedited Events reporting process 
eg, due to e-CRF system failure, 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 and parents, 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. 
The investigator and the sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
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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 /sub-investigator 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 
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
• When archiving or processing personal data pertaining to the investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the investigator in compliance with all applicable 
laws and regulations. 
Patients’ race or ethnicity (eg, "Caucasian/white, Black, Asian/Oriental, others") will be collected 
in this study because these data are required by several regulatory authorities (eg, on Afro-
American population for Food and Drug Administration, on Japanese population for the PMDA in 
Japan). 
The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). They may be further 
processed if they have been anonymized. 
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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.  
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. 
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14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio; 
• Patient enrollment is unsatisfactory; 
• The investigator has received from the Sponsor all IMPs, means and information 
necessary to perform the clinical trial and has not included any patient after a reasonable 
period of time mutually agreed upon; 
• 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; 
• 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. 
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 CSR and to provide a summary of study results to 
the investigator. 
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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. 
(electronic 
 
 
 
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Amended Clinical Trial Protocol 02  
23-Aug-2016 
HOE901-EFC13957 -  insulin glargine 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
Page 99 
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 of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
investigator must receive an IRB/IEC approval/favorable opinion concerning the revised informed 
consent form prior to implementation of the change and patient signature should be re-collected if 
necessary. 
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Amended Clinical Trial Protocol 02  
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HOE901-EFC13957 -  insulin glargine 
Version number: 1 
 
Property of the Sanofi Group- strictly confidential 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 
Global IDF/ISPAD Guideline for Diabetes in Childhood and Adolescence; International 
Diabetes Federation. 2011. 
2. 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000284/WC500036082.pdf 
3. 
Investigator's Brochure HOE901, latest Edition. 
4. 
American Diabetes Association; Workgroup on Hypoglycemia. Defining and Reporting 
Hypoglycemia in Diabetes, Diabetes Care. 2005;28(5):1245-49. 
5. 
Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fisch L, et al. Hypoglycemia 
dn diabetes. A report of a workgroup of the American Diabetes Association and the 
Endocrine Society. Diabetes Care. 2013;36(5):1384-95. 
6. 
Standards of Medical Care in Diabetes – 2015; Children and Adolescents. Diabetes Care. 
2015;38(Suppl 1):S70-6. 
7. 
Ziegler R, Heidtmann B, Hilgard D, Hofer S, Rosenbauer J, Holl R, et al. Frequency of 
SMBG correlates with HbA1c and acute complications in children and adolescents with 
type 1 diabetes. Pediatr Diabetes. 2011;12(1):11-7. 
8. 
Clarke W, Jones T, Rewers A, Dunger A, Klingensmith GJ. Assessment and management 
of hypoglycemia in children and adolescents with diabetes. Pediatric Diabetes. 
2009;10(Suppl. 12):134-45. 
9. 
Schwartz GJ, Brion LP, Spitzer A. The use of plasma creatinine concentration for 
estimating glomerular filtration rate in infants, children and adolescents. Pediatr Clin 
North Am. 1987;34(3):571-90. 
10. 
Wolfsdorf JI, Allgrove J, Craig ME, Edge J, Glaser N, Jain V, Lee WW, et al. ISPAD 
Clinical Practice Consensus Guidelines 2014 Compendium. Diabetic ketoacidosis and 
hyperglycemic hyperosmolar state. Pediatr Diabetes. 2014: 15(Suppl 20):154-79. 
11. 
EMA. Guideline on clinical investigation of medicinal products in the treatment or 
prevention of diabetes mellitus. 14 May 2012.CPMP/EWP/1080/00 Rev. 1. 
12. 
US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). 
Guidance for Industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics 
for Guidance for Industry Treatment and Prevention. Draft guidance. 2008 
13. 
Kock GG, Comments on ‘Current issues in non-inferiority trials’. Statist. Med. 
2008;27:333-42. 
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning direct 
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According to template: QSD-002643 VERSION 5.0 (27-JUL-2015) 
Page 1
STATISTICAL ANALYSIS PLAN 
6-Month, Multicenter, Randomized, Open-label, 2-Arm, Parallel-group Study 
Comparing the Efficacy and Safety of a New Formulation of Insulin Glargine and 
Lantus® Injected Once Daily in Children and Adolescents age 6 - 17 years with 
Type 1 Diabetes Mellitus with a 6-month Safety Extension Period 
HOE901-EFC13957 
STATISTICIAN: 
 
BIOSTATISTICS PROJECT LEADER: 
 
DATE OF ISSUE: 20-Apr-2017 
Total number of pages: 
61 
(electronic 1.0)
NCT Number: NCT02735044


Statistical Analysis Plan  
20-Apr-2017 
HOE901-EFC13957 - insulin glargine 
Version number: 1 
Property of the Sanofi Group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN....................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..........................................................................5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN.................................................................................7 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................7 
1.2 
OBJECTIVES...................................................................................................................................7 
1.2.1 
Primary objectives............................................................................................................................7 
1.2.2 
Secondary objectives .......................................................................................................................7 
1.3 
DETERMINATION OF SAMPLE SIZE.............................................................................................8 
1.4 
STUDY PLAN...................................................................................................................................8 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN......................11 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .....................................................................12 
2.1 
ANALYSIS ENDPOINTS................................................................................................................12 
2.1.1 
Demographic and baseline characteristics ....................................................................................12 
2.1.2 
Prior or concomitant medications...................................................................................................14 
2.1.3 
Efficacy endpoints ..........................................................................................................................15 
2.1.3.1 
Primary efficacy endpoint(s)...........................................................................................................16 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................16 
2.1.4 
Safety endpoints.............................................................................................................................17 
2.1.4.1 
Hypoglycemia events .....................................................................................................................17 
2.1.4.2 
Hyperglycemia with ketosis............................................................................................................19 
2.1.4.3 
Adverse events variables ...............................................................................................................19 
2.1.4.4 
Deaths............................................................................................................................................20 
2.1.4.5 
Laboratory safety variables ............................................................................................................20 
2.1.4.6 
Vital signs variables........................................................................................................................20 
2.1.4.7 
Tanner puberty stage variables......................................................................................................21 
2.1.4.8 
Immunogenicity variables...............................................................................................................21 
2.1.5 
Pharmacokinetic variables .............................................................................................................22 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................22 
2.1.7 
Quality-of-life endpoints..................................................................................................................23 
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2.1.8 
Health economic endpoints............................................................................................................23 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................23 
2.2.1 
Randomization and drug dispensing irregularities .........................................................................25 
2.3 
ANALYSIS POPULATIONS ...........................................................................................................26 
2.3.1 
Efficacy populations .......................................................................................................................26 
2.3.1.1 
Intent–to-treat population ...............................................................................................................26 
2.3.2 
Safety population............................................................................................................................26 
2.3.3 
PK population.................................................................................................................................27 
2.4 
STATISTICAL METHODS .............................................................................................................27 
2.4.1 
Demographics and baseline characteristics ..................................................................................27 
2.4.2 
Prior or concomitant medications...................................................................................................27 
2.4.3 
Extent of investigational medicinal product exposure and compliance..........................................28 
2.4.3.1 
Extent of investigational medicinal product exposure ....................................................................28 
2.4.3.2 
Daily insulin doses..........................................................................................................................29 
2.4.3.3 
Compliance ....................................................................................................................................30 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................30 
2.4.4.1 
Analysis of primary efficacy endpoint(s).........................................................................................30 
2.4.4.2 
Analyses of secondary efficacy endpoints .....................................................................................36 
2.4.4.3 
Multiplicity issues............................................................................................................................38 
2.4.4.4 
Additional efficacy analyses ...........................................................................................................39 
2.4.5 
Analyses of safety data ..................................................................................................................39 
2.4.5.1 
Analyses of Hypoglycemia events..................................................................................................40 
2.4.5.2 
Analyses of Hyperglycemia with ketosis ........................................................................................42 
2.4.5.3 
Analyses of adverse events ...........................................................................................................43 
2.4.5.4 
Deaths............................................................................................................................................45 
2.4.5.5 
Analyses of laboratory variables ....................................................................................................45 
2.4.5.6 
Analyses of vital sign variables ......................................................................................................46 
2.4.5.7 
Analyses of Tanner puberty stage measurement ..........................................................................47 
2.4.6 
Analyses of anti-insulin antibody data ............................................................................................47 
2.4.7 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................48 
2.4.8 
Analyses of quality of life/health economics variables ...................................................................49 
2.5 
DATA HANDLING CONVENTIONS...............................................................................................49 
2.5.1 
General conventions ......................................................................................................................49 
2.5.2 
Data handling conventions for secondary efficacy variables..........................................................50 
2.5.3 
Missing data ...................................................................................................................................51 
2.5.4 
Windows for time points.................................................................................................................53 
2.5.5 
Unscheduled visits .........................................................................................................................54 
2.5.6 
Pooling of centers for statistical analyses ......................................................................................55 
2.5.7 
Statistical technical issues .............................................................................................................55 
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Statistical Analysis Plan  
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Page 4 
3 
INTERIM ANALYSIS .....................................................................................................................56 
4 
DATABASE LOCK ........................................................................................................................57 
5 
REFERENCES...............................................................................................................................58 
6 
LIST OF APPENDICES .................................................................................................................59 
APPENDIX A 
EFFICACY MULTIPLE IMPUTATION PROCEDURE FOR HBA1C FOR PRIMARY 
EFFICACY ANALYSIS...................................................................................................................60 
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Statistical Analysis Plan  
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Page 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
american diabetes association 
ADaM: 
Analysis Data Model 
AE: 
adverse event 
AIA: 
anti-insulin antibodies 
ALP: 
alkaline phosphatase 
ALT: 
alanine aminotransferases 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotranferases 
ATC: 
anatomic category class 
BMI: 
body mass index 
CI: 
confidence interval 
CMH: 
Cochran-Mantel-Haenszel 
CSR: 
clinical study report 
e-CRF: 
e-case report form 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end of treatment 
FDA: 
Food and Drug Administration 
GFR: 
glomerular filtration rate 
HbA1c: 
Glycated hemoglobin A1c 
HLGT: 
high-level group term 
HLT: 
high-level term 
IMP: 
investigational medicinal product 
ISPAD: 
International Society for Pediatric and Adolescent Diabetes 
ITT: 
intent-to-treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
KM: 
Kaplan-Meier 
MCMC: 
Markov Chain Monte Carlo 
MedDRA: 
Medical Dictionary for Regulatory Activities 
NIMP: 
non-investigational medical product 
PCSA: 
potentially clinically significant abnormality 
PK: 
pharmacokinetics 
PKDM: 
pharmacokinetics, dynamics and metabolism 
PT: 
preferred term 
ROW: 
rest of the world 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SAS: 
statistical analysis system 
SD: 
standard deviation 
SE: 
standard error 
SEM: 
standard error of the mean 
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Statistical Analysis Plan  
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Page 6 
SMPG: 
self-measured plasma glucose 
SMQ: 
standardized medDRA query 
SOC: 
system organ class 
T1DM: 
type 1 Diabetes Mellitus 
TEAE: 
treatment-emergent adverse event 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
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Statistical Analysis Plan  
20-Apr-2017 
HOE901-EFC13957 - insulin glargine 
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Page 7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN   
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is an open-label, 1:1 randomized, active-controlled, 2-arm parallel-group, multicenter 
international, phase 3b study comparing HOE901-U300 versus Lantus in children and adolescents 
with T1DM. Patients will continue their fast-acting mealtime insulin analogue during the study. 
Randomization will be stratified by age group (<12 years and ≥12 years) and by HbA1c (<8.5% 
and ≥8.5%) at screening. Inclusion in the study is configured to ensure at least 30% of participants 
in the age range below 12 years. 
At the end of the screening period, eligible patients will be randomized to one of the two treatment 
groups: HOE901-U300 or Lantus. 
Approximately 450 patients (225 patients per treatment group) will be randomized from 
approximately 109 sites. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate the non-inferiority of a new formulation of 
insulin glargine (HOE901-U300) to Lantus in terms of change of HbA1c from baseline to 
endpoint (Month 6) in children and adolescents age 6-17 years with type 1 diabetes mellitus 
1.2.2 Secondary objectives 
• 
To compare HOE901-U300 and Lantus in terms of: 
- 
Percentage of patients reaching target HbA1c (<7.5%) at Month 6 overall and without 
any episode of severe and/or documented hypoglycemia during last 3 months of the 
main 6-month randomized period, 
- 
Change from baseline to endpoint (Month 6) in fasting plasma glucose (central 
laboratory), 
- 
Percent of patients reaching target FPG value (≤130 mg/dL [7.2 mmol/L]) at Month 6 
overall and without any episode of severe and/or documented hypoglycemia during the 
last 3 months of the main 6-month randomized period, 
- 
Change in mean self-monitored plasma glucose (8-point SMPG profiles per time-point 
[pre-prandial and 2-hour postprandial plasma glucose at breakfast, lunch and dinner, 
bedtime plasma glucose, nocturnal plasma glucose], 24-hour mean plasma glucose, 
variability of 24-hour mean plasma glucose) from baseline to Month 6. 
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Statistical Analysis Plan  
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• 
To assess the safety of HOE901-U300 including analysis of events of hypoglycemia, 
events of hyperglycemia with ketosis and development of anti-insulin-antibodies. 
• 
To assess the extent of accumulation and metabolism of HOE901-U300 versus Lantus in 
this age group. 
1.3 
DETERMINATION OF SAMPLE SIZE 
The sample size calculation is based on the primary efficacy variable of HbA1c change from 
baseline to Month 6/Week 26. 
A sample size of 450 randomized patients (225 for HOE901-U300 and 225 for Lantus) will ensure 
that the upper bound of the two-sided 95% confidence interval (CI) for the adjusted mean 
difference between HOE901-U300 and Lantus would not exceed a non-inferiority margin of 0.3% 
with 92% power. This calculation assumes a common standard deviation (SD) of 0.95%, with a 
one-sided test at the 2.5% significant level and a true difference of zero in HbA1c between 
treatment groups. 
Calculations were made using East® Software Version 6.3. 
1.4 
STUDY PLAN 
The following figure describes the design of the study: 
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Statistical Analysis Plan  
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Page 9 
 
The study consists of: 
• 
A 2-week screening period. 
• 
A 6-month comparative efficacy and safety treatment period. 
• 
A 6-month comparative safety extension period. 
• 
A 4-week post-treatment follow up period. 
In case of premature permanent discontinuation of study treatment, patients will be asked to 
continue attending study visits and undergo assessments according to the schedule until the 
planned end of study treatment (Month 12), including assessments normally scheduled for the  
4-week post-treatment follow up period. As a minimum, visit at Week 26/Visit 14 (assessments of 
primary and secondary efficacy endpoints) should be conducted. For safety considerations, 
patients/parents who withdraw consent for further participation in the study, at the minimum 
should be contacted 2 days after last intake of the IMP. 
In total the study duration per patient will be approximately 58 weeks (2 weeks of screening + 
52 weeks of treatment + 4 weeks of post-treatment follow up). 
(electronic 
 
 
 
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Statistical Analysis Plan  
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Page 10 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes made after study start (after the first patient was enrolled). 
There are no planned interim analyses. 
Table 1 - Protocol amendment statistical changes 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
2 
23-Aug-2016 
FDA recommendation 
Mixed-effect model with repeated measures 
(MMRM) for the analysis of the primary and 
secondary endpoints is replaced by a multiple 
imputation approach where missing data from 
subjects who do not adhere to therapy are 
represented by the data from those subjects 
on the same arm that also did not adhere to 
therapy but had the measurement for the 
primary endpoint. Change to statistical 
methodology in primary and secondary 
endpoint analyses sections 
2 
23-Aug-2016 
Correction of software used for 
sample size calculation 
nQuery Advisor® Software Version 7.0. 
replaced by East® Software Version 6.3. 
2 
23-Aug-2016 
Clarification of baseline definition for 
efficacy variables  
Definition of baseline for efficacy variables is 
defined in the SAP as the last available value 
obtained up to the date and time of 
randomization or up to the time of first 
injection of IMP if occurred at the day of 
randomization 
2 
23-Aug-2016 
BfArM requests 
The objective of non-inferiority testing is 
clearly and more prominently presented in 
section 1.2.1 Primary objectives. 
 
Data from the extension period relative to 
efficacy will be analyzed and the 
corresponding endpoints are clearly added in 
the section 2.1.3.2 Secondary efficacy 
endpoints 
2 
23-Aug-2016 
Modifications for clarification 
The key sensitivity analysis in the protocol is 
renamed supportive analysis in the SAP and 
the text is updated for clarification 
2 
23-Aug-2016 
Deletion of penalized multiple 
imputation analysis as it is included in 
the tipping-point analysis for the 
sensitivity analysis of the primary 
efficacy analysis 
The sensitivity analysis, penalized multiple 
imputation analysis, is deleted 
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Statistical Analysis Plan  
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Page 11 
Amendment  
Number 
Date 
Approved 
Rationale 
Description of statistical changes 
2 
23-Aug-2016 
Modification for consistency with the 
primary efficacy analysis 
Imputation models in the tipping-point analysis 
include change from baseline HbA1c at post-
baseline time points instead of HbA1c value 
for consistency with primary efficacy analysis 
2 
23-Aug-2016 
Correction 
PK population is updated as below: “All 
patients randomized and treated patients who 
provided at least one PK measurement will be 
included in the PK population “ 
2 
23-Aug-2016 
Correction for more relevant analyses 
Analyses of hypoglycemia planned in the 
protocol on severe and/or documented 
symptomatic hypoglycemia are planned in the 
SAP on severe and/or documented 
hypoglycemia (“symptomatic” deleted) 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable 
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Page 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES 
Any technical details related to computation, dates and imputation for missing dates are described 
in Section 2.5. 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The baseline value is defined generally as the last available value obtained up to the date and time 
of randomization or up to the time of first injection of IMP if occurred at the day of 
randomization. 
All baseline safety and efficacy parameters (apart from those listed below) are presented along 
with the summary statistics in the safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic and disease characteristics at baseline will be provided overall and by randomization 
stratum of age at screening (<12 years and ≥12years). 
Demographic characteristics 
Demographic characteristics at baseline 
• 
Age (years). 
• 
Randomization strata of age group (<12, ≥ 12 years of age). 
• 
Randomization strata of screening HbA1c categories (<8.5; ≥8.5%). 
• 
Gender (Male, Female). 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Japanese, Not reported, Unknown). 
• 
Ethnicity (Hispanic, not Hispanic, Not reported, Unknown). 
• 
Regions (North America, South/Latin America, Western Europe, Eastern Europe, Rest of 
the World (ROW)) / Countries. 
• 
Body height (cm). 
• 
Body weight (kg). 
• 
Body Mass Index (kg/m²) percentile (1). 
• 
BMI percentile categories: <5th percentile; 5th-<85th percentile; 85th-<95th percentile; ≥95th 
percentile. 
• 
Tanner puberty stage evaluation (pre-pubertal, adolescent, adult). 
• 
For girls, postmenarchal status (Yes/No). 
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Page 13 
• 
Estimated glomerular filtration rate (eGFR, using Schwartz formula (2, 3), 
mL/min/1.73m²), 
• 
Estimated GFR categories (mL/min/1.73m2):  
- 
≥90; [60 – 90[; [30 – 60[; <30. 
- 
<30; [30-60[; ≥60 
Medical or surgical history 
All medical/surgical history information (including allergies, diabetic ketoacidosis, diabetic 
complications, history of seizure/coma and/or hospitalization due to severe hypoglycemia), will be 
coded to a “lower level term (LLT), “preferred term (PT), “high level term (HLT)”, “high level 
group term (HLGT)” and associated primary “system organ class (SOC) using the version of 
Medical Dictionary for Regulatory Activities (MedDRA) currently in effect at Sanofi at the time 
of database lock. 
Disease characteristics at baseline   
Diabetes history will include:  
• 
Duration of diabetes (years). 
• 
Category of duration of diabetes (<2; [2 - 5[; ≥5 years). 
• 
Age (years) at onset of diabetes. 
• 
Antibody (GAD2, Insulinoma-Associated Protein 2, Islet Cell 512 antibodies)) status at 
diagnosis (positive, negative). 
• 
C-peptide at diagnosis (positive, negative). 
• 
Previous basal insulin treatment: 
- 
Daily dose (U and U/kg) = median of previous basal insulin daily doses during the last 
3 days prior to the first IMP (or prior to randomization for not treated patients), 
- 
Daily injection number (once daily, twice daily, more than twice daily), 
- 
Product, for last 3 month before visit 1 only, (insulin glargine, insulin detemir, NPH, 
other); daily dose and daily injection number will be provided by product too. 
• 
Previous mealtime insulin treatment: 
- 
Daily dose (U and U/kg) = median of previous mealtime insulin daily doses during the 
last 3 days prior to the first IMP (or prior to randomization for not treated patients),  
- 
Product; daily dose will be provided by product too. 
• 
Previous total insulin treatment:  
- 
Daily dose (U and U/kg): sum of previous basal plus mealtime, during the last 3 days 
prior to the first IMP (or prior to randomization for not treated patients). 
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Statistical Analysis Plan  
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Page 14 
• 
Previous anti-hyperglycemic treatment other than insulin within 3 months prior to first 
IMP: 
- 
Previous anti-hyperglycemic treatment by chemical class. 
• 
History of acute and chronic diabetic complications will be collected via the standard 
medical history form. 
Baseline efficacy data 
The baseline value for efficacy variables is the last available value obtained up to the date and 
time of randomization or up to the time of first injection of IMP if occurred at the day of 
randomization. 
The following baseline efficacy data will be provided: 
• 
HbA1c (% and mmol/mol). 
• 
FPG (mmol/L and mg/dL). 
• 
Mean of SMPG (mmol/L and mg/dL) from 8-point profiles measured on a 24-hour period, 
and SMPG per time-point. 
• 
Average pre-breakfast SMPG (mmol/L and mg/dL) = mean of pre-breakfast (fasting) 
SMPG values in the last 7 days prior the 1st IMP (see Section 2.5.3 for handling of missing 
data). 
Insulin dose at baseline 
• 
Basal insulin daily dose at baseline (U and U/kg) = intended dose reported in the e-CRF. 
• 
Mealtime insulin daily dose at baseline (U and U/kg) = median of mealtime insulin daily 
doses of the 3 first days from the first IMP. The first mealtime insulin daily dose is 
identified by the start date reported on the visit 4 form for the IMP exposure in the e-CRF. 
• 
Total insulin daily dose at baseline (U and U/kg) = intended dose of basal insulin plus 
median of mealtime insulin daily dose. 
Smoking/alcohol habits 
• 
Tobacco habits (never, current, former, including the average number of cigarettes per 
day). 
• 
Alcohol habits (never, occasional, at least monthly, at least weekly, at least daily) 
including the number of daily standard drink (1 or 2, >2). 
2.1.2 Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
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• 
Prior medications are those the patient used within 3 months before screening and from 
screening to first investigational medicinal product (IMP) intake. Prior medications can be 
discontinued before first administration or can be ongoing during treatment phase.  
• 
Concomitant medications are any treatments received by the patient concomitantly to the 
IMP, from first injection of IMP to the last injection of IMP + 2 days (or 0 day for  
anti-diabetic therapies). A given medication can be classified both as a prior medication 
and as a concomitant medication. 
• 
Post-treatment medications are those the patient took in the period running from the last 
injection of IMP + 3 days (or 1 day for anti-diabetic therapies) to the end of the study. 
Anti-diabetic medications will be identified by a pre-defined list of ATC codes provided in the 
ADaM metadata. 
2.1.3 Efficacy endpoints 
The baseline value for efficacy variables is the last available value obtained up to the date and 
time of randomization or up to the time of first injection of IMP if occurred at the day of 
randomization. 
In case of premature permanent IMP discontinuation, the process described in Section 2.5.4 will 
be applied to retrieve efficacy assessments performed at the end of treatment visit. 
Observation period for efficacy endpoints 
• 
The main 6-month randomized period for efficacy variables is defined as the time from 
randomization up to Month 6 (Visit 14) for randomized patients, regardless of study 
treatment discontinuation. 
• 
The 12-month randomized period for efficacy variables is defined as the time from 
randomization date up to Month 12 (Visit 18) for randomized patients, regardless of study 
treatment discontinuation. 
• 
The main 6-month on-treatment period for efficacy variables is defined as the time from 
the first dose of IMP up to Month 6 (visit 14) or, in case of premature treatment 
discontinuation before Month 6, up to: 
- 
7 days after the last dose of IMP for HbA1c, 
- 
2 days after the last dose of IMP for hypoglycemia, 
- 
1 day after the last dose of IMP for FPG and SMPG value. 
• 
The 12-month on-treatment period for efficacy variables is defined as the time from the 
first dose of IMP up to: 
- 
7 days after the last dose of IMP for HbA1c, 
- 
2 days after the last dose of IMP for hypoglycemia, 
- 
1 day after the last dose of IMP for FPG and SMPG value. 
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2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy variable is the change in HbA1c from baseline to Week 26 which is defined 
as: HbA1c value at Week 26 – HbA1c value at baseline (%) in the ITT population, using all 
HbA1c values regardless of adherence to treatment (ITT estimand). Results for the primary 
efficacy variable will also be presented in mmol/mol. 
2.1.3.2 Secondary efficacy endpoint(s) 
All secondary endpoints are calculated on the main 6-month randomized period using the ITT 
population (ITT estimand). 
• 
Percentage of patients with HbA1c values of <7.5% at Week 26. 
• 
Percentage of patients with HbA1c values of <7.5% at Week 26 without any episode of 
severe and/or documented (SMPG <54 mg/dL; 3.0 mmol/L) hypoglycemia during the last 
3 months of the main 6-month randomized period (from randomization date up to Month 6 
(Visit 14), regardless of study treatment discontinuation). 
• 
Change in FPG from baseline to Week 26 (central laboratory). 
• 
Percentage of patients with fasting plasma glucose (FPG) ≤130 mg/dL (7.2 mmol/L) at 
Week 26. 
• 
Percentage of patients with fasting plasma glucose (FPG) ≤130 mg/dL (7.2 mmol/L) at 
Week 26 without any episode of severe and/or documented (SMPG <54 mg/dL; 
3.0 mmol/L) hypoglycemia during the last 3 months of the main 6-month randomized 
period. 
• 
Change in 24-hour mean plasma glucose based on 8-point SMPG profiles from baseline to 
Week 26. 
• 
Change in variability of 24-hour mean plasma glucose based on 8-point SMPG profiles 
from baseline to Week 26 (the variability being assessed by the mean of coefficient of 
variation calculated over the 8-point SMPG). 
• 
Change in 8-point self-monitored plasma glucose (SMPG) profiles per time-point from 
baseline to Week 26 (pre-prandial and 2-hour postprandial plasma glucose at breakfast, 
lunch and dinner, bedtime plasma glucose, nocturnal plasma glucose). 
The change in average pre-breakfast SMPG from baseline to Week 26 will be analyzed as 
additional exploratory secondary efficacy endpoint. 
For descriptive purpose, all secondary endpoints will be evaluated at end of the 12-month 
randomized period, ie, at Week 52. They will be also evaluated at intermediary timepoints 
(Week 12, Week 20, Week 38) when applicable. 
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2.1.4 Safety endpoints 
The safety analysis will be based on hypoglycemia events, injection site reactions, hypersensitivity 
reactions, hyperglycemia with ketosis, adverse events and other safety information, such as 
clinical laboratory data, vital signs. 
In case of premature permanent IMP discontinuation, the process described in Section 2.5.4 will 
be applied to retrieve safety assessments performed at the end of treatment visit. 
Observation period of safety endpoints 
The observation period of safety data will be divided as follows: 
• 
The pre-treatment period is defined as the time between the date of the informed consent 
and the first injection of IMP. 
• 
The main 6-month TEAE period is defined as the time from the first injection of open 
label IMP up to Month 6/ Week 26 (visit 14) or up to 2 days after the last injection of IMP, 
whichever comes earlier. 
• 
The 12-month TEAE period is defined as the time from the first injection of IMP up to 
2 days after the last injection of IMP. 
• 
The post-treatment period is defined as the time starting 3 days after last injection of IMP 
(after the TEAE period). 
The on-study observation period is defined as the time from start of treatment until the end of the 
study (defined as last protocol planned visit or the resolution/stabilization of all serious adverse 
events and adverse events of special interest). 
2.1.4.1 Hypoglycemia events 
Hypoglycemia events will be categorized as follows using the criteria published by the ADA (4, 5) 
and ISPAD (6): 
• 
Severe hypoglycemia 
Severe hypoglycemia is defined as the child/adolescent having altered mental status and cannot 
assist in their care, is semiconscious or unconscious, or in coma ± convulsions and may require 
parenteral therapy (glucagon or glucose). 
• 
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). 
• 
Asymptomatic hypoglycemia 
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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 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 child/adolescent with diabetes reports any of 
the typical symptoms of hypoglycemia, but with a measured plasma glucose concentration greater 
than 70 mg/dL (3.9 mmol/L); symptoms are relieved with a countermeasure. 
The composite category of severe and/or documented (≤70 mg/dL; 3.9 mmol/L) hypoglycemia 
will be presented too. 
In addition to the threshold of ≤70 mg/dL (3.9 mmol/L), the following hypoglycemia categories 
will be also evaluated for the more stringent SMPG threshold of <54 mg/dL (3.0 mmol/L): 
documented symptomatic hypoglycemia; asymptomatic hypoglycemia; severe and/or documented 
hypoglycemia. 
Hypoglycemia episodes will be analyzed regardless of the time of onset and in the following time 
periods defined by time of the day: 
• 
Nocturnal hypoglycemia (defined by time of the day): any hypoglycemia that occurs 
between 00:00 and 05:59 a.m. hours, regardless whether patient was awake or woke up 
because of the event. 
• 
Daytime hypoglycemia (defined by time of the day): any hypoglycemia that occurs 
between 6:00 a.m. to 23:59. 
• 
Nocturnal hypoglycemia (defined by sleep status): any hypoglycemia waking the patient up 
from sleep after having gone to bed in the evening and before getting up in the morning 
(ie, before the morning determination of fasting pre-breakfast SMPG and before 
administration of insulin (IMP or NIMP). 
Some analyses will be also performed by distribution by hour of the day (0:00-23:59). 
Hypoglycemia episodes will be also analyzed according the following periods:  
• 
For the 6-month CSR: 
- 
6-month TEAE period,  
- 
From first injection of IMP to end of Week 8,  
- 
From start of Week 9 to Month 6. 
• 
for the 12-month CSR: 
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- 
12-month TEAE period.  
- 
Post-treatment period (4-week follow-up). 
Some analyses will be also performed by monthly rates. 
All hypoglycemia events reported by the investigator as severe and/or reported as serious adverse 
events including those with seizure, loss of consciousness, coma and/or events treated with iv 
glucose or glucagon will be independently reviewed under blinded conditions by the External 
Endpoint Assessment Committee. The result of this external review of severe hypoglycemia 
classification will be analyzed separately. 
2.1.4.2 Hyperglycemia with ketosis 
Hyperglycemia with ketosis data will be analyzed according to the two definitions: 
• 
Self-measured blood ketones ≥1.5 mmol/L. 
• 
Self-measured plasma glucose ≥252 mg/dL (14 mmol/L) and self-measured blood ketones 
≥1.5 mmol/L. 
Ketosis/ ketoacidosis related adverse events will be identified using MedDRA searches listed in 
the ADaM metadata. 
Hyperglycemia with ketosis analyses will be performed according the following periods:  
• 
For the 6-month CSR: 
- 
6-month TEAE period. 
• 
For the 12-month CSR: 
- 
12-month TEAE period,  
- 
Post-treatment period (4-week follow-up). 
2.1.4.3 Adverse events variables 
Adverse event observation period  
• 
Pre-treatment adverse events are adverse events that developed or worsened or became 
serious from the signed informed consent date up to first administration of IMP. 
• 
Treatment-emergent adverse events are adverse events that developed or worsened or 
became serious during the treatment-emergent adverse event period. 
• 
Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period. 
All adverse events will be coded to a “Preferred Term” (PT) and “High Level Group 
Term”(HLGT), “High Level Term” (HLT) and primary “System Organ Class” (SOC) using the 
version of MedDRA currently in use by the sponsor at the time of database lock. 
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Injection site reaction adverse events and hypersensitivity reactions adverse events will be 
identified using MedDRA searches listed in the ADaM metadata. 
Adverse events of special interest include: 
• 
Symptomatic overdose (accidental or intentional) with IMP/NIMP (event suspected by the 
investigator or spontaneously notified by the patient/parent [not based on systematic drug 
accountability]). 
• 
ALT increase (>=3 ULN or >2 times the baseline value). 
• 
Pregnancy. 
2.1.4.4 Deaths 
The deaths observation period are per the observation periods defined above.  
• 
Death on-study:  deaths occurring during the on-study observation period. 
• 
Death on-treatment:  deaths occurring during the treatment-emergent adverse event period. 
• 
Death post-study:  deaths occurring after the end of the study.  
2.1.4.5 Laboratory safety variables 
The following laboratory safety variables will be analyzed: 
• 
Hematology:  
- 
Red blood cells and platelets erythrocytes, hemoglobin, hematocrit, leukocytes and 
platelets, 
- 
White blood cells:  differential blood count (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils). 
• 
Clinical chemistry: 
- 
Electrolytes: sodium, potassium, calcium, chloride, 
- 
Renal function: creatinine, eGFR (Schwartz formula), 
- 
Liver function: total bilirubin, AST (Aspartate aminotransferase), ALT (Alanine 
aminotransferase), ALP (Alkaline phosphatase). 
• 
C-peptide (Visit 3, Day 1); 
Technical formulas are described in Section 2.5.1. 
2.1.4.6 Vital signs variables 
Vital signs include:  BMI percentile, systolic and diastolic blood pressure (mmHg) and heart rate 
(beats per minute). 
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2.1.4.7 Tanner puberty stage variables 
Tanner puberty stage (pre-pubertal, adolescent, adult) will be analyzed. 
2.1.4.8 Immunogenicity variables 
The evaluation of anti-insulin antibodies (AIA), corresponding more specifically to anti-insulin 
glargine antibodies, will consist of: 
• 
AIA status: positive/negative/ inconclusive. 
• 
AIA titer. 
• 
Cross-reactivity to Human insulin: positive/negative/not evaluable. 
• 
Pre-existing, treatment-induced, treatment-boosted. 
• 
Relationship (yes or likely, no or unlikely) provided by the committee of experts, 
establishing the relationship of AIA to potential indicators of insulin resistance or to 
hypersensitivity events in patients with treatment-induced or treatment-boosted AIA. 
Definitions of potential indicators of insulin resistance, hypersensitivity events are 
provided in the Operation Manual for Blinded External Endpoint Assessment Committee 
of the study. 
The following definitions will be used to identify patients with a change in AIA response during 
the on-treatment period (7): 
• 
Patients with treatment-induced AIAs are defined as patients with AIAs that are developed 
de novo (seroconversion) following the IMP administration (ie, patients with at least one 
positive AIA sample at any time during the on-treatment period, in those patients without 
pre-existing AIA or with missing baseline sample). 
• 
Patients with treatment-boosted AIAs are defined as patients with pre-existing AIAs that 
are boosted to a significant higher titer following the IMP administration (ie, patients with 
at least one AIA sample with at least a 4-fold increase in titers compared to baseline value 
at any time during the on-treatment period, in those patients with pre-existing AIA). 
Patients with treatment-emergent AIA (Yes, No) will be derived as follows: 
• 
Patients with treatment-emergent AIAs (AIA incidence) are defined as patients with 
treatment-induced or treatment-boosted AIAs. 
• 
Patients without treatment-emergent AIAs are defined as patients without 
treatment-induced or treatment-boosted AIAs. 
• 
Inconclusive patients (patients who could not irrefutably be classified as patients without 
treatment-emergent AIAs are not included in the above categories and are listed separately. 
Treatment-emergent AIAs at last on-treatment value (Yes, No) is also derived, using the same 
definitions based on results obtained at the last on-treatment visit (ie, taking into account the 
closest value prior to the last dose of IMP). 
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For patients with treatment-induced and treatment-boosted AIAs, the peak titer is defined as the 
maximal titer observed during the on-treatment period and the kinetics of AIA response is further 
classified as follows: 
• 
Transient AIA response, defined as a response detected only at one sampling time point 
during the on-treatment period (excluding the last sampling time point); or response 
detected at two or more sampling time points during the on-treatment period, where the 
first and last AIA-positive samples (irrespective of any negative samples in between) are 
separated by a period less than 16 weeks, and the patient’s last sampling time point is  
AIA-negative. 
• 
Persistent AIA response, defined as a response detected at two or more sampling time 
points during the on-treatment period, where the first and last AIA-positive on-treatment 
sample (irrespective of any negative samples in between) are separated by at least 
16 weeks; or response detected in the last two sampling time points, irrespective of the 
time period in between. 
• 
Indeterminate AIA response, defined as a response where only the last sampling time point 
is positive and all previous samples are negative. 
2.1.5 Pharmacokinetic variables 
The plasma concentration of insulin glargine will be analyzed by the six time points based on 
relative time from PK date/time to last IMP injection date/time. The analyses windows considered 
for the analyses are provided in Section 2.5.4. 
 
Basal insulin dosing 
regimen 
Time point 
Pre-dose 
4h post-dose 
Morning 
8h post-dose 
 
 
12h post-dose 
16h post-dose 
Evening 
20h post-dose 
 
2.1.6 Pharmacodynamic/genomics endpoints 
Not applicable 
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2.1.7 Quality-of-life endpoints 
Not applicable 
2.1.8 Health economic endpoints 
Not applicable. 
2.2 
DISPOSITION OF PATIENTS 
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Randomized patients consist of all screened patients with a randomized treatment allocated and 
recorded in the IVRS/IWRS database, regardless of whether the treatment kit was used or not. 
The total number of patients for each of the following categories will be presented in the CSR of 
the main 6-month period and in the CSR of the 12-month study period separately, using a  
flow-chart diagram or summary tables: 
• 
Screened patients: all patients who have originally met inclusion criteria and have signed 
the informed consent. 
• 
Screen failure patients and reason for screen failure. 
• 
Randomized patients: all screened patients with a treatment arm allocated and recorded in 
the IVRS/IWRS database, regardless of whether the treatment was used or not. 
• 
Treated but not randomized patients. 
• 
Randomized but not treated patients. 
• 
Randomized and treated patients. 
• 
The intent-to-treat (ITT) population (as defined in Section 2.3.1.1, analyzed as 
randomized): 
- 
The randomization strata (screening HbA1c categories [<8.5%, ≥8.5%] and age group 
at screening visit [<12 years and ≥12 years] assigned by IVRS/IWRS will be 
summarized. The discrepancy between the strata assigned by IVRS/IWRS and the 
information reported on e-CRF will be listed for all randomized patients. 
• 
Disposition for the main 6-month period: 
- 
Patients who completed the main 6-month treatment period (patients who have 
performed Visit 14 [Week 26] and who did not permanently discontinue treatment), 
- 
Patients who completed the main 6-month study period (patients who have performed 
Visit 14 [Week 26]), 
- 
Patients who permanently discontinued the IMP during the main 6-month treatment 
period, and the reasons for permanent treatment discontinuation, 
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- 
Patients who permanently discontinued the study during the main 6-month period, and 
the reasons for permanent study discontinuation, 
- 
Patient's decision for treatment discontinuation decision for treatment discontinuation 
during the main 6-month period, 
- 
Status at last study contact of patients who permanently discontinued the treatment 
during the main 6-month period. 
• 
Disposition for the main 12-month period: 
- 
Patients who completed the 12-month treatment period (patients who have performed 
Visit 18 [Week 52] and who did not permanently discontinue treatment), 
- 
Patients who completed the main 12-month study period (patients who have performed 
Visit 18 [Week 52]), 
- 
Patients who permanently discontinued the IMP during the 12-month treatment period, 
and the reasons for permanent treatment discontinuation, 
- 
Patients who permanently discontinued the study during the 12-month period, and the 
reasons for permanent study discontinuation, 
- 
Patient's decision for treatment discontinuation decision for treatment discontinuation 
during the main 12-month period, 
- 
Status at last study contact of patients who permanently discontinued the treatment 
during the main 12-month period. 
For all categories of patients except the screened, screened failure and treated not randomized 
patients, percentages will be calculated using the number of randomized patients as denominator 
for different treatment groups. 
Patients with the following deviations will be identified and described in separate listings 
• 
Treated but not randomized. 
• 
Randomized but not treated. 
• 
Randomized but not treated as randomized. 
A list of patients who prematurely discontinued the treatment, along with reasons for 
discontinuation, will be provided. 
Kaplan-Meier (KM) plots/estimates of the cumulative incidence of IMP discontinuation due to 
any reason, or due to AE, will be provided for the main 6-month and for the 12-month  
on-treatment period separately. Time to treatment discontinuation will be defined as the number of 
days from the first dose of IMP until the day of treatment discontinuation. All completers will be 
considered as censored observations. The censoring time will be the number of days from the first 
dose of IMP until the last dosing date. 
Additionally, the analysis populations for safety, efficacy and PK will be summarized in a table by 
number of patients on the randomized population. 
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• 
Efficacy population: intent-to-treat (ITT) population. 
• 
Safety population. 
• 
PK population. 
2.2.1 Randomization and drug dispensing irregularities 
Randomization and drug-dispensing irregularities occur whenever: 
1. A randomization is not in accordance with the protocol-defined randomization method, 
such as a) an ineligible patient is randomized, b) a patient is randomized based on an 
incorrect stratum, c) a patient is randomized twice, or d) in a dynamic randomization 
scheme the treatment assignment is, in fact, not random, due to a computer program error, 
OR 
2. A patient is dispensed an IMP kit not allocated by the protocol-defined randomization, 
such as a) a patient at any time in the study is dispensed a different treatment kit than as 
randomized (which may or may not contain the correct-as-randomized IMP), or b) a 
nonrandomized patient is treated with IMP reserved for randomized patients. 
Randomization and drug-dispensing irregularities will be monitored throughout the study and 
reviewed on an ongoing basis.  
All randomization and drug-dispensing irregularities will be documented in the clinical study 
report. If the number of irregularities is large enough to make a tabular summary useful, the 
irregularities will be categorized and summarized among randomized patients (number and 
percentages). Nonrandomized, treated patients will be described separately. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are not 
limited to:  
 
Randomization and drug allocation irregularities 
Kit dispensation without IVRS transaction 
Erroneous kit dispensation 
Kit not available 
Randomization by error 
Patient randomized twice 
Forced randomization 
Stratification error 
Patient switched to another site 
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2.3 
ANALYSIS POPULATIONS 
Patients who are dispensed study drug without calling the IVRS or before calling the IVRS are 
considered nonrandomized patients.  They are excluded from any population for analysis, 
including safety.  However, if these patients experienced any significant safety event, they should 
be documented separately in the clinical study report. 
The randomized population includes any patient who has been allocated to a randomized 
treatment regardless of whether the treatment kit was used. 
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. 
2.3.1 Efficacy populations 
The primary efficacy analysis population will be the intent-to-treat (ITT) population, as defined in 
the protocol. 
2.3.1.1 Intent–to-treat population 
The ITT population includes all randomized patients regardless of whether a treatment kit was 
used, and analyzed according to the treatment group allocated by randomization. 
2.3.2 Safety population 
The safety population is defined as the randomized population who actually received at least 
1 dose or part of a dose of the 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. 
In addition:  
• 
Nonrandomized but treated patients will not be part of the safety population; however, 
their safety data will be presented separately. 
• 
Randomized patients for whom it is unclear whether they took the IMP will be included in 
the safety population and analyzed according to the randomized treatment. 
• 
Patients receiving more than 1 IMP during the trial will be analyzed in the treatment group 
in which he/she was treated longer. 
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2.3.3 PK population 
All patients randomized and treated patients who provided at least one PK measurement will be 
included in the PK population. 
2.4 
STATISTICAL METHODS 
Continuous data will be summarized by treatment group using the number of available 
observations (N), mean, standard deviation (SD), minimum, median and maximum. 
Categorical and ordinal data will be summarized using the number and percentage of patients in 
each treatment group. 
In general, descriptive statistics of quantitative efficacy and safety parameters (result and change 
from baseline) by scheduled post-baseline visits will be provided on observed cases, ie, the 
inclusion of only patients having non-missing assessments at a specific visit. All statistical 
analyses (descriptive statistics, plots, and statistical models) will be performed on visits defined 
using the time windows provided in Section 2.5.4. 
2.4.1 Demographics and baseline characteristics 
Parameters will be summarized on the randomized population and analyzed in the treatment group 
to which patients were randomized.  
Parameters described in Section 2.1.1 will be summarized by treatment group and overall 
treatment groups, using descriptive statistics. 
Medical/surgical history will be classified into primary system organ class (SOCs) and HLTs 
using MedDRA and will be summarized by treatment groups. Events will be sorted by SOC 
internationally agreed order and decreasing frequency of HLT based on incidence in the overall 
treatment group. 
P-values on demographic and baseline characteristic data will not be calculated. 
2.4.2 Prior or concomitant medications 
The prior, concomitant and post-treatment medications will be presented for the randomized 
population separately for anti-diabetic medications and other (i.e non-anti-diabetic) medications.  
Medications will be summarized by treatment group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the first 
3 digits of the ATC class (therapeutic category).  All ATC codes corresponding to a medication 
will be summarized, and patients will be counted once in each ATC category (anatomic or 
therapeutic) linked to the medication. Therefore patients may be counted several times for the 
same medication.  
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The tables for prior other medications will be sorted by decreasing frequency of anatomic class 
followed by therapeutic class (ATC2) based on the overall incidence across treatment groups. In 
case of equal frequency, alphabetical order will be used. 
The table for prior anti-diabetic medications will be sorted by decreasing frequency of 
pharmacological class (ATC3) followed by chemical class (ATC4) and standardized medication 
name based on the overall incidence across treatment groups. In case of equal frequency, 
alphabetical order will be used. 
The tables for concomitant and post-treatment other medications will be sorted by decreasing 
frequency of anatomic class followed by therapeutic class (ATC2) based on the incidence in the 
HOE901-U300 group. In case of equal frequency, alphabetical order will be used. 
The tables for concomitant and post-treatment anti-diabetic medications will be sorted by 
decreasing frequency of pharmacological class (ATC3) followed by chemical class (ATC4) and 
standardized medication name based on the incidence in the HOE901-U300 group. In case of 
equal frequency, alphabetical order will be used. 
Frequency statistics including number of patients and percentage will be provided. No statistical 
test for the between-group difference will be performed. 
The prohibited medications will be presented by prohibited medication category as defined in 
deviation and by standardized medication name. 
Medications will be presented for the main 6-month and for the 12-month study period separately. 
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of IMP exposure and compliance will be assessed and summarized by actual treatment 
in the safety population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure 
The extent of IMP exposure will be assessed by the duration of IMP exposure. 
The duration of exposure to the IMP during the study will be the total number of days of 
administration of IMP, ignoring temporary drug discontinuation (see Section 2.5.1 for calculation 
in case of missing or incomplete data), and is defined as: 
(Date of the last IMP administration – date of the first IMP administration) + 1 
Duration of IMP exposure will be summarized descriptively as a quantitative variable (number, 
mean, SD, median, minimum, and maximum). In addition, duration of treatment exposure will 
also be summarized categorically by numbers and percentages for each of the following categories 
and cumulatively according to these categories: 
• 
Up to 2 weeks. 
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• 
>2 to 4 weeks. 
• 
>4 to 8 weeks. 
• 
>8 to 12 weeks. 
• 
>12 to 16 weeks. 
• 
>16 to 20 weeks. 
• 
>20 to 25 weeks. 
• 
>25 to 26 weeks. 
• 
>26 to 38 weeks. 
• 
>38 to 51 weeks. 
• 
>51 to 52 weeks. 
• 
>52 weeks. 
The exposure parameters will be provided for the main 6-month on-treatment period and for the 
12-month on-treatment period, respectively. 
Additionally, the cumulative duration of treatment exposure will be provided, defined as the sum 
of the duration of treatment exposure for all patients, and will be expressed in patient years. 
2.4.3.2 Daily insulin doses 
Daily insulin doses for the main 6-month period and 12-month period 
The process described in Section 2.5.4 will be applied to assign visits to the insulin doses 
transferred from the e-diary into the clinical database, and to retrieve doses in case of premature 
treatment discontinuation. 
At each visit, the average daily basal, mealtime, and total (basal plus mealtime) insulin doses 
(U and U/kg body weight) will be calculated as the mean of daily insulin doses collected in the 
week before the visit. Technical details related to the computation and handling of missing data 
are described in Section 2.5.3. 
The daily insulin doses (basal, mealtime, total) will be described at each visit, as well as the 
changes from baseline, relative change from baseline and change from previous visit. 
The calculation of daily insulin doses at baseline is defined in Section 2.1.1.  
Daily insulin doses for the post-treatment period (4-week follow-up) 
Insulin dose after switch-back to a non-study therapy during the initial four weeks after change 
over from the study treatment will be evaluated. 
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A summary table will be provided for anti-diabetic therapies taken during the follow-up period 
based on WHO-DD coding. 
Observed value and change in daily basal insulin dose (U and U/kg body weight) from the 4-week 
follow-up baseline (end of treatment: Month 12) to visit 20 will be calculated. 
During the post-treatment period (4-week follow-up) the change in daily basal/mealtime/total 
insulin, evaluated between the day following last IMP intake and visit 20, will be the average daily 
insulin doses computed on a weekly basis. In case of any missed doses, corresponding days are not 
to be taken into account in the determination of the average daily insulin doses. 
Descriptive statistics will be provided for the above variables based on safety population. 
2.4.3.3 Compliance 
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol. No imputation will be made for patients with 
missing or incomplete data. 
Percentage of compliance for a patient will be defined as the exposure duration of study minus 
number of days with a dose equal to 0 divided by the duration of the IMP exposure. 
Treatment compliance will be summarized descriptively as quantitative variables (number, mean, 
SD, median, minimum, and maximum). The percentage of patients whose compliance is <80% 
will be summarized. 
Cases of symptomatic overdose with IMP/NIMP will be listed as such in Section 2.4.5.3. More 
generally, dosing irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints 
Figures will be provided with 2 different axes by parameter when applicable. For example, for 
HbA1c, figures will be presented by % and mmol/mol. 
Analyses windows considered for the analysis of HbA1c and FPG endpoints are defined in 
Section 2.5.4. 
2.4.4.1 Analysis of primary efficacy endpoint(s) 
2.4.4.1.1 Primary efficacy analysis 
The primary efficacy variable (change in HbA1c from baseline to Week 26 in % as defined in 
Section 2.1.3.1) will be analyzed for non-inferiority assessment, in the ITT population using  
post-baseline HbA1c data available on the main 6-month randomized period (defined in 
Section 2.1.3, ITT estimand). 
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A multiple imputation approach will be used where missing data from patients who do not adhere 
to IMP will be represented by the data from those patients in the same treatment group who also 
do not adhere to IMP but have the measurement for the primary endpoint. Details of the proposed 
multiple imputation analysis in two parallel parts (according the status of the patients), are 
provided below: 
Part1: Imputation for missing data in patients who prematurely discontinued IMP during the main 
6-month treatment period 
Missing data in patients who prematurely discontinued IMP during the main 6-month treatment 
period will be imputed using a model estimated solely from data observed in other patients who 
prematurely discontinue IMP during the main 6-month treatment period and have change in 
HbA1c available at Week 26. Due to the anticipated small number of these latter patients, a basic 
imputation model will be built, including only the treatment group as predictor. Missing data will 
be imputed using the regression method. 
Part2: Imputation for missing data in patients who complete the main 6-month treatment period 
Missing data in patients who complete the main 6-month treatment period will be imputed 
separately, using a model estimated from data observed in other patients who complete the main 
6-month treatment period and have change in HbA1c available at Week 26. Since in general, the 
missing pattern will not be monotone, a two-step approach will be used: 
- Step 1: the Markov Chain Monte Carlo (MCMC) method will be used in conjunction with the 
IMPUTE=MONOTONE option to create an imputed data set with a monotone missing pattern. 
The imputation model will include the continuous fixed covariates of the baseline HbA1c value as 
well as the changes from baseline in HbA1c at Week 12 and Week 26. 
- Step 2: using the monotone data set from step 1, missing data will be imputed using the 
regression method. The imputation model will include the fixed categorical effects of the 
treatment group, the randomization stratum of age group at screening visit (<12 years and 
≥12 years) as well as the continuous fixed covariates of the baseline HbA1c value and the changes 
from baseline in HbA1c at Week 12 and Week 26. 
Missing values will be imputed 1,000 times. Completed datasets from the two parts detailed above 
will be combined into a single dataset. Each completed dataset will be analyzed using an analysis 
of covariance (ANCOVA) of change from baseline to Week 26 in HbA1c, including the fixed 
categorical effects of the treatment group, the randomization stratum of age group at screening 
visit (<12 years and ≥12 years), as well as the continuous fixed covariates of the baseline HbA1c 
value. The final results will be obtained by combining the least squares means and least squares 
mean differences from these 1,000 analyses, using Rubin’s formula. 
This model will provide baseline adjusted least squares (LS) means estimates at Week 26 for both 
treatment groups, as well as, the differences of these estimates, with their corresponding SEs and 
95% CIs. These values will be calculated using adequate contrasts at Week 26, based on the 
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observed proportions of patients in the randomization stratum and the observed baseline mean 
HbA1c in the ITT population. 
Programming procedure is detailed in Appendix A. 
The primary efficacy variable will be assessed for non-inferiority for the primary efficacy analysis. 
To assess non-inferiority of HOE901-U300 versus Lantus, the upper bound of the two-sided 95% 
CI (Confidence Interval) for the difference in the mean change in HbA1c from baseline to 
endpoint (Month 6) between HOE901-U300 and Lantus on ITT population will be compared with 
the predefined non-inferiority margin of 0.3%. Non-inferiority will be demonstrated if this upper 
bound is <0.3%. 
Only if non-inferiority of HOE901-U300 versus Lantus is demonstrated, superiority of HOE901-
U300 over Lantus in HbA1c change from baseline to Week 26 will be assessed. Superiority of 
HOE901-U300 over Lantus 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 26 between HOE901-U300 
and Lantus is < 0. The superiority comparison is considered as a secondary analysis of the primary 
efficacy variable. 
The tests for the primary endpoint (Week 26) will be performed one-sided at level α = 0.025.  
2.4.4.1.2 Description of missing data 
Missing data in the primary efficacy analysis: 
The following analyses will be performed on the ITT population to explore the missing data 
frequency and pattern in the primary efficacy analysis: 
• 
As described in Section 2.2, Kaplan-Meier plots/estimates of the cumulative incidence of 
IMP discontinuation will be provided by treatment group, with hazard ratio and 95% CI 
estimated using Cox regression model. 
• 
In order to explore missing data patterns for HbA1c in the primary efficacy analysis, 
number and percentage of patients in each of the following categories will be presented by 
treatment group: 
- 
Pattern 1: patients without baseline if any, 
- 
Pattern 2: patients with baseline but without post-baseline value during the main  
6-month randomized period, 
- 
Pattern 3: patients with baseline and at least one post-baseline value during the main  
6-month randomized period but not at Week 26, 
- 
Pattern 4: patients with baseline and Week 26 value during the main 6-month 
randomized period. 
• 
Baseline characteristics and HbA1c values by visit will be presented by missing data 
pattern for each treatment group, using descriptive statistics and/or graphs. 
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Further exploratory analyses will be performed to evaluate factors influencing missing data: for 
each baseline characteristic, a logistic regression will be performed to model the missingness 
(Yes, No) at Week 26 (Visit 14). The model will include the treatment group, and the categorical 
or continuous covariate of the studied baseline characteristic. Estimates and p-value will be 
provided for descriptive purpose. A separate model will be run for each baseline characteristic; 
additional multivariate analyses may be performed if needed. 
2.4.4.1.3 Supportive analysis 
A supportive analysis of the primary efficacy analysis will be performed on the change in HbA1c 
from baseline to Month 6 in the ITT population, during the main 6-month on-treatment period 
(on-treatment estimand), as defined in Section 2.1.3. A multiple imputation approach will be used 
as described below. 
Missing data, (ie, all patients without change from baseline HbA1c at Week 26 during the main  
6-month on-treatment period) will be imputed using a model estimated from data observed in 
other patients who have change in HbA1c at Week 26. Since in general, the missing pattern will 
not be monotone, a two-step approach will be used: 
• 
Step 1: the Markov Chain Monte Carlo (MCMC) method will be used in conjunction with 
the IMPUTE=MONOTONE option to create an imputed data set with a monotone missing 
pattern. The imputation model will include the continuous fixed covariates of the baseline 
HbA1c value as well as the changes from baseline in HbA1c at Week 12 and Week 26. 
• 
Step 2: using the monotone data set from step 1, missing data will be imputed using the 
regression method. The imputation model will include the fixed categorical effects of the 
treatment group, the randomization stratum of age group at screening visit (<12 years and 
≥12 years) as well as the continuous fixed covariates of the baseline HbA1c value and the 
changes from baseline in HbA1c at Week 12 and Week 26. 
Missing values will be imputed 1,000 times. Each completed dataset will be analyzed using an 
analysis of covariance (ANCOVA) of change from baseline to Week 26 in HbA1c, including the 
fixed categorical effects of treatment group, randomization stratum of age group at screening visit 
(<12 years and ≥12 years), as well as, the continuous fixed covariate of the baseline HbA1c value. 
The final results will be obtained by combining the least squares means and least squares mean 
differences from these 1,000 analyses, using Rubin’s formula. 
This model will provide baseline adjusted least squares (LS) means estimates at Week 26 for both 
treatment groups, as well as, the differences of these estimates, with their corresponding SEs and 
95% CIs. These values will be calculated using adequate contrasts at Week 26, based on the 
observed proportions of patients in the randomization stratum and the observed baseline mean 
HbA1c in the ITT population. 
2.4.4.1.4 Sensitivity analysis to handle missing data 
Sensitivity analysis will be conducted to assess the robustness of primary efficacy analysis with 
regard to missing data (8). 
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Tipping point analysis 
In order to assess the impact of missing data, a tipping-point analysis based on the pattern mixture 
model approach will be performed as below.  
The considered pattern mixture model will introduce a sensitivity parameter, δ, corresponding to 
the difference in mean change from baseline in HbA1c between patients with missing data and 
patients with observed data. 
The change in HbA1c from baseline to Month 6 in % using HbA1c values during the main  
6-month randomized period (all post baseline available data), will be analyzed in the ITT 
population using a multiple imputation approach. Missing data (ie, all patients without change 
from baseline HbA1c at Week 26 during the main 6-month randomized period) will be imputed 
using a model estimated from data observed in other patients who have change in HbA1c at 
Week 26. 
Missing data will be imputed 1,000 times to generate 1,000 complete data sets with the MI SAS 
procedure. Since in general, the missing pattern will not be monotone, a two-step approach will be 
used: 
• 
Step 1: the Markov Chain Monte Carlo (MCMC) method will be used in conjunction with 
the IMPUTE=MONOTONE option to create an imputed data set with a monotone missing 
pattern. The imputation model will include the continuous fixed covariates of the baseline 
HbA1c value as well as the changes from baseline in HbA1c at Week 12 and Week 26. 
• 
Step 2: using the monotone data set from step 1, missing data will be imputed using the 
regression method. The imputation model will include the fixed categorical effects of the 
treatment group, the randomization stratum of age group at screening visit (<12 years and 
≥12 years) as well as the continuous fixed covariates of the baseline HbA1c value and the 
changes from baseline in HbA1c at Week 12 and Week 26. 
The imputed change HbA1c at Week 26 in the HOE901-U300 group will then be penalized by 
adding δ to the change whereas the imputed change HbA1c in the Lantus group will not be 
penalized (δ = 0 corresponds to the MAR assumption). 
The 1,000 complete data sets will then be analyzed using an analysis of covariance (ANCOVA) 
model including the fixed categorical effects of the randomization stratum of age group at 
screening visit (<12 years and ≥12 years), the treatment group, as well as, the continuous fixed 
covariate of the baseline HbA1c value. The MIANALYZE procedure will then be used to generate 
valid statistical inferences by combining results from the 1,000 analyses using Rubin’s formulae. 
This procedure will provide baseline adjusted least-squares means estimates at Week 26 for both 
treatment groups, as well as, the differences of these estimates, with their corresponding SEs and 
95% CIs. 
To investigate how the conclusions depend on the adopted values of δ, the testing will be repeated 
over a range of plausible values for δ, the treatment effect being penalized by a positive value and 
favored by a negative value.  
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A specific illustration on the value of the minimum penality leading to a non-rejection of the null 
hypothesis (confidence interval upper limit greater than 0.3%) will be provided (9). 
2.4.4.1.5 Subgroup analyses 
The primary efficacy endpoint will be further analyzed to examine whether the treatment effect 
varies in subgroups defined by the following baseline covariates, list not exhaustive: 
• 
Randomization strata of age group (<12, ≥ 12 years of age). 
• 
Randomization strata of screening HbA1c categories (<8.5; ≥8.5%). 
• 
Gender (Male, Female). 
• 
Race (Caucasian/White, Black, Asian/Oriental, Other). 
• 
Ethnicity (Hispanic, not Hispanic). 
• 
Regions (North America, South/Latin America, Western Europe, Eastern Europe, Rest of 
the World [ROW]). 
• 
Baseline BMI percentile: <5th percentile; 5th-<85th percentile; 85th-<95th percentile; ≥95th 
percentile. 
• 
Baseline Tanner puberty stage evaluation (pre-pubertal, adolescent, adult). 
• 
Baseline Estimated GFR categories (mL/min/1.73m²): (<30; [30-60[; ≥60). 
• 
Duration of diabetes (<2; [2 - 5[; ≥5 years). 
For each subgroup, the primary efficacy variable will be analyzed in the ITT population. The same 
multiple imputation approach as described for primary analysis will be applied, using 1,000 
completed datasets generated for the primary analysis. Each completed dataset will be analyzed 
using an ANCOVA of change from baseline to Week 26 in HbA1c, including the fixed categorical 
effects of the treatment group, randomization stratum of age group at screening visit (<12 years 
and ≥12 years), the continuous fixed covariate of the baseline HbA1c value, and adding the 
corresponding subgroup factor and subgroup factor-by-treatment interaction. The final results will 
be obtained by combining the LS means and LS mean differences within each subgroup from 
these 1,000 analyses, using Rubin’s formula. 
When the subgroup considered is equal to the randomization strata of age group (<12; ≥12), the 
categorical stratum of age group will be removed from the model. 
When the subgroup considered is equal to the randomization strata of screening HbA1c (<8.5, 
≥8.5%), the baseline HbA1c value will be removed from the model. 
Least Square Means Difference versus Lantus at Week 26 will be provided, as well as the 
corresponding SEs and 95% CI, within each subgroup. The significance level of the treatment-by-
subgroup factor interaction term at Week 26 will also be provided for each factor for purpose 
flagging the subgroups where the treatment difference does not seem to be homogeneous. Forest 
plots will be provided for a better visual evaluation. 
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HbA1c by randomization stratum of age at screening (<12 years and ≥12years) 
In each, subgroup defined by randomization stratum of age at screening (<12 years and ≥12years), 
summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of primary efficacy endpoint (estimated values and changes from baseline following 
multiple imputation approach for each visit) and adjusted least-squares means estimates will be 
presented at each visit by treatment group using tables and graphs. The differences of these 
estimates versus Lantus, with their corresponding associated standard errors and 95% confidence 
intervals will also be calculated. 
Further subgroup analyses may be performed if deemed necessary for interpretation of results. 
2.4.4.1.6 Assessment of treatment effect at 12 months 
The change in HbA1c from baseline to Week 52 will be described in the ITT population, using all 
post-baseline HbA1c data available during the 12-month randomized period. 
For descriptive purpose, the treatment effect at Week 52 will be evaluated using the same multiple 
imputation approach as for primary analysis (Section 2.4.4.1.1) and as described below for the two 
parallel parts.  
Missing data in patients who prematurely discontinued IMP during the main 12-month treatment 
period will be imputed using a model including only the treatment group as predictor (Part 1). 
Missing data in patients who complete the 12-month treatment period will be imputed in step 1 
using a model including the continuous fixed covariates of the baseline HbA1c value as well as 
the changes from baseline in HbA1c at Week 12, Week 26, Week 38 and Week 52, and in step 2 
using a model including the fixed categorical effects of the treatment group, the randomization 
stratum of age group at screening visit (<12 years and ≥12 years) as well as the continuous fixed 
covariates of the baseline HbA1c value and the changes from baseline in HbA1c at Week 12, 
Week 26, Week 38 and Week 52 (Part 2). 
2.4.4.2 Analyses of secondary efficacy endpoints 
Secondary efficacy endpoints defined in Section 2.1.3.2 will be analyzed in the ITT population, 
using all post-baseline data available during the main 6-month randomized period. 
All secondary endpoints will be also described at end of the 12-month randomized period 
(Week 52). 
2.4.4.2.1 Continuous endpoints 
Change from baseline in FPG at Week 26 and at Week 52 will be analyzed using a similar 
multiple imputation in two parallel parts, as described before for the primary efficacy endpoint, 
adding screening HbA1c (<8.5%; ≥8.5%) in Part 2, step 2 imputation model (ie, for missing data 
in patients who complete the main 6-month treatment period).  
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• 
At week 26,  
- 
Missing data in patients who prematurely discontinued IMP during the main 6-month 
treatment period will be imputed using a model including only the treatment group as 
predictor (Part 1), 
- 
Missing data in patients who complete the main 6-month treatment period will be 
imputed in step 1 using a model including the continuous fixed covariates of the 
baseline FPG value and the change from baseline in FPG at Week 12 and Week 26, in 
step 2 using a model including the fixed categorical effects of the treatment group, the 
randomization stratum of age group at screening visit (<12 years and ≥12 years), 
randomization strata of screening HbA1c (<8.5, ≥8.5%) as well as the continuous fixed 
covariates of the baseline FPG value and the changes from baseline in FPG at Week 12 
and Week 26 (Part 2). 
• 
At week 52,  
- 
Missing data in patients who prematurely discontinued IMP during the 12-month 
treatment period will be imputed using a model including only the treatment group as 
predictor (Part 1), 
- 
Missing data in patients who complete the 12-month treatment period will be imputed 
in step 1 using a model including the continuous fixed covariates of the baseline FPG 
value as well as the changes from baseline in FPG at Week 12, Week 26, Week 38 and 
Week 52, in step 2 using a model including the fixed categorical effects of the 
treatment group, the randomization stratum of age group at screening visit (<12 years 
and ≥12 years), the randomization strata of screening HbA1c (<8.5, ≥8.5%) as well as 
the continuous fixed covariates of the baseline FPG value and the changes from 
baseline in FPG at Week 12, Week 26, Week 38 and Week 52 (Part 2). 
The other continuous endpoints listed below will be analyzed with an ANCOVA model and 
descriptively with mean, median, SD, minimum and maximum for values and for changes from 
baseline and will be presented by treatment group for each visit. 
• 
Change from baseline in 24-hour mean plasma glucose based on 8-point SMPG profiles at 
Week 26 and Week 52. 
• 
Change from baseline in variability of 24-hour mean plasma glucose based on 8-point 
SMPG profiles at Week 26 and Week 52. 
• 
Change from baseline in 8-point self-monitored plasma glucose (SMPG) profiles per time-
point (pre-prandial and 2-hour postprandial plasma glucose at breakfast, lunch and dinner, 
bedtime plasma glucose, nocturnal plasma glucose) at Week 26 and Week 52. The  
analysis will be performed taking into account the time-points corrected by the investigator 
in the e-CRF. 
• 
Change from baseline in average pre-breakfast SMPG at Week 26 and at Week 52. 
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The ANCOVA model will include treatment, randomization stratum of screening HbA1c  
(<8.5 and ≥8.5%), and randomization stratum of age group at screening visit (<12 years and 
≥12 years), and the baseline value as a covariate. For change in variability of the 24-hour mean 
plasma glucose, an ANOVA model with treatment, randomization stratum of screening HbA1c 
(<8.5 and ≥8.5%), and randomization stratum of age group at screening visit (<12 years and 
≥12 years) will be used. The adjusted treatment mean estimates with standard errors, the adjusted 
estimate of treatment mean difference (between HOE901-U300 and Lantus) with standard error, 
and associated 95% confidence interval will be provided.  
Observed values and change from baseline in average pre-breakfast SMPG will be also described 
for all visits (on-site and phone visits) with mean, median, SD, minimum and maximum. A figure 
representing the mean (+/- SE) change from baseline at each visit will be produced by treatment 
group. 
2.4.4.2.2 Categorical endpoints 
The categorical efficacy parameters (percentage of patients with HbA1c <7.5% and percentage of 
patients with FPG ≤130 mg/dL (7.2 mmol/L)) will be analyzed by using Cochran-Mantel-
Haenszel (CMH) method with treatment as factors, stratified by randomization stratum of HbA1c 
(<8.5%, ≥8.5%) and by randomization stratum of age group (<12 years and ≥12 years) at 
screening.  
The analyses will be performed: 
• 
At Week 26. 
• 
At Week 26 and without any episode of severe and/or documented (SMPG <54 mg/dL; 
3.0 mmol/L) hypoglycemia during the last 3 months of the main 6-month randomized 
period. 
95 % confidence interval for the treatment difference or ratios will be provided. 
If any table cell frequency in a stratum is zero, continuity correction (10) will be applied. 
Patients, who have prematurely discontinued the study and without any available hypoglycemia 
event during the study period, will be considered as a failure, ie, having a hypoglycemia event. 
2.4.4.3 Multiplicity issues 
In order to handle the multiple comparisons of the non-inferiority and then the superiority of 
HOE901-U300 over Lantus, corresponding respectively to the primary efficacy analysis and a 
secondary analysis of the primary efficacy variable, the type-I error will be controlled by the use of 
the sequential inferential approach. Only if non-inferiority is demonstrated, superiority of 
HOE901-U300 over Lantus of the mean change from baseline to Month 6/ Week 26 in HbA1c 
will be assessed. The tests for the primary endpoint (Week 26) will be performed one-sided at 
level α = 0.025. 
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The other secondary efficacy variables will be analyzed for exploratory purpose only. 
2.4.4.4 Additional efficacy analyses 
No additional efficacy analyses are planned. 
2.4.5 Analyses of safety data 
The summary of safety results will be presented by treatment group on treated population. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• 
Safety data in patients who do not belong to the safety population (eg, exposed but not 
randomized) will be listed separately. 
• 
The baseline value is defined as the last available value prior to the first injection of IMP. 
When the time of assessment is not available, the value is considered as baseline if 
assessment date is the date of 1st IMP intake. 
• 
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 clinical 
laboratory tests, vital signs (PCSA criteria will be provided in the ADaM metadata). 
• 
PCSA criteria will determine which patients had at least 1 PCSA during the TEAE period, 
taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations. The number of all such patients will be the 
numerator for the on-treatment PCSA percentage. 
• 
The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of patients assessed for that given parameter in the treatment-emergent 
adverse event period by treatment group on the safety population. 
• 
For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group. Summaries will include the last on-treatment value. The last  
on-treatment value is defined as the value collected at the same day/time of the last dose of 
investigational product. If this value is missing, this on-treatment value is the closest one 
prior to the last dose intake. 
• 
The analysis of the safety variables will be essentially descriptive and no systematic testing 
is planned. Relative risks versus Lantus and their 95% confidence intervals may be 
provided, if relevant. 
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2.4.5.1 Analyses of Hypoglycemia events 
All analyses of hypoglycemia events will be performed on the safety population, separately on 
events occurring during the main 6-month TEAE period (for the main 6-month CSR) and during 
the 12-month TEAE period (for the 12-month CSR) (as defined in Section 2.1.4). The analyses 
planned to be done by treatment period will include also the analyses performed by the following 
periods:  from first injection of IMP to end of Week 8, from start of Week 9 to Month 6,  
post-treatment period (depending on the CSR, at 6 month or 12 month) (as defined in 
Section 2.1.4.1). 
Incidence of patients with at least one hypoglycemia event 
• 
Incidence of patients with at least one hypoglycemia event and 95% CI estimated by 
Clopper-Pearson exact method, will be presented for any hypoglycemia and for each 
hypoglycemia category, overall and by time of the day (as described in Section 2.1.4.1). 
• 
Incidence of patients with at least one hypoglycemia event and 95% CI estimated by 
Clopper-Pearson exact method, will be presented by treatment period (as described in 
Section 2.1.4.1) for any hypoglycemia and for each hypoglycemia category (except 
probable, pseudo), overall and by time of the day. 
• 
For any hypoglycemia and for each hypoglycemia category (except probable, pseudo), 
incidence of patients with at least one hypoglycemia will be compared, overall and by 
treatment period (except post-treatment period), for HOE901-U300 versus Lantus using a 
CMH method with treatment group as a factor and stratified on randomization strata 
(screening HbA1c (<8.5%, ≥8.5%); age group (<12, ≥ 12 years of age)). If any table cell 
frequency in a stratum is zero, continuity correction (10) will be applied. Relative risk and 
95% CI will be displayed using forest plots. This analysis will be done also for nocturnal 
(00:00 to 05:59 a.m. hours) hypoglycemia. 
• 
Incidence of patients with at least one severe and/or documented (≤70 mg/dL and 
<54 mg/dL) hypoglycemia event will be summarized by hour of the day. Histograms will 
be provided. 
• 
Incidence of patients with at least one severe and/or documented (≤70 mg/dL and 
<54 mg/dL) hypoglycemia event will be presented over time. Percentages will be 
calculated using the number of patients at risk at the beginning of each month. Histograms 
will be provided. This analysis will be done for any time of the day and for the nocturnal 
(00:00 to 05:59) period. 
• 
Incidence of patients with at least one severe hypoglycemia event will be summarized by 
hour of the day. Histograms will be provided. 
• 
Incidence of patients with at least one severe hypoglycemia event will be presented over 
time. Percentages will be calculated using the number of patients at risk at the beginning of 
each month. Histograms will be provided. This analysis will be done for any time of the 
day and for the nocturnal (00:00 to 05:59) period. 
• 
Incidence of patients with at least one severe hypoglycemia event will be summarized by 
symptom, overall and by time of the day. 
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• 
Incidence of patients with at least one severe and/or documented (≤70 mg/dL and 
<54 mg/dL) hypoglycemia will be presented by subgroup and will be compared by 
subgroup for HOE901-U300 versus Lantus using a CMH method with treatment group as 
a factor and stratified on randomization strata (screening HbA1c (<8.5%, ≥8.5%); age 
group (<12, ≥ 12 years of age) if it is not a subgroup factor. If any table cell frequency in a 
stratum is zero, continuity correction (10) will be applied. The treatment-by-subgroup 
factor interaction will be tested for descriptive purpose using a logistic regression model 
with the corresponding subgroup, treatment, randomization strata and the interaction 
treatment-by-subgroup factor. Forest plots will be provided. The following subgroups will 
be displayed: 
- 
Randomization stratum of screening HbA1c (<8.5%, ≥8.5%), 
- 
Randomization stratum of screening of age group (<12, ≥ 12 years of age), 
- 
Gender (male, female), 
- 
Baseline tanner puberty stage evaluation (pre-pubertal, adolescent, adult), 
- 
Baseline BMI percentiles (<5th percentile; 5th-<85th percentile; 85th-<95th percentile; 
≥95th percentile), 
- 
Baseline pre-breakfast SMPG, 
- 
These subgroup analyses will be done for any time of the day and for the nocturnal 
(00:00 to 05:59) period. 
• 
Further subgroup analyses may be performed if deemed necessary for interpretation of 
results. 
Number and rate of hypoglycemia event 
• 
Number and rate of hypoglycemia event per patient-year will be summarized for any 
hypoglycemia and for each hypoglycemia category, overall and by time of day (as 
described in Section 2.1.4.1). Non classified hypoglycemia will be displayed. 
• 
Number and rate of hypoglycemia event per patient-year will be presented by treatment 
period (as described in Section 2.1.4.1) for any hypoglycemia and for each hypoglycemia 
category (except probable, pseudo), overall and by time of the day. 
• 
For any hypoglycemia and for each hypoglycemia category (except probable, pseudo), the 
number of hypoglycemia events per patient-year will be compared, overall and by 
treatment period (except post-treatment period), for HOE901-U300 versus Lantus using a 
negative binomial regression model with a log-link function, and the logarithm of the 
treatment-emergent analyzed period as offset. The model will include the treatment group 
and randomization strata (screening HbA1c (<8.5%, ≥8.5%); age group (<12, ≥ 12 years of 
age)). If the negative binomial model does not converge (e.g., due to sparse data), 
randomization strata may be removed from the model. Relative risk and 95%CI will be 
displayed using forest plots. This analysis will be done also for nocturnal (00:00 to 
05:59 am hours) hypoglycemia. 
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• 
Cumulative number and rate of severe and/or documented (≤70 mg/dL and <54 mg/dL) 
hypoglycemia event per 100 patient-days will be summarized by hour of the day. Figures 
will be provided. Same analysis will be done for severe hypoglycemia. 
• 
Cumulative mean number of severe and/or documented (≤70 mg/dL and <54 mg/dL) 
hypoglycemia will be summarized over time using Nelson-Aalen estimates. Figures will be 
provided. This analysis will be done also for nocturnal (00:00 to 05:59 am hours) severe 
and/or documented (≤70 mg/dL and <54 mg/dL) hypoglycemia. Same analyses will be 
done for severe hypoglycemia. 
Hypoglycemia data from the external committee 
Incidence of patients with at least one hypoglycemia event qualifying for review by the external 
committee will be summarized, and among these, proportion of patients with at least one 
hypoglycemia event classified as severe by the external committee will be presented overall, by 
treatment period (except the post-treatment period), over time (by month) and by time of the day 
(as described in Section 2.1.4.1). Number and rate of hypoglycemia events per patient-year 
qualifying for review by the external committee will be summarized overall, by treatment period  
(except post-treatment period) and by time of the day, and among these, the number and rate of 
hypoglycemia events classified as severe by the external committee per patient-year. 
2.4.5.2 Analyses of Hyperglycemia with ketosis 
All analyses of hyperglycemia with ketosis events will be performed on the safety population, 
separately on events occurring during the main 6-month and 12-month TEAE periods (as defined 
in Section 2.1.4). The analyses planned to be done by treatment period will include also the 
analysis performed for the post-treatment period for the 12-month CSR (as defined in 
Section 2.1.4.2). 
All analyses of hyperglycemia with ketosis events will be done for categories of hyperglycemia 
with ketosis defined in Section 2.1.4.2. 
Incidence of patients with at least one hyperglycemia with ketosis event 
• 
Incidence of patients with at least one hyperglycemia with ketosis event and 95% CI 
estimated by Clopper-Pearson exact method, will be presented overall and by treatment 
period. 
• 
Incidence of patients with at least one hyperglycemia with ketosis event and 95% CI 
estimated by Clopper-Pearson exact method, will be also presented by subgroup for 
HOE901-U300 versus Lantus. The following subgroups will be displayed: 
- 
Randomization stratum of screening HbA1c (<8.5%, ≥8.5%), 
- 
Randomization stratum of screening of age group (<12, ≥ 12 years of age), 
- 
Gender (male, female), 
- 
Baseline tanner puberty stage evaluation (pre-pubertal, adolescent, adult), 
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- 
Baseline BMI percentiles (<5th percentile; 5th-<85th percentile; 85th-<95th percentile; 
≥95th percentile), 
- 
Baseline pre-breakfast SMPG. 
Number and rate of hyperglycemia with ketosis event 
• 
Number and rate of hyperglycemia with ketosis events per patient-year will be summarized 
overall, by treatment period.  
• 
Cumulative mean number of hyperglycemia with ketosis will be summarized over time 
using Nelson-Aalen estimates. Figures will be provided. 
In case of too few patients with hyperglycemia with ketosis and/or events of hyperglycemia with 
ketosis, some of the analyses described above may not be done and may be replaced by listings. 
Analyses of hyperglycemia with ketosis adverse events will be included in the analysis of the other 
TEAEs as described in the Section 2.4.5.3. 
2.4.5.3 Analyses of adverse events 
Generalities 
The primary focus of adverse event reporting will be on TEAEs. Pre- and post-treatment AEs will 
be described separately. 
All adverse events will be reported for the main 6-month TEAE period and for the 12-month 
TEAE period separately. 
Multiple occurrences of the same event in the same patient will be counted only once in the tables 
within a treatment phase. The denominator for computation of percentages will be the safety 
population within each treatment group. 
Sorting within tables should ensure the same presentation for the set of all AEs within the 
observation period (pre-treatment, treatment-emergent, and post-treatment). For that purpose, the 
table of all TEAEs presented by SOC and PT sorted by internationally agreed order of SOC and 
decreasing frequency of PTs within SOC will define the presentation order for all other tables 
unless otherwise specified. Sorting will be based on results for the HOE901-U300 treatment arm. 
Analysis of all TEAE(s) 
The following TEAE summaries will be generated for the safety population: 
• 
Overview of TEAEs, summarizing number (%) of patients with any: 
- 
TEAE, 
- 
Serious TEAE, 
- 
TEAE leading to death, 
- 
TEAE leading to permanent treatment discontinuation, 
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• 
All TEAEs by primary SOC, showing number (%) of patients with at least one TEAE, 
sorted by internationally agreed order of primary SOC. 
• 
All TEAEs by primary SOC, HLGT, HLT, and PT, showing number (%) of patients with 
at least one TEAE sorted by SOC internationally agreed order. The other levels (HLGT, 
HLT, PT) will be presented in an alphabetic order. 
• 
Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing 
incidence of PT. 
• 
All TEAEs by primary SOC and PT, showing number (%) of patients with at least one 
TEAE, sorted by SOC internationally agreed order and decreasing incidence of PTs within 
SOC. This sorting order will be applied to all other tables, unless otherwise specified. 
• 
Number (%) of patients experiencing common TEAE(s) (HLT incidence ≥2% in any 
treatment group) presented by primary SOC, HLT, and PT, sorted by SOC internationally 
agreed order. The other levels (HLT, PT) will be presented in an alphabetic order. Analysis 
performed overall and by subgroup of age, race, gender. 
• 
All TEAEs regardless of relationship and related to IMP by primary SOC, HLGT, HLT, 
and PT, showing number (%) of patients with at least one TEAE, sorted by SOC 
internationally agreed order. The other levels (HLGT, HLT, PT) will be presented in an 
alphabetic order. 
• 
All TEAEs by maximal severity, presented by primary SOC and PT, showing number (%) 
of patients with at least one TEAE by severity (ie, mild, moderate, or severe), sorted by the 
sorting order defined above. 
• 
Number (%) of patients experiencing TEAE(s) presented by Primary and Secondary SOC, 
HLGT, HLT, and PT, sorted by SOC internationally agreed order. The other levels 
(HLGT, HLT, PT) will be presented in an alphabetic order. 
Analysis of all treatment-emergent SAE(s) 
• 
All treatment-emergent SAEs by primary SOC, HLGT, HLT, and PT, showing number 
(%) of patients with at least one serious TEAE, sorted by SOC internationally agreed 
order. The other levels (HLGT, HLT, PT) will be presented in an alphabetic order. 
• 
All treatment-emergent SAEs regardless of relationship and related to IMP by primary 
SOC, HLGT, HLT, and PT, showing number (%) of patients with at least one treatment-
emergent SAE, sorted by SOC internationally agreed order. The other levels (HLGT, HLT, 
PT) will be presented in an alphabetic order. 
Analysis of all TEAE(s) leading to treatment discontinuation 
• 
All TEAEs leading to treatment discontinuation, by primary SOC, HLGT, HLT, and PT, 
showing number (%) of patients sorted by SOC internationally agreed order. The other 
levels (HLGT, HLT, PT) will be presented in an alphabetic order. 
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Analysis of TEAE(s) related to injection site reactions, hypersensitivity reactions 
• 
All TEAEs related to injection site reactions or hypersensitivity reactions by PT, showing 
number (%) of patients sorted by decreasing incidence of PT in the HOE901-U300 
treatment arm. 
• 
All TEAEs related to injection site reactions, hypersensitivity reactions, regardless of 
relationship and related to IMP, by PT, showing number (%) of patients sorted by 
decreasing incidence of PT in the HOE901-U300 treatment arm. 
Analysis of adverse events of special interest 
• 
A listing of patients with symptomatic overdose with IMP/NIMP, increase of ALT, and 
pregnancy will be provided. 
Analysis of pre-treatment and post-treatment adverse events 
• 
A listing of all pre-treatment and post-treatment AEs will be provided. 
2.4.5.4 Deaths 
The following deaths summaries will be generated on the safety population, during the main  
6-month on-treatment period and for the 12-month on-treatment period separately: 
• 
Number (%) of patients who died by study period (on-study, on-treatment, post-study) and 
reasons for death. 
• 
All TEAEs leading to death (death as an outcome on the adverse event e-CRF page as 
reported by the investigator), by primary SOC, HLGT, HLT, and PT, showing number (%) 
of patients sorted by SOC internationally agreed order. The other levels (HLGT, HLT, PT) 
will be presented in an alphabetic order. 
• 
A listing of all deaths. 
2.4.5.5 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit or study assessment (baseline, each post-baseline time-point, last on-
treatment value during the main 6-month and 12-month on-treatment periods) by treatment group. 
This section will be organized by biological function as specified in Section 2.1.4.5. 
The incidence of PCSAs at any time during the main 6-month on-treatment period and during the 
12-month on-treatment period will be summarized by biological function and treatment group 
whatever the baseline level and according to the following baseline status categories: 
• 
Normal/missing. 
• 
Abnormal according to PCSA criterion or criteria. 
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For parameters for which no PCSA criteria are defined, similar table(s) using the normal range 
will be provided. 
Drug-induced liver injury 
The liver function tests, namely AST, ALT, alkaline phosphatase, and total bilirubin, are used to 
assess possible drug-induced liver toxicity. The proportion of patients with PCSA values at any 
post-baseline visit by baseline status will be displayed by treatment group for each parameter. 
A graph of distribution of peak values of ALT versus peak values of total bilirubin will also be 
presented. Note that the ALT and total bilirubin values are presented on a logarithmic scale. The 
graph will be divided into 4 quadrants with a vertical line corresponding to 3 x ULN for ALT and 
a horizontal line corresponding to 2 x ULN for total bilirubin. 
Listing of possible Hy’s law cases identified by treatment group (eg, patients with any elevated 
ALT>3 x ULN, and associated with elevated in bilirubin ≥2 x ULN) will be provided with ALT, 
AST, alkaline phosphatase, total bilirubin, and the following complementary parameters: 
conjugated bilirubin and prothrombin time/international normalized ratio, creatine phosphokinase, 
serum creatinine, complete blood count. 
The incidence of liver-related adverse events will be summarized by treatment group. The 
selection of preferred terms will be based on the hepatic disorder SMQ. 
2.4.5.6 Analyses of vital sign variables 
The summary statistics (including number, mean, median, standard deviation, minimum, and 
maximum) of all vital signs variables (raw values and changes from baseline) described in 
Section 2.1.4.6 will be calculated for each visit or study assessment (baseline, each post-baseline 
time-point, last on-treatment during the main 6-month and 12-month on-treatment periods) by 
treatment group. 
The incidence of PCSAs at any time during the treatment-emergent adverse event period will be 
summarized during the main 6-month and the 12-month on-treatment period by treatment group 
irrespective of the baseline level and/or according to the following baseline status categories: 
• 
Normal/missing. 
• 
Abnormal according to PCSA criterion or criteria. 
The incidence of PCSAs at any time during the TEAE period will be summarized by treatment 
group whatever the baseline level and according to baseline status. 
The change in BMI percentile from baseline will be analyzed in the safety population using an 
ANCOVA model including the treatment group, randomization strata, as well as the baseline BMI 
percentile value. 
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2.4.5.7 Analyses of Tanner puberty stage measurement 
Tanner puberty stage (pre-pubertal, adolescent, adult) will be described using count and 
percentage. 
2.4.6 Analyses of anti-insulin antibody data  
The analyses of AIA data will be performed based on the safety population, for the main 6-month 
on-treatment period and for the 12-month on-treatment period separately. 
The number and percentage of patients with anti-insulin glargine antibody positive and antibody 
negative sample will be summarized by treatment group and visit. Results at the last on-treatment 
visit will be also provided. 
On the group of patients with anti-insulin glargine antibody positive sample at a given visit, anti-
insulin glargine antibody titers will be summarized  (using descriptive statistics by number (N), 
median, Q1, Q3, variation coefficient, minimum, maximum, geometric mean, SD, and 95% CI), 
and the number and percentage of patients with cross-reactivity to human insulin will be provided.  
The number and percentage of patients will be provided by treatment group for each of the 
following categories: 
• 
Patients with treatment-induced AIAs. 
• 
Patients with treatment-boosted AIAs. 
• 
Patients with treatment-emergent AIA (AIA incidence). 
• 
Patients without treatment-emergent AIA.  
• 
Patients with pre-existing AIAs or treatment-induced AIAs or treatment-boosted (AIA 
prevalence). 
For patients with treatment-induced and treatment-boosted AIAs, the kinetics of AIA response 
(transient, persistent, or indeterminate AIA response as defined in Section 2.1.4.8) will be further 
summarized using number and percentage of patients, and the peak titer will be described using 
median, Q1 and Q3. 
Theses analyses will be performed for the overall safety population and by AIA subgroup (as 
defined above). 
In order to assess the relationship between immunogenicity and efficacy assessments, the change 
in HbA1c from baseline will be summarized by treatment-emergent AIA (Yes, No) and treatment-
emergent AIA at last on-treatment value (Yes, No). 
The following safety data will be also summarized descriptively by treatment-emergent AIA (Yes, 
No) and AIA incidence at last on-treatment value (Yes, No): 
• 
Hypoglycemia (any, severe, documented symptomatic, and severe and/or documented, at 
any time and nocturnal). 
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• 
Common TEAEs (ie, with HLT ≥2%) and SAEs. 
• 
Injection site and hypersensitivity reactions. 
For hypoglycemia, the proportion of patients with at least one event in each category listed above 
will be compared between treatment groups using a logistic regression model. Odds-ratios and 
95% CIs will be provided. 
Plots of the rate per year of event in each category of hypoglycemia listed above will be provided. 
Insulin doses will be also described by treatment-emergent AIA (Yes, No) and treatment-emergent 
AIA at last on-treatment value (Yes, No). 
Box plot of the maximal AIA titer during the main 6-month on-treatment period and during the 
12-month on-treatment period will be provided by treatment group and according to the treatment-
emergent AIA status. Baseline characteristics, insulin doses, HbA1c, hypoglycemia data and 
hypersensitivity reactions as well as injection site reactions will be listed for patients with 
treatment-emergent AIA and maximal titer above or equal to the upper whiskers in the boxplot, 
defined as 1.5 times the interquartile range. 
Analyses of data from the external committee: 
Hypersensitivity events and potential indicators of insulin resistance in patients with treatment-
induced or treatment-boosted AIA status and assessed by the Committee as mediated or likely 
mediated by AIA will be analyzed as below: 
• 
Percentage of patients with treatment-induced or treatment boosted AIA and 
hypersensitivity TEAE, overall and by AIA-mediated assessment (yes/no).  
• 
Percentage of patients with treatment-induced or treatment boosted AIA and potential 
indicators of insulin resistance, overall and by AIA-mediated assessment (yes/no). 
2.4.7 Analyses of pharmacokinetic and pharmacodynamic variables 
Plasma concentrations of insulin glargine will be summarized on the PK population, by time point 
and by treatment group using descriptive statistics by N, mean, SD, geometric mean, coefficient of 
variation, SEM, median, minimum, and maximum. Only samples within the analyses windows 
defined in the Section 2.5.4 will be included in the calculations. Individual data might be listed as 
deemed necessary.  
These tables will be performed overall and by AIA status (positive/negative) of patients at 
Week 26. In case of no AIA value available at week 26, the patient will be excluded from this PK 
analysis by AIA status. 
Plots for concentration time profiles will be provided as follows: 
• 
Plots of mean (+/-SD) by treatment group: mean (+/-SD) calculated in the above summary 
table and including samples within the analyses windows defined in the Section 2.5.4 
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• 
Spaghetti plots with all individual data by treatment group, including all samples 
regardless of analyses windows. 
Population PK modeling will be performed by the Pharmacokinetics, Dynamics and Metabolism 
(PKDM) group at Sanofi, which is not in the scope of this SAP and would be reported separately. 
2.4.8 Analyses of quality of life/health economics variables 
Not applicable. 
2.5 
DATA HANDLING CONVENTIONS 
This section describes general rules for data handling conventions, especially for patients with 
missing data. 
2.5.1 General conventions 
The following formulas will be used for computation of parameters. 
Reference day 
The reference day for the calculation of extent of exposure, time to onset and relative days is the 
day of the first administration of open-label IMP, denoted as Day 1. 
First IMP 
The first IMP is identified by the start date reported for the IMP exposure in the e-CRF. 
Demographic formulas 
Body Mass Index (kg/m²)= (Weight in kg) / (Height in meters)² 
Body Mass Index percentile will be derived according the WHO Child Growth Standards (1). 
Details will be provided in the ADaM metadata. 
Disease characteristics formulas 
Duration of diabetes (years) = (Date of informed consent – date of diagnosis of diabetes 
+1)/365.25. 
Age at onset of diabetes (years) = (Date of diagnosis of diabetes – date of birth +1) /365.25. 
Duration of previous basal insulin treatment (years) = (Date of informed consent – date of first 
dose of previous basal insulin+1)/365.25. In case of unavailable date of birth, only the year of the 
date of diabetes diagnosis and the year of the date of birth (retrieve using the age recorded at 
screening) will be considered in the age at onset calculation. 
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Duration of previous non-insulin antihyperglycemic treatment (years) = (Date of informed consent 
- date of first dose of previous non-insulin antihyperglycemic treatment +1) /365.25. 
HbA1c transformation 
To transform HbA1c in % to mmol/mol, the following formula (11) is used: 
IFCC = (10.93*NGSP) - 23.50 
NGSP (National Glycohemoglobin Standardization Program network) corresponds to Hba1c (%) 
band IFCC (International Federation of Clinical Chemistry network) to HbA1c (mmol/mol) 
Rate of hypoglycemia event per patient-year 
Computed as [sum of number of episodes of hypoglycemia for all patients] / [sum of patient-year 
of exposure for all patients] with patient-year of exposure calculated per patient as number of days 
of exposure divided by 365.25.  
Rate of hyperglycemia with ketosis event per patient-year 
Computed as [sum of number of episodes of hyperglycemia for all patients] / [sum of patient-year 
of exposure for all patients] with patient-year of exposure calculated per patient as number of days 
of exposure divided by 365.25.  
Estimated Glomerular Filtration Rate (eGFR) derived using Schwartz formula 
Estimated Glomerular Filtration Rate (eGFR) by Schwartz = 0.413 x (Height/Enzymatic Serum 
Creatinine) 
Where: 
eGFR is reported as ml/min/SSA (#) 
Height is reported in cm (#.#) 
Enzymatic Serum Creatinine is reported in mg/dL 
# = Numerical value entered with number of significant digits 
For purposes of reporting in our system 1.73m^2 has been given the unit of SSA, which is short 
for Standard Surface Area. 
2.5.2 Data handling conventions for secondary efficacy variables 
Not applicable. 
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2.5.3 Missing data 
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified.  When relevant, the number of patients with missing data 
is presented. 
Derived variables are considered missing if the original variables required to calculate them are 
missing. For example, if either a baseline assessment or an endpoint assessment is missing for a 
particular patient, then the change from baseline at endpoint is missing. Depending upon the 
assessment, analyses may not include all patients in the analysis population, because certain 
patients in the intended population may have missing data. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing 
For the calculation of the treatment duration, the date of the last dose of IMP is equal to the date of 
last administration reported on the end-of-treatment e-case report form page.  If this date is 
missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the e-case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed.  If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and post-treatment medication. 
Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
No imputation of adverse event/hypoglycemia dates/times will be performed.   
By default all adverse events/hypoglycemia are emergent except if additional information allows 
to classify otherwise. 
Handling of adverse events/hypoglycemia, laboratory data, vital signs when date and time of 
first investigational medicinal product administration is missing 
When the date and time of the first IMP administration is missing, all adverse 
events/hypoglycemia that occurred on or after the day of randomization should be considered as 
treatment-emergent adverse events/hypoglycemia. The exposure duration should be kept as 
missing. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product 
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If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of potentially clinically significant abnormalities 
If a patient has a missing baseline he will be grouped in the category “normal/missing at baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is > 0.5 GIGA/L or >ULN 
if ULN ≥0.5 GIGA/L.  When ULN is missing, the value 0.5 should be used. 
Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
Handling of missing data in the calculation of HbA1c responders, FPG responders 
For HbA1c responders (defined by HbA1c<7.5% overall and without any episode of severe and/or 
documented (SMPG <54 mg/dL; 3.0 mmol/L) hypoglycemia during the last 3 months of the main 
6-month randomized period), patients without any available assessment at endpoint Week 26 will 
be treated as failures (non-responders) in the analysis. 
Similar rule to apply for FPG responders (defined by FPG ≤130 mg/dL (7.2 mmol/L) overall and 
without any episode of severe and/or documented (SMPG <54 mg/dL; 3.0 mmol/L) hypoglycemia 
during the last 3 months of the main 6-month randomized period). 
Handling of hypoglycemia event classification when some classification items are missing 
Rule for handling missing data in classification items for hypoglycemia event will be provided in 
ADaM metadata. 
Handling of missing data in the calculation of 8-point SMPG variables 
For a given 8-point SMPG profile, at least 5 available measurements in the last 7 days are required 
to be taken into account in the statistical analyses (including the descriptive analyses at each  
time-point). 
Handling of missing data in the calculation of average pre-breakfast SMPG, 
At least 3 pre-breakfast (fasting) SMPG values in the last 7 days are required to be taken into 
account in the statistical analyses (including descriptive analyses at each time-point). 
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Handling of missing data in the calculation of insulin doses 
At each visit, the average daily insulin doses (basal, mealtime, and total) will be calculated as the 
average of the daily insulin doses available in the week (7 days) before the visit. 
No minimum number of available doses will be required. 
For insulin doses in U/kg, if the body weight measurement is missing at a given visit, the last 
available measurement from previous visit will be used. 
2.5.4 Windows for time points 
The following process will be applied for visit re-allocation. Re-allocated visits will be used in all 
statistical analyses (descriptive statistics, plots, and statistical models). 
No re-allocation will be performed for nominal visits already provided in the clinical database 
(Visit 1 to Visit 20). 
SMPG 
In the clinical database, SMPG profiles transferred from the e-diary will not be assigned to a 
protocol visit. For the analysis, they will be assigned to the next visit actually performed by the 
patient after the date/time of data collection (visit 3 to visit 20, or visit 700). 
In the clinical database, SMPG assessments which do not correspond to an 8-point profile 
transferred from the e-diary will not be assigned to a protocol visit. For the analysis, they will be 
assigned to the next visit after the date/time of data collection (visit 2 to visit 20, or visit 700). 
Insulin doses 
In the clinical database, insulin doses transferred from the e-diary will not be assigned to a 
protocol visit. For the analysis, they will be assigned to the next on-site visit actually performed by 
the patient after the date/time of data collection. 
End of treatment visit 
The following analysis windows will be applicable to re-allocate the premature end of treatment 
assessments (premature EOT visit) for HbA1c and FPG assessments. 
Table 2 - Analysis windows definition 
Time point 
Targeted study day 
Analysis window in study days 
WEEK 12 
84 
54 to 114 
WEEK 26 
182 
152 to 212 
WEEK 38 
266 
236 to 296 
WEEK 52 
364 
334 to 394 
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Study days are calculated form the day of first IMP injection; the day of first IMP injection being 
Day1. 
To retrieve all safety and AIA assessments performed at the end of treatment visit, the following 
process will be followed: if a patient discontinues the treatment prematurely, end of treatment 
assessments will be re-allocated to the next scheduled on-site visit for the patient. The next 
scheduled on-site visit for each patient will be determined as the next on-site visit that should be 
performed as per protocol, following the last visit actually performed by the patient before end of 
treatment visit. 
For a given parameter, the value will not be re-allocated in the following cases: 
• 
If the parameter is not planned to be collected at the re-allocation visit. 
• 
If a value is already available for the parameter at the re-allocation visit. 
Pharmacokinetic samples 
The following analysis windows will be considered to select samples included in the PK analyses. 
 
Basal insulin 
dosing 
regimen 
Time point 
Analysis time window  
Pre-dose 
within 1h before time of dosing 
4h post-dose 
3h to 5h post dose 
Morning 
8h post-dose 
7h to 9h post-dose 
 
 
 
12h post-dose 
11h to 13h post-dose 
16h post-dose 
15h to 17h post-dose 
Evening 
20h post-dose 
19h to 21h post-dose 
 
2.5.5 Unscheduled visits 
• 
The analysis windows mentioned in Section 2.5.4 will be applicable to re-allocate the 
unscheduled assessments (measurements from the central laboratory only) for HbA1c and 
FPG assessments. 
• 
After applying the time windows as mentioned in Section 2.5.4, if two assessments are 
associated to the same time point, the closest from the targeted study day is used. In case of 
equality, the earliest measurement is used. 
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•
The determination of baseline for HbA1c and FPG variables is based on all measurements
from both scheduled and unscheduled visits (measurements from the central laboratory
only). The determination of baseline for safety parameters is based on all assessments from
both scheduled and unscheduled visits too. The determination of the last on-treatment
value for safety parameters is also based on all assessments from both scheduled and
unscheduled visits. Measurements from the unscheduled visits (including results from
local laboratory when no corresponding central laboratory results are available) are also
considered for PCSA summary of safety parameters.
•
Unscheduled visit measurements are not included in the by-visit summaries.
2.5.6 Pooling of centers for statistical analyses 
No pooling of centers is planned for statistical analyses. Center and country will not be included in 
the statistical analysis. 
2.5.7 Statistical technical issues 
None. 
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3 
INTERIM ANALYSIS 
Not applicable. 
This controlled open-label study will not to be terminated early with a positive claim for efficacy 
or safety.  
The primary analysis of the efficacy and safety will be performed on the data collected during the 
main 6-month comparative treatment period. The timing of this analysis is when the last 
randomized patient has completed the main 6-month comparative treatment period. 
The results of the primary analysis are not used to change the conduct of the ongoing study in any 
aspect. 
The second analysis will be performed on all data collected during the 12-month study period. 
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4 
DATABASE LOCK 
It is planned to lock the database approximately 4 weeks after Last Patient Last Visit of the 
comparative treatment phase (6 months). 
It is further planned to lock the database approximately 4 weeks after Last Patient Last Visit of the 
safety extension phase and the follow-up period. Software documentation 
All summaries and statistical analyses will be generated using SAS Enterprise Guide version 5.1 
or higher. 
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5 
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