Clinical trial NCT02451137
Conditions: Diabetes Mellitus, Type 2
Sponsor: Sanofi
Start date: 2015-06-16; Completion date: 2018-08-09
Enrollment: 3304 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

Demonstrate clinical benefit of Toujeo in achieving individualized Healthcare Effectiveness Data and Information Set (HEDIS) glycated hemoglobin (HbA1c) targets (\<8% if age \>=65 years or with defined comorbidities or otherwise \<7%) at 6 months without documented symptomatic (Blood Glucose \<=70 mg/deciliter \[mg/dL\]) and/or severe hypoglycemia at any time of day from baseline to 6 months in uncontrolled insulin naive participants with type 2 diabetes initiating basal insulin therapy in a real world setting.

Secondary Objectives:

Compare Toujeo to other commercially available basal insulins at 6 months after initiating insulin therapy in a real world setting in terms of:

* Participant persistence with assigned basal insulin therapy.
* Risk of hypoglycemia including the incidence and rate of documented symptomatic and severe hypoglycemia.
* Changes in HbA1c, fasting plasma glucose, body weight
* Differences in participant and provider- reported outcomes (including Diabetes Treatment Satisfaction Questionnaire Status and Change Versions (DTSQs) and (DTSQc), Hypoglycemia Patient Questionnaire, and participant and provider reported Global Effectiveness Scale (GES).
* Healthcare resource utilization including hospitalizations and emergency department or other provider visits and healthcare costs.

Detailed description:
The total study duration per patient will be up to 53 weeks, consisting of a 1-week screening period at the site, a 26-week treatment period, and a 26-week extension period.

Arms: arm 1: Toujeo® (Insulin glargine, 300 units per millilitre \[U/mL\]) subcutaneous (SC) injection once daily up to Month 12, with or without available participant support program. arm 2: Lantus® (Insulin glargine, 100 U/mL) SC injection administered once daily; or Levemir® (Insulin detemir) SC injection administered either once or twice daily up to Month 12, with or without available participant support program.
Interventions: intervention 1: Insulin glargine, 300 U/ml intervention 2: Insulin glargine, 100 U/ml intervention 3: Insulin detemir intervention 4: Background Therapy
Intervention descriptions: intervention 1: Pharmaceutical form: solution

Route of administration: subcutaneous intervention 2: Pharmaceutical form: solution

Route of administration: subcutaneous intervention 3: Pharmaceutical form: solution

Route of administration: subcutaneous intervention 4: Anti-diabetic drugs at investigator discretion and consistent with local labeling guidelines for use with insulin.

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 01 
COMPOUND: Toujeo / insulin glargine 300 units/ml – HOE901 
A randomized, open-label, parallel group real world pragmatic trial to assess the 
clinical and health outcomes of Toujeo® compared to commercially available basal 
insulins for initiation of therapy in insulin naïve patients with uncontrolled type 2 
diabetes mellitus 
STUDY NUMBER: LPS14347 
STUDY NAME: Achieve Control Real Life Study Program 
VERSION DATE / STATUS: Approval date (12-Oct-2016) / Approved 
Protocol Amendment 01 
Version number: 1 (electronic 1.0) 
Date : 12-Oct-2016 
Clinical Trial Protocol 
Version number: 1 (electronic 3.0) 
Date : 20-Feb-2015 
EudraCT:
Not applicable
IND Number(s): 
Not applicable 
Version Number: 
1 
WHO universal trial number: 
Not applicable 
Date: 
12-Oct-2016 
Total number of pages: 
90 
(electronic 1.0)
NCT Number: NCT02451137


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
 
 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: Toujeo (insulin 
glargine 300 units/ml) – HOE901 
STUDY No: LPS14347 
STUDY NAME: Achieve Control Real Life Study Program 
TITLE 
A randomized, open-label, parallel group real world pragmatic trial to assess 
the clinical and health outcomes of Toujeo® compared to commercially 
available basal insulins for initiation of therapy in insulin naïve patients with 
uncontrolled type 2 diabetes mellitus 
INVESTIGATOR/TRIAL LOCATION 
US, Canada 
PHASE OF DEVELOPMENT 
Phase IV 
STUDY OBJECTIVE(S) 
 
Primary Objective 
• 
Demonstrate clinical benefit of Toujeo in achieving individualized 
HEDIS HbA1c targets (<8% if age ≥ 65 years or with defined 
comorbidities (as listed in Appendix G) or otherwise <7%) at 
6 months without documented symptomatic (BG ≤ 70mg/dl) or 
severe hypoglycemia at any time of day from baseline to 6 months 
in uncontrolled insulin naive patients with type 2 diabetes initiating 
basal insulin therapy in a real world setting. 
 
Secondary Objectives 
Secondary objectives are to compare Toujeo to other commercially available 
basal insulins at 6 and 12 months after initiating insulin therapy in a real world 
setting in terms of: 
• 
Patient persistence with assigned basal insulin therapy, 
• 
Risk of hypoglycemia including the incidence and rate of 
documented symptomatic and severe hypoglycemia, 
• 
Changes in HbA1c, fasting plasma glucose, body weight, 
• 
Differences in patient and provider reported outcomes (including 
Diabetes Treatment Satisfaction Questionnaire Status and Change 
Versions [DTSQs and DTSQc]), Hypoglycemia Patient 
Questionnaire, and patient and provider reported Global 
Effectiveness Scale (GES), 
• 
Healthcare resource utilization including hospitalizations and 
emergency department or other provider visits and healthcare 
costs. 
STUDY DESIGN 
 
Potential study patients within designated practice sites who meet eligibility 
criteria may be identified by review of either payer or provider data bases. The 
inclusion/exclusion criteria will be applied to relevant databases to identify 
appropriate subjects with 12 months of baseline medical data available and 
who had actively sought care at the site in the last 12 months. 
 
Achieve Control includes a planning phase and the prospective study phase. 
During the planning phase of the trial, payer, research organization, and HCP 
databases are reviewed to identify appropriate sites and patients eligible for 
the study. Patients may also be identified through ongoing review of these 
databases including at the site level on an ongoing basis during the trial. 
Patients will be screened at the practice site to determine eligibility for study 
enrollment. Patients will be assigned to one of two treatment groups using a 
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patient-level randomization. Given the potential impact of certain variables on 
the primary endpoint, randomization will be stratified by individualized HbA1c 
target (<8%/<7%), SU use ever (y/n), GLP-1 RA use ever (y/n) and baseline 
HbA1c (<9%/≥9%). 
The two treatment arms of the study will be: 
1) Toujeo with its available patient support program,  
2) Commercially available insulin detemir (Levemir®) or insulin 
glargine-U100 (Lantus®) with or without a patient support program.  
 
Randomization will be 1:1 between the two arms of the study and the choice 
of comparator basal insulin will be based on the usual practice at the clinical 
site and not by randomization. 
The study will include a 6 month treatment period ending in assessment of the 
primary and secondary endpoints followed by a 6 month extension period for 
assessment of certain additional endpoints.  It will also include an interim 
analysis (IA) for overwhelming efficacy on the primary endpoint, planned to be 
conducted when approximately 1800 patients have been randomized and 
completed their 6-month visit. If the targeted sample size (1800) cannot be 
reached, it could be considered to include a lower number of patients, 
however not below 1700. In this case, the nominal significance level to be 
spent at interim and at final 6-month analyses would be recalculated 
accordingly before the database lock for IA. 
An independent Data Monitoring Committee (DMC) will review data from this 
IA. 
 
Dose regimen: Patients will be initiated on basal insulin therapy per the 
prescribing instructions for each insulin and titrated to a target fasting glucose 
consistent with the individualized HbA1c target according to the typical 
protocol used at each site and investigator discretion.  
Financial support will be provided by Sanofi for the cost of commercially 
available basal insulin as well as for Toujeo. 
 
Collection of hypoglycemia events and symptoms: 
A glucometer with wireless data transmission capabilities will be used to 
collect self-measured plasma glucose (SMPG) including SMPG associated 
with hypoglycemic symptoms. An electronic diary (eDiary) will be used to 
record the symptoms of hypoglycemia and other relevant clinical information. 
STUDY POPULATION  
Main selection criteria 
Inclusion criteria: 
• 
Patients with T2DM, as defined by the ADA/WHO, diagnosed for at 
least 1 year at the time of the screening visit, insufficiently controlled 
after at least 1 year of treatment with 2 or more of the following: oral 
agents (metformin, sulfonylureas, thiazolidinediones, DPP-4 
inhibitors, or SGLT-2 inhibitors) or GLP-1 receptor agonists for daily 
use and approved for use with insulin (Victoza®, Byetta®, Adlyxin®). 
• 
Adult patients who have signed an Informed Consent Form and 
Health Insurance Portability and Accountability Act (HIPAA) 
Authorization Form  
Exclusion criteria 
• 
HbA1c <8.0% or >11.0%, 
• 
Males or females <18 years of age, 
• 
Type 1 diabetes mellitus, 
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• 
Any clinically significant abnormality identified on physical 
examination, laboratory tests, or vital signs at the time of screening, 
or any major systemic disease resulting in short life expectancy that 
in the opinion of the Investigator would restrict or limit the patient’s 
successful participation for the duration of the study, 
• 
Use of any product containing insulin (Lantus, Levemir, Humulin®, 
Novolin®, Humalog®, Novolog®, Apidra®, Afrezza®, Toujeo®, 
Tresiba®) since the time of diagnosis with T2DM prior to the time of 
screening other than temporary use such as during a pregnancy or 
hospitalization or short term outpatient use (≤10 days) during an 
acute medical event,  
• 
Use of oral hypoglycemic agents other than those noted in the 
inclusion criteria; GLP-1 receptor agonists for weekly use (Trulicity®, 
Tanzeum®, Bydureon®), or not approved for use with insulin, or any 
investigational agent (drug, biologic, device) within 3 months prior to 
the time of screening, 
• 
All contraindications to commercially available insulin therapy or 
warnings/precautions of use as displayed in the respective national 
product labeling for these products, 
• 
Pregnancy or lactation, 
• 
Women of childbearing potential with no effective contraceptive 
method. 
Total expected number of patients 
3324 patients ( 1662 per arm), 160 from Canada 
Approximately 439 sites in US, 20 sites in Canada 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation 
Tested Drug:  
Toujeo/HOE901-U300 will be commercially available 300 U/mL insulin 
glargine solution for subcutaneous (sc) injection in1.5 ml cartridges in the 
marketed Toujeo SoloSTAR® pen device.  
The disposable pen injector allows for dose setting in the range of 1-80 U with 
minimum dose increments of 1.0 U. 
Dilution or mixing of Toujeo with other insulin is not allowed. 
 
Control Drugs: 
Comparator basal insulins (Lantus/Levemir) will be commercially available 
formulations and used according to label. 
Route(s) of administration 
Tested drug or Control drugs:  
Insulin glargine given as either commercially available Toujeo/HOE901-U300 
or Lantus U100 will be self-administered by sc injection once daily in the 
morning or evening according to label. 
Commercially available Levemir will be self- administered by sc injection once 
or twice daily in the morning or evening according to local label. 
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Dose regimen 
Tested drug or Control drugs: 
Dosing of insulin glargine given as Toujeo/HOE901-U300 or Lantus U100 and 
dosing of Levemir will be titrated to a target fasting glucose consistent with the 
individualized HbA1c target according to the typical protocol used at each site 
and investigator discretion.  
Initiation of the basal insulin will be done according to the label and titration 
will be done according to local guidelines and investigator discretion. 
The titration regimen is to be done according to real world practice and there 
is no recommended or forced titration in the protocol. 
Noninvestigational medicinal 
product(s) (if applicable) 
 
Formulation 
Patients in both treatment groups will continue with other anti-diabetes drugs 
as background therapy at the discretion of the investigator and consistent with 
labeling guidelines for use with insulin. 
Route(s) of administration 
Oral anti-diabetic agents 
GLP-1 receptor agonists for daily use which are approved for use with basal 
insulin and are injectable (Victoza, Byetta, Adlyxin). 
Dose regimen 
 
According to label and at investigator discretion 
ENDPOINT(S) 
 
Primary endpoint 
Proportion of patients with individualized HbA1c target attainment per HEDIS 
criteria (<8% if age ≥ 65 years or with defined comorbidities listed in  
Appendix G or otherwise <7%) at 6 months without documented or severe 
symptomatic (BG ≤ 70 mg/dl) hypoglycemia at any time of day from baseline 
to 6 months. 
The individual components of individualized HbA1c target attainment and 
absence of any documented symptomatic or severe hypoglycemia (BG 
≤70 mg/dl) will also be evaluated as supportive analyses to evaluate 
consistency. 
 
Secondary endpoint(s) 
• 
Change in HbA1c from baseline (obtained at screening visit within 
one week of study initiation) to 6 months, 
• 
Proportion of patients who remain on assigned basal insulin therapy 
(persistent with assigned therapy) at 6 and 12 months, 
• 
Proportion of patients with individualized HbA1c target attainment 
per HEDIS criteria at 6 months without documented symptomatic 
(BG <54 mg/dl) or severe hypoglycemia at any time of day from 
baseline to 6 months, 
• 
Proportion of patients with individualized HbA1c target attainment 
(per HEDIS criteria) at 12 months without documented symptomatic 
(BG ≤70 mg/dl) or severe hypoglycemia at any time of day from 
baseline to 12 months, 
• 
Proportion of patients with individualized HbA1c target attainment 
per HEDIS criteria at 12 months without documented symptomatic 
(BG <54 mg/dl) or severe hypoglycemia at any time of day from 
baseline to 12 months. 
 
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Patient Reported Outcomes Endpoints: 
• 
Proportion of patient and provider reported “Excellent” or “Good” 
responses to GES question at 6 months and 12 months, 
• 
Average scores on total treatment satisfaction, hyperglycemia 
perception, and hypoglycemia perception from DTSQs at 6 months 
and 12 months, 
• 
Average scores on change in total treatment satisfaction, 
hyperglycemia perception, and hypoglycemia perception from 
DTSQc at 12 months, 
• 
Proportion of patients who report moderate or severe hypoglycemia 
since last visit on the Hypoglycemia Patient Questionnaire 
(questions 4 and 5) at 6 months and 12 months. 
 
Healthcare Utilization Endpoints: 
• 
Mean number and proportion of patients with hospitalizations over a 
6 month and 12 month period, 
• 
Mean number and proportion of patients with emergency room visits 
over a 6 month and 12 month period, 
• 
Mean number of provider office visits and proportion of patients with 
specialty visits over a 6 month and 12 month period, 
• 
Mean overall and diabetes-related costs at 6 months and 
12 months. 
 
Other endpoint(s) 
• 
Change in HbA1c from baseline to 12 months, 
• 
Change in fasting plasma glucose from baseline to 6 months and 
12 months, 
• 
Change in body weight from baseline to 6 months and 12 months, 
• 
Basal insulin dose at 6 and 12 months. 
 
Safety: 
Hypoglycemia will be classified in categories (Section 9.2.3.1): 
• 
Incidence of documented symptomatic (BG ≤ 70 mg/dl) nocturnal 
(0000-0559) hypoglycemia from baseline to 6 and 12 months, and 
24-hour hypoglycemia from baseline to 12 months, 
• 
Rate of documented symptomatic (BG ≤ 70 mg/dl) hypoglycemia 
(24 hour and nocturnal ) from baseline to 6 and 12 months, 
• 
Incidence and rate of documented symptomatic (BG <54) 
hypoglycemia (24 hour and nocturnal) from baseline to 6 and 
12 months, 
• 
Incidence and rate of severe hypoglycemia (24 hour, per ADA 
definition) from baseline to 6 and 12 months. 
Other safety and tolerability analyses will include adverse events and serious 
adverse events as well as product technical complaint events (PTC). This will 
include injection site reactions, hypersensitivity reactions and vital signs. 
ASSESSMENT SCHEDULE 
See flow chart, Section 1.2 
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STATISTICAL CONSIDERATIONS 
 
Sample Size Determination: 
An original sample size of 1635 patients per treatment arm would provide at 
least 90% power to demonstrate superiority with an absolute difference of at 
least 5.5% in favor of Toujeo versus comparator basal insulins in the 
proportion of patients reaching individualized HbA1c target at month 6 without 
a documented symptomatic (BG ≤ 70 mg/dl) or severe  hypoglycemic event 
from baseline to month 6, assuming 30% of patients enrolled have a target 
HbA1c <8 per HEDIS criteria due to being older or due to the presence of 
medical comorbidities, and the remaining 70% having a target HbA1c <7%. 
Due to the addition of the interim analysis the sample size will be increased to 
a total of 3324 patients (1662 patients per treatment group). The calculation 
takes into account one interim analysis using a group sequential approach 
with an efficacy boundary based on a gamma (-3) alpha spending function. 
The number of patients meeting each of these criteria will be monitored via 
demographic and ICD-9 data to avoid significant deviations from the 
assumptions above. 
The total sample size calculation of 3324 is based on the assumption of a 
maximum of a 33% overall (weighted average) response rate with Lantus, 
and at least a 5.5% increase in response rate with Toujeo, and assumes an 
overall 2-sided test with alpha-level 0.05 with an interim analysis performed 
on 1800 patients followed 6 months. 
 
Analysis Populations: 
The primary analysis will be performed on the Intent-To-Treat (ITT) 
population, which will comprise all randomized patients, irrespective of the 
treatment actually being received at the time of analysis. 
Safety will be assessed on an as-treated population, defined as all 
randomized patients who actually received at least 1 dose or part of a dose of 
IMP, analyzed according to the treatment actually received. 
Primary Analysis: 
The proportion of patients reaching individualized HbA1c target at 6 months 
without documented symptomatic (BG ≤ 70 mg/dl) or severe hypoglycemia 
will be compared between treatment groups using a logistic model with log 
link, adjusting for individualized HbA1c target (<8%/<7%) and other 
stratification factors used at randomization: SU use ever (y/n), GLP-1 RA use 
ever (y/n), and baseline HbA1c (as continuous). As a sensitivity analysis, a 
multivariate analysis will be performed, adding the following baseline 
characteristics BMI, Patient Activation Measure (PAM) as an assessment of 
patient engagement, duration of diabetes and age.  
 
One interim analysis is planned for the purpose of overwhelming efficacy on 
the primary composite endpoint when 1800 patients have been randomized 
and completed their 6-month visit (54.2% information fraction), using a two-
sided nominal significance level of 0.010 based on a Gamma (-3) alpha-
spending function. 
The final 6-month analysis will be conducted when all randomized patients 
(3324) have performed their 6-month visit. The two-sided nominal significance 
level to be used at this final 6-month analysis is 0.046. 
Patients with missing HbA1c data at 6 months will be regarded as not having 
reached HbA1c target. 
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In order to examine the consistency of the primary analysis, the individual 
components of HbA1c target attainment and absence of any documented 
symptomatic (BG ≤ 70 mg/dl) or severe hypoglycemia will also be evaluated. 
The proportion of patients without documented symptomatic (BG ≤ 70 mg/dl) or 
severe hypoglycemia will be compared between treatment groups using logistic 
regression, adjusting for randomization strata and other baseline characteristics 
as clinically appropriate. The proportion of patients reaching individualized 
HbA1c target will be analyzed as for the composite primary endpoint. 
Further, a predictive subgroup identification method will be employed to 
identify subgroups of potential responders. 
 
Analysis of secondary endpoints 
Persistence: 
• 
The incidence of patients completing the 6 month and the 12 month 
periods will be described by treatment arm, 
• 
The proportion of patients who withdraw at Month 6 and Month 12 
will be analyzed by treatment group using a logistic regression 
methodology as described above, 
• 
Cumulative incidence of treatment discontinuation will be 
plots/estimates by treatment arm using a Kaplan-Meier (KM) by 
treatment arm, 
• 
Extent of exposure as well as treatment compliance will also be 
described by treatment arm. 
In addition, for US patients, a medication possession ratio (MPR) will be 
assessed based on number of days that patients had possession of study 
drug based on prescription date and days of supply. A MPR of 80% would be 
indicative of patients being persistent on study medication. 
For patients from US and Canada where there is not data available for 
calculation of the MPR, the extent of study treatment exposure and 
compliance will be assessed and summarized by observance of the actual 
treatment received within the safety population.  
The duration of exposure during the study will be the total number of days of 
administration of IMP, accounting for 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. 
 
Efficacy Endpoints: 
The change in HbA1c from baseline to 6 months will be analyzed using a 
mixed-effect model with repeated measures (MMRM) approach under the 
missing at random framework, using an adequate contrast at Month 6. The 
model will include fixed categorical effects of treatment arm, visit, treatment-
by-visit interaction, randomization strata: individualized HbA1c target 
(<8%/<7%), SU use ever (y/n), GLP-1 RA use ever (y/n), and baseline HbA1c 
(as continuous), as well as baseline HbA1c-by-visit interaction. 
The change in fasting plasma glucose and bodyweight from baseline to 6 and 
12 months will be analyzed in a similar fashion to the change in HbA1c. 
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The proportion of patients with individualized HbA1c target attainment without 
hypoglycemia will be analyzed as described for the primary endpoint.  
PROs:  
Self-reported patient satisfaction and hypoglycemia (DTSQ and 
Hypoglycemia Patient Questionnaire): Satisfaction scores at 6 and 12 months 
will be compared between treatment groups using a MMRM approach as 
described for the continuous efficacy variables.  To adjust for the baseline 
differences between treatment groups, logistic regression will be conducted, 
adjusting for randomization strata; individualized HbA1c target (<8%/<7%), 
SU use ever(y/n), GLP-1 RA use ever(y/n) and baseline HbA1c(as 
continuous). 
Global Effectiveness Scale (GES): At each study endpoint, the proportion of 
patients and providers who reported “Excellent” or “Good” at 6 and 12 months 
will be analyzed using logistic regression as described previously. 
Health resource utilization for each treatment group will be analyzed by 
descriptive analysis. Multivariate analysis will be used to evaluate the 
difference in health resource utilization and cost between treatment groups 
with adjustment for specific covariates.  
Safety Endpoints: 
The incidence of hypoglycemia will be analyzed using logistic regression, 
adjusting for randomization strata and other baseline characteristics as 
clinically appropriate and if the model permits. 
The rate per patient-year of hypoglycemic events will be analyzed using an 
over-dispersed Poisson regression model, adjusting for randomization strata 
and other baseline characteristics as clinically appropriate and if the model 
permits. 
DURATION OF STUDY PERIOD (per 
patient)  
The prospective phase of the trial will consist of: 
• 
1 week screening period at site, 
• 
26 week (6 month) treatment period, 
• 
26 week (6 month) extension period,  
• 
The maximum study duration will be 53 weeks per patient. 
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1 
FLOW CHARTS 
1.1 
GRAPHICAL STUDY DESIGN  
 
 
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1.2 
STUDY FLOW CHART 
 
Screening 
Treatment Period 
VISIT 
1 
2 
 
 
3 
4 
WEEK 
-1 
0 
 
 
26±4 
52±4 
DAY 
-7 
1±7 
45 
90 
180±30 
360±30 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
Patient Demography 
X 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
Prior Medication History 
X 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
X 
Vital Signs (including body weight) 
X 
 
 
 
X 
X 
DTSQs 
x 
x 
 
 
X 
X 
DTSQc 
 
 
 
 
 
x 
Hypoglycemia Patient Questionaire 
x 
x 
 
 
x 
X 
PAM 
x 
 
 
 
 
 
Patient: Global Effectiveness Scale 
 
 
 
 
x 
x 
Provider: Global Effectiveness Scale 
 
 
 
 
x 
x 
Randomization 
 
X 
 
 
 
 
IVRS call 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
Treatment: 
 
 
 
 
 
 
Dispensation of IMP  
 
X 
 
 
 
 
Concomitant Medication 
X 
X 
 
 
X 
X 
Compliance 
 
 
 
 
X 
X 
Insulin Pen Instruction 
 
X 
 
 
 
 
Blood glucose meter dispensing and 
training 
 
x 
 
 
 
 
E-diary dispensing and training 
 
x 
 
 
 
 
Offer to Enroll in PSP 
 
X 
 
 
 
 
Insulin dose 
 
 
 
 
x 
x 
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Screening 
Treatment Period 
Safety: 
 
 
 
 
 
 
AE /SAE recording 
X 
X 
 
 
X 
X 
Diary Reviews at visits 
 
X 
 
 
X 
X 
Hypoglycemia review of electronic sourcea 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
Health Care Utilization 
 
X 
 
 
X 
X 
 
Laboratory Testing: 
Hemoglobin A1c 
X 
 
 
 
X 
X 
Fasting plasma glucose 
X 
 
 
 
x 
X 
Serum creatinine 
X 
 
 
 
 
 
Serum LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
 
 
 
 
 
Pregnancy test (for women of childbearing 
potential)b 
X 
 
 
 
X 
X 
a Approximately Day 45 and approximately Day 90, review of electronic source without on site or telephone visit 
b Pregnancy status should be checked by serum pregnancy testing prior to exposure to the investigational product, urine pregnancy tests may be done at subsequent visits 
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2 
TABLE OF CONTENTS 
 
1 
FLOW CHARTS.............................................................................................................................11 
1.1 
GRAPHICAL STUDY DESIGN ......................................................................................................11 
1.2 
STUDY FLOW CHART..................................................................................................................12 
2 
TABLE OF CONTENTS ................................................................................................................14 
3 
LIST OF ABBREVIATIONS ..........................................................................................................19 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
5 
STUDY OBJECTIVES ...................................................................................................................24 
5.1 
PRIMARY.......................................................................................................................................24 
5.2 
SECONDARY OBJECTIVES.........................................................................................................24 
6 
STUDY DESIGN ............................................................................................................................25 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................25 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................25 
6.2.1 
Duration of study participation for each patient .............................................................................25 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................26 
6.3 
INTERIM ANALYSIS......................................................................................................................26 
6.4 
STUDY COMMITTEES..................................................................................................................26 
6.4.1 
Data Monitoring Committee ...........................................................................................................26 
7 
SELECTION OF PATIENTS..........................................................................................................28 
7.1 
INCLUSION CRITERIA..................................................................................................................28 
7.2 
EXCLUSION CRITERIA ................................................................................................................28 
7.2.1 
Exclusion criteria related to study methodology ............................................................................28 
7.2.2 
Exclusion criteria related to the active comparator and/or mandatory background therapies.......29 
7.2.3 
Exclusion criteria related to the current knowledge of Sanofi compound......................................29 
8 
STUDY TREATMENTS .................................................................................................................30 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) .....................................................................30 
8.1.1 
Name of the investigational medicinal product ..............................................................................30 
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8.1.2 
Pharmaceutical forms of the investigational medicinal product and injection devices ..................30 
8.1.3 
The dose of the administered Toujeo and control drugs ...............................................................31 
8.1.4 
Route and method of investigational medicinal product administration.........................................31 
8.1.5 
Timing of investigational medicinal product ...................................................................................31 
8.1.6 
Starting dose of investigational medicinal product.........................................................................31 
8.1.7 
Evaluation of patients not meeting glycemic goals........................................................................32 
8.1.8 
Reasons for treatment discontinuation ..........................................................................................32 
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS (NIMP) ........................................................32 
8.3 
BLINDING PROCEDURES............................................................................................................33 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP ..............................................33 
8.5 
PACKAGING AND LABELING ......................................................................................................33 
8.6 
STORAGE CONDITIONS AND SHELF LIFE................................................................................34 
8.7 
RESPONSIBILITIES ......................................................................................................................34 
8.8 
TREATMENT ACCOUNTABILITY AND COMPLIANCE ...............................................................35 
8.9 
CONCOMITANT MEDICATION.....................................................................................................35 
8.9.1 
Prohibited medications...................................................................................................................36 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................37 
9.1 
PRIMARY ENDPOINT ...................................................................................................................37 
9.2 
SECONDARY ENDPOINTS ..........................................................................................................37 
9.2.1 
Secondary efficacy endpoints........................................................................................................37 
9.2.2 
Other endpoint(s) ...........................................................................................................................38 
9.2.2.1 
Observation period of efficacy variables........................................................................................38 
9.2.2.2 
Efficacy assessment methods .......................................................................................................38 
9.2.3 
Safety endpoints ............................................................................................................................39 
9.2.3.1 
Hypoglycemia classification...........................................................................................................40 
9.2.3.2 
Adverse events, serious adverse events .......................................................................................41 
9.2.3.3 
Adverse event observation period .................................................................................................41 
9.2.3.4 
Death observation periods .............................................................................................................42 
9.2.3.5 
Laboratory safety variables............................................................................................................42 
9.2.3.6 
Vital Signs ......................................................................................................................................42 
9.2.3.7 
Electrocardiogram variables ..........................................................................................................42 
9.2.3.8 
Injection site reactions, hypersensitivity reactions and immunogenicity........................................42 
9.3 
OTHER ENDPOINTS ....................................................................................................................43 
9.3.1 
Patient reported outcomes.............................................................................................................43 
9.3.2 
Health utilization endpoints ............................................................................................................43 
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9.4 
FUTURE USE OF SAMPLES........................................................................................................44 
9.5 
APPROPRIATENESS OF MEASUREMENTS..............................................................................44 
10 
STUDY PROCEDURES ................................................................................................................45 
10.1 
VISIT SCHEDULE..........................................................................................................................45 
10.1.1 
Screening Period............................................................................................................................46 
10.1.1.1 On-site Visit 1 (Week -1) Screening visit .......................................................................................46 
10.1.1.2 Baseline Visit 2 (Week 0, Day1) +/-7 days ....................................................................................47 
10.1.1.3 Visit 3 (Day 180) +/- 30 days .........................................................................................................48 
10.1.1.4 Visit 4 (Day 360) +/- 30 days .........................................................................................................48 
10.1.1.5 Unscheduled phone visits ..............................................................................................................49 
10.1.1.6 Glucose review at Day 45 and Day 90 ..........................................................................................49 
10.1.1.7 “Standard of Care” visits ................................................................................................................49 
10.2 
DEFINITION OF SOURCE DATA..................................................................................................50 
10.2.1 
Source data to be found in patient’s file.........................................................................................50 
10.2.1.1 Source data verification requirements for screen failures .............................................................50 
10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................51 
10.3.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................51 
10.3.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................51 
10.3.3 
List of criteria for permanent treatment discontinuation.................................................................51 
10.3.4 
Handling of patients after permanent treatment discontinuation ...................................................52 
10.3.5 
Procedure and consequence for patient withdrawal from study....................................................52 
10.4 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................53 
10.4.1 
Definitions of adverse events.........................................................................................................53 
10.4.1.1 Adverse event ................................................................................................................................53 
10.4.1.2 Serious adverse event ...................................................................................................................53 
10.4.1.3 Adverse event of special interest...................................................................................................54 
10.4.2 
Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities.......................................................................................................................................55 
10.4.3 
General guidelines for reporting adverse events...........................................................................55 
10.4.4 
Instructions for reporting serious adverse events..........................................................................56 
10.4.5 
Guidelines for reporting adverse events of special interest...........................................................56 
10.4.6 
Guidelines for management of specific laboratory abnormalities ..................................................56 
10.5 
OBLIGATIONS OF THE SPONSOR .............................................................................................57 
10.6 
SAFETY INSTRUCTIONS.............................................................................................................58 
10.6.1 
Hypoglycemia.................................................................................................................................58 
10.6.2 
Local safety....................................................................................................................................59 
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10.6.3 
Follow-up of laboratory abnormalities............................................................................................59 
10.6.4 
SMPG.............................................................................................................................................60 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................60 
11 
STATISTICAL CONSIDERATIONS..............................................................................................61 
11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................61 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................61 
11.3 
ANALYSIS POPULATIONS...........................................................................................................62 
11.3.1 
Efficacy populations .......................................................................................................................62 
11.3.1.1 Intent–to-treat population...............................................................................................................62 
11.3.2 
Safety population ...........................................................................................................................62 
11.4 
STATISTICAL METHODS .............................................................................................................62 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................62 
11.4.1.1 Extent of investigational medicinal product exposure....................................................................62 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................62 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................62 
11.4.3 
Analyses of safety data..................................................................................................................64 
11.4.4 
Analyses of Patient Reported Outcomes.......................................................................................64 
11.4.5 
Health-related Quality of Life/health economics variables.............................................................65 
11.5 
INTERIM ANALYSIS......................................................................................................................65 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................66 
12.1 
ETHICAL AND REGULATORY STANDARDS..............................................................................66 
12.2 
INFORMED CONSENT .................................................................................................................66 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............67 
13 
STUDY MONITORING ..................................................................................................................68 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................68 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................68 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................69 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................69 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................69 
14 
ADDITIONAL REQUIREMENTS...................................................................................................70 
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14.1 
CURRICULUM VITAE ...................................................................................................................70 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................70 
14.3 
CONFIDENTIALITY .......................................................................................................................70 
14.4 
PROPERTY RIGHTS.....................................................................................................................71 
14.5 
DATA PROTECTION.....................................................................................................................71 
14.6 
INSURANCE COMPENSATION....................................................................................................71 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................72 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................72 
14.8.1 
By the Sponsor...............................................................................................................................72 
14.8.2 
By the Investigator .........................................................................................................................73 
14.9 
CLINICAL TRIAL RESULTS..........................................................................................................73 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................73 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................74 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................75 
17 
APPENDICES................................................................................................................................77 
APPENDIX A 
PATIENT SUPPORT PROGRAM .......................................................................................78 
APPENDIX B 
GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI......................................................................................................79 
APPENDIX C GLOBAL EVALUATION OF TREATMENT EFFECTIVENESS ..........................................83 
APPENDIX D DIABETES TREATMENT SATISFACTION QUESTIONNAIRE .........................................84 
APPENDIX E 
DIABETES TREATMENT SATISFACTION QUESTIONNAIRE (CHANGE).......................85 
APPENDIX F INSIGNIA PATIENT ACTIVATION MEASURE ...................................................................86 
APPENDIX G 
HEALTHCARE EFFECTIVENESS DATA AND INFORMATION SET (HEDIS) 
CRITERIA FOR INDIVIDUALIZED HBA1C TARGETS.................................................................88 
APPENDIX H HYPOGLYCEMIA PATIENT QUESTIONNAIRE.................................................................89 
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3 
LIST OF ABBREVIATIONS  
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
AESI: 
adverse event of special interest 
BG: 
blood glucose 
CDE: 
certified diabetes educator 
CRF: 
case report form 
DTSQc: 
diabetes treatment satisfaction questionaire change version 
DTSQs: 
diabetes treatment satisfaction questionaire status version 
FDA: 
Food and Drug Administration 
FPG: 
fasting plasma glucose 
GES: 
global effectiveness scale 
GLP: 
glucagon like peptide 
GSO: 
global safety officer 
HbA1c: 
glycosylated hemoglobin 
HIPAA: 
health insurance portability and accountability act 
HLGT: 
high group level term 
HLT: 
high level term 
IMP: 
investigational medicinal product 
IVRS/IWRS: 
interactive voice response system/interactive web response system 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MPR: 
medication possession ratilo 
NIMP: 
non-investigational medicinal product 
OAD: 
oral anti-diabetic agent 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PRO: 
patient reported outcomes 
PSP: 
patient support program 
PT: 
preferred term 
SMPG: 
self-measured plasma glucose 
SOC: 
system organ class 
T2DM: 
type 2 diabetes 
 
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4 
INTRODUCTION AND RATIONALE  
Type 2 diabetes mellitus is a progressive disease characterized by relative insulin deficiency and 
eventual need for supplemental insulin therapy (1), (2).  Appropriate initiation and titration of 
insulin therapy is essential to enhance adherence to therapy and reach glycemic targets (3).  
Attainment of these targets is associated with a reduction in the incidence of long term diabetes-
related microvascular complications such as retinopathy, nephropathy, and neuropathy (4), (5). 
Currently available basal insulins are effective but associated with undesirable adverse effects 
such as hypoglycemia and weight gain (3).  Insulins currently in development seek to provide 
similar or improved efficacy with an improved safety profile.  Toujeo (insulin glargine 
300 units/ml) is a basal insulin currently submitted for FDA approval and potential launch in 
2015. Toujeo has distinct pharmacokinetic (PK) and pharmacodynamic (PD) profiles compared to 
Lantus (insulin glargine 100 units/ml) which arise from its unique formulation (6), (7).  The 
higher concentration of insulin in Toujeo allows a smaller volume to deliver the same number of 
glargine units as Lantus with a corresponding smaller surface area for the subcutaneous glargine 
depot which forms after injection. This smaller surface area results in a more gradual release of 
insulin glargine resulting in a flatter and smoother PK profile and longer duration of action on the 
PD profile (6), (7). 
Toujeo has been shown to be non-inferior to Lantus with respect to glycosylated hemoglobin 
(HbA1c) reduction in phase 3 studies (the EDITION program) (8), (9), (10).  Of note, a 
significantly lower percentage of patients with type 2 diabetes experienced confirmed or severe 
nocturnal hypoglycemic events on Toujeo compared to Lantus (8), (9), (10).  This finding 
suggests that a safer initiation and titration of basal insulin may be possible with Toujeo compared 
to other currently available basal insulins especially when coupled with adequate patient support. 
Although the EDITION studies provided efficacy and safety data required for regulatory review 
of Toujeo by the appropriate agencies, reimbursement for a new insulin by payers will require 
additional evidence establishing the value of Toujeo in real world clinical practice.  The unique 
profile of Toujeo compared to Lantus and other basal insulins should allow target HbA1c 
achievement with a lower risk of hypoglycemia. This, in turn, should result in greater patient 
satisfaction with treatment.  A greater number of patients at glycemic goal without hypoglycemia 
should also lead to decreased resource utilization and associated healthcare costs.  This 
combination of improved clinical outcomes accompanied by greater patient satisfaction and 
decreased healthcare costs is of considerable interest to payers globally (11). 
Real world study design is particularly relevant to payers as it is not constrained by the parameters 
required for traditional clinical trials which demonstrate benefit in a narrowly defined target 
population which may not be representative of the population that may benefit from treatment. 
Real world studies should mimic real world clinical practice by: minimizing the requirement for 
monitoring (typically possible only when treatment is approved and available) and limiting 
protocol mandated visits to only those needed for designated endpoints. Integrity of the “real 
world” nature should be preserved as much as possible since each compromise will decrease 
impact and relevance to payers.  This also pertains to use of study specific treatment algorithms 
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and interventions and treatment should be according to the usual practice at the site. In addition, 
patients should be selected and identified through clinical practice sites and not through research 
sites as in clinical trials. Minimal study inclusion and exclusion criteria should be considered so as 
to include a broad patient profile for generalizability of results.  
The proposed pragmatic trial design seeks to demonstrate the benefit of Toujeo with its associated 
patient support program in achieving individualized glycemic targets without hypoglycemia in 
uncontrolled insulin naive patients with type 2 diabetes who are initiating basal insulin therapy in 
a clinical practice setting. The study is a randomized, controlled, open label parallel group real 
world study with few inclusion/exclusion criteria and conducted at clinical practice sites without 
study mandated titration algorithms.  
The importance of diabetes education and patient self-management in the overall management of 
diabetes has been demonstrated with improvements in some clinical outcomes and also in 
measures of health care utilization. The best strategy needs to be determined in the real world 
setting for the support of patients who are insulin naïve and initiating insulin treatment. In this 
pragmatic study, a real world approach to providing patient education and support is incorporated 
via the patient support programs. 
Achieve Control includes a planning phase and the prospective study phase. During the planning 
phase of the trial, payer, research organization, and HCP databases are reviewed to identify 
appropriate sites and patients eligible for the study, Patients may also be identified through review 
of these databases including at the site level on an ongoing basis during the trial. The 
inclusion/exclusion criteria will be applied to relevant databases to identify appropriate subjects, 
ensuring that at least 12 months of baseline medical data are available and patients had actively 
sought care at the site in the last 12 months. The intent of the study is to demonstrate the efficacy 
of Toujeo in a Real World setting where there is ongoing care provided by the site investigator 
prior to, during the trial, and after the trial is over. 
In the prospective phase prospective and will begin after potential candidates are screened, and 
subsequently randomized to:  
1) Toujeo with its available patient support program (Appendix A) or 
2) Lantus (12) or Levemir (13) with or without a patient support program.  
Randomization will be 1:1 between the two arms of the study and the choice of comparator basal 
insulin will be based on the usual practice at the clinical site and not by randomization. 
The prospective phase will include an initial 6 month period for assessment of primary and 
secondary efficacy endpoints and safety endpoints followed by a 6 month extension period for 
evaluation of additional endpoints to include PRO and health care utilization endpoints at 1 year 
after randomization.  It will also include an interim analysis (IA), for overwhelming efficacy on 
the primary endpoint, planned to be conducted when 1800 patients have been randomized and 
completed their 6-month visit. An independent Data Monitoring Committee (DMC) will review 
data from this IA. 
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The primary endpoint is defined as the proportion of patients with individualized HbA1c target 
attainment per Healthcare Effectiveness Data and Information Set (HEDIS) criteria (14) (provided 
in Appendix G) at 6 months without documented symptomatic (BG ≤ 70 mg/dl) or severe 
hypoglycemia at any time of day from baseline to 6 months. 
Based on data from the EDITION program (8), (9), (10) the expected difference in achievement 
of this endpoint for the two target HbA1c levels specified by HEDIS are as follows: 1) 5.5% 
difference in favor of Toujeo with target HbA1c <7%, with a 30.1% rate in the Toujeo arm, and 2) 
5.4% difference in favor of Toujeo with target HbA1c <8%, with a 55.8% rate in the Toujeo arm.  
This difference was used in the calculation of the estimated sample size based on the assumption 
from commercially insured population databases that 70% of the study patients would have a 
target HbA1c <7% and 30% would have a target HbA1c <8% (15). 
The proposed study also intends to collect data on several secondary endpoints. These include:  
1. Change in HbA1c from baseline to 6 months and 12 months;  
2. Persistence/discontinuation of basal insulin therapy;  
3. Patient reported outcomes of treatment satisfaction and experience of hypoglycemia; 
4. Health resource utilization and cost and; 
5. Hypoglycemia. 
Persistence/Discontinuation of basal insulin therapy:  
Discontinuation from basal insulin therapy will be defined as a patient not being persistent with 
their therapy. In the US, reimbursement vouchers will be used to evaluate discontinuation at 6 and 
12 months for patients enrolled in the study.  Additionally, a medication possession ratio (MPR) 
will be assessed based on number of days that patients had possession of study drug based on 
prescription date and days of supply. A medication possession ratio (MPR) of 80% would be 
indicative of patients being persistent on study medication (16).  
Patient-Reported Outcomes (PRO):  
Patients will complete self-reported questionnaires at designated time points in the study: 
The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) (17) will be used to 
evaluate patient satisfaction with treatment and patient perception of blood glucose control over a 
several week period. The DTSQs is comprised of 8 questions which are answered on a Likert 
scale from 0 to 6. Responses to these questions would be summarized into the three domain scores 
GES of Total Treatment Satisfaction, Hyperglycemia Perception and Hypoglycemia Perception 
such that a higher score would be indicative of better satisfaction.. 
The Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) will be used to 
measure change in treatment satisfaction at 12 months.  
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Patients will also complete the Hypoglycemia Patient Questionnaire (18) which will require them 
to report frequency of hypoglycemia experienced during the course of the study. Proportion of 
patients reporting moderate or severe hypoglycemia will be compared between treatment groups. 
Patient and Physician reported Global Effectiveness Scale (GES): The measure, originally 
developed to assess the impact of treatment on asthma control, will be adapted for diabetes.  
Health Resource Utilization 
The proposed study also intends to collect data on health resource utilization from payer patients 
who agree to release their claims data which will include physician office visits, emergency room 
(ER) visits and hospitalizations and health care costs. Data for these endpoints will be obtained 
from the health claims database of the payer involved in the study.  Occurrence of the events will 
be summarized over 6 and 12 month time periods for each patient to confirm presence of the 
events at the corresponding time points.  
Health resource utilization information will be collected through the supplemental case report 
form (CRF) at each site for all patients in US and Canada, whether they have claims data or not.  
Health care costs will not be collected from non-payer sites. 
 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
• Demonstrate clinical benefit of Toujeo in achieving individualized HEDIS HbA1c targets 
(<8% if age ≥ 65 years or with defined comorbidities (as listed Appendix G or otherwise 
<7%) at 6 months without documented symptomatic (BG ≤ 70 mg/dl) or severe 
hypoglycemia at any time of day from baseline to 6 months in uncontrolled insulin naive 
patients with type 2 diabetes initiating basal insulin therapy in a real world setting. 
5.2 
SECONDARY OBJECTIVES 
Secondary objectives are to compare Toujeo to other commercially available basal insulins at 6 
and 12 months after initiating insulin therapy in a real world setting in terms of: 
• Patient persistence with assigned basal insulin therapy. 
• Risk of hypoglycemia including the incidence and rate of documented symptomatic and 
severe hypoglycemia. 
• Changes in HbA1c, fasting plasma glucose (FPG), body weight. 
• Differences in patient and provider reported outcomes (including Diabetes Treatment 
Satisfaction Questionnaire Status and Change Versions [DTSQs and DTSQc]), 
Hypoglycemia Patient Questionnaire, and patient and provider reported Global 
Effectiveness Scale (GES). 
• Healthcare resource utilization including hospitalizations and emergency department or 
other provider visits and healthcare costs. 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is a multi-center open label randomized active controlled 2 arm parallel group comparative 
“real world” or “pragmatic”  trial in patients with type 2 diabetes who are insulin naïve and 
uncontrolled on two or more diabetes medications including oral anti-diabetic agents (OADs) 
and/or GLP-1 RA.  Patients are randomized 1:1 to Toujeo or “Standard of Care” insulin without 
further sub randomization and with use of the SOC insulin determined by preference of site 
investigator and practice patterns of the site. 
The goal of the study is to demonstrate that Toujeo with its available patient support program will 
be superior to other commercially available basal insulin, specifically Lantus and Levemir with a 
patient support program recommended by the site in attainment of individualized HEDIS HbA1c 
targets at 6 months without documented symptomatic (BG ≤ 70 mg/dl) or severe hypoglycemia at 
any time of day from baseline to 6 months. 
The protocol allows for nearly all OADs and GLP-1 RA for daily use as background medication 
as allowed for use with insulin in the label. 
Stratification factors for randomization include GLP-1 RA use ever (y/n), SU use ever (y/n) and 
HbA1c (<9%/ ≥9%). 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
During the planning phase of the trial, payer, research organization, and provider data bases will 
be reviewed to identify sites and patients eligible for the study. 
After the data base review, the trial will consist of: 
•
1 week screening period at site by clinician to screen the identified potential subjects
•
26 week treatment period for primary efficacy endpoint
•
26 week extension period for collecting persistence data and additional safety data.
The maximum study duration will be 53 weeks per patient.  
For patients who prematurely discontinue the trial, the end of treatment visit assessments 
(Day 180 data) will be performed at the time of discontinuation at an EOT visit. In addition, an 
early end of trial (EOT) CRF page will be completed which includes the reason for stopping the 
treatment.  Patients are then asked to return for their regularly schedule visits off treatment. 
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6.2.2 Determination of end of clinical trial (all patients) 
The end of the clinical trial is reached as soon as last patient visit is performed. 
6.3 
INTERIM ANALYSIS 
One formal IA is planned for the purpose of overwhelming efficacy of primary endpoint when 
1800 patients have been randomized and completed their 6 month visit (Day 180). Statistical 
operating characteristics of this analysis, including the α-spending function to control the Type I 
error, are described in the statistical considerations (see Section 11.5). 
Limited efficacy data is available regarding the initiation of insulin treatment in a “Real World” or 
pragmatic study.  Achieve Control is a study designed to provide data on the efficacy and safety 
of Toujeo in a “Real World” setting.  The unique primary composite endpoint has clinical 
relevance for managed care organizations and the study will provide safety and efficacy data for 
health care providers in their usual practice setting, rather than a traditional RCT.  
The unanticipated challenges of recruiting patients in this unique trial design have resulted in 
delayed enrollment. Based on the need for real life Toujeo data for informing the decision makers 
on insulin use in managed care organizations, the objective of the study and IA is to generate real 
world evidence for the purpose of healthcare reimbursement and scientific communication only. 
Results of this IA will be reviewed by the DMC (Section 6.4.1). The DMC procedures will be 
done with the utmost possible care for protecting clinical data integrity and for maintaining the 
blinding of Sponsor representatives and trial team so as not to impact final interpretation of the 
study results. 
6.4 
STUDY COMMITTEES 
6.4.1 Data Monitoring Committee 
An independent DMC will be in charge of reviewing the unblinded efficacy results of the interim 
analysis. The DMC will give appropriate recommendations to the Sponsor on whether 
overwhelming efficacy is reached or not for the primary composite endpoint.  The DMC may 
make recommendations regarding any measures that may be required for ensuring the integrity of 
the study results during the execution of its primary mission including assessing the risk benefit.  
Overwhelming efficacy will be shown if the p-value of the superiority test for comparison of 
Toujeo and comparator basal insulins on the primary endpoint is below 0.010 with a higher 
proportion of patients reaching the primary endpoint in the Toujeo group. 
The corresponding power to show overwhelming efficacy at interim analysis under the alternative 
hypothesis is of 45%.   
If overwhelming efficacy is not shown (probability of 55% under the alternative hypothesis) the 
Sponsor would not see the unblinded data, and no results would be communicated. If 
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overwhelming efficacy is shown (probability of 45% under the alternative hypothesis) the 
Sponsor would see the data, and results would be communicated in agreement with the DMC.  It 
could be considered to stop the recruitment (total sample size at that time estimated to be between 
2600-3000 patients). However, study participation for patients already recruited would continue 
as planned.  In either case (superiority achieved at interim or not), the study will  continue up to 
month  6 and up to month 12 as planned, with analyses performed on whole study population. 
The DMC consists of 3 members 2 of whom are clinicians with expertise in diabetology and one 
biostatistician. Members of the DMC are independent of those performing these studies, being 
neither Investigators nor employees of the Sponsor and without conflict of interest regarding 
study outcomes. For details, please refer to the DMC charter.  
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7 
SELECTION OF PATIENTS 
7.1 
INCLUSION CRITERIA 
I 01. Patients with type 2 diabetes (T2DM), as defined by the ADA/WHO, diagnosed for at least 
1 year at the time of the screening visit, insufficiently controlled after at least 1 year of 
treatment with 2 or more of the following: oral agents (metformin, sulfonylureas, 
thiazolidinediones, DPP-4 inhibitors, or SGLT-2 inhibitors) or GLP-1 receptor agonists for  
daily use and approved for use with insulin (Victoza®
, Byetta®, Adlyxin®).  
I 02. Adult patients who have signed an Informed Consent Form and Health Insurance 
Portability and Accountability Act (HIPAA) Authorization Form  
7.2 
EXCLUSION CRITERIA 
Patients who have met all the above inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria which are sorted and numbered in the following 4 subsections: 
7.2.1 Exclusion criteria related to study methodology 
E 01. HbA1c <8.0% or >11.0%. 
E 02. Males or females <18 years of age. 
E 03. Type 1 diabetes mellitus 
E 04. Any clinically significant abnormality identified on physical examination, laboratory tests, 
or vital signs at the time of screening, or any major systemic disease resulting in short life 
expectancy that in the opinion of the Investigator would restrict or limit the patient’s 
successful participation for the duration of the study. 
E 05. Use of any product containing insulin (Lantus, Levemir, Humulin, Novolin, Humalog, 
Novolog, Apidra, Afrezza, Toujeo, Tresiba) since the time of diagnosis with T2DM prior 
to screening other than temporary use such as during a pregnancy or hospitalization or 
other short term outpatient use (≤ 10 days) during an acute medical event.  
E 06. Use of oral hypoglycemic agents other than those noted in the inclusion criteria; GLP-1 
receptor agonists for weekly use (Trulicity®, Tanzeum®, Bydureon®) or not approved for 
use with insulin or any investigational agent (drug, biologic, device) within 3 months prior 
to the time of screening. 
E 07. All contraindications to commercially available insulin therapy or warnings/precautions of 
use as displayed in the respective national product labeling for these products. 
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7.2.2 Exclusion criteria related to the active comparator and/or mandatory background 
therapies  
E 08. All contraindications of the positive control/calibrator/protocol-mandated background 
therapy(ies) or warning/precaution of use (when appropriate) as displayed in the respective 
National Product Labeling that was used for defining these exclusion criteria. 
7.2.3 Exclusion criteria related to the current knowledge of Sanofi compound  
E 09. Pregnant or breastfeeding woman. 
E 10. Woman of childbearing potential not protected by highly-effective method(s) of birth 
control (as defined in a local protocol amendment in case of specific local requirement) 
and/or who are unwilling or unable to be tested for pregnancy. 
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8 
STUDY TREATMENTS 
Diet and lifestyle counseling is an essential component of this trial. Patients in the trial will have 
ongoing diet and lifestyle counseling provided at their clinical practice site by the clinician or staff 
as per their usual custom.  Patients may also be enrolled in diabetes education programs at the 
discretion of the investigator.  At the time of randomization, the patients randomized to Toujeo 
will be offered the additional support through an available patient support program (PSP) unique 
for Toujeo. This will include an initial detailed session by a professional competent in treating 
type 2 diabetes mellitus. Patients randomized to the “standard of care” arm of the trial will be 
offered a support program that may be office based, hospital affiliated, community based or 
provided by a payer. 
Investigators and site staff will provide educational materials and training both oral and written 
consistent with the local standard of care to ensure their patients understand the importance of 
routine monitoring and dose adjustment of their basal insulin. The goal for all patients must be to 
attain good glycemic control by treating to a defined glucose target without an increase in 
hypoglycemia. This should be done consistent with the “real world setting”. 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT (IMP) 
8.1.1 Name of the investigational medicinal product 
Sanofi’s Toujeo HOE/901 U300 glargine is the tested drug and U100 insulin glargine (Lantus) 
and insulin detemir (Levemir) are the comparator/control drugs. 
8.1.2 Pharmaceutical forms of the investigational medicinal product and injection 
devices  
Handling procedures of the pen and needles and administration technique is provided; see 
package insert for Toujeo SoloSTAR pen and Sanofi sponsored materials for Lantus U100 
SoloSTAR™ pen and Novo sponsored materials for the Levemir® FlexTouch™. 
Patients will be trained by the staff at the practice site, or by a certified diabetes educator (CDE) 
on the use of the injection devices as close as is possible to time of the randomization visit. A 
training pen may be requested by the site.  Training may be performed with the initial pen to be 
used for administration of insulin after obtained from pharmacy in the US or with a training pen. 
Canadian sites may use one of the pens dispensed by the site. 
The disposable pen injector allows for dose setting in the range of 1-80 U with minimum dose 
increments of 1.0 U. 
If a pen-related event occurs, a PTC form should be completed if appropriate. 
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8.1.3 The dose of the administered Toujeo and control drugs 
The dose of the administered basal insulin either Toujeo or the control drugs Lantus and Levemir 
depends on the self-measured plasma glucose (SMPG) data and occurrence of hypoglycemia and 
is at the discretion of the Investigator according to their usual practice in the real world setting. 
There is no recommended titration algorithm. Initial dose of basal insulin is to be consistent with 
the label. 
8.1.4 Route and method of investigational medicinal product administration 
Toujeo or the control drugs Lantus and Levemir are self-administered by deep subcutaneous 
injection, in the abdomen, thigh, arm or buttock and rotated within that area. Area and sites of 
injection will not be collected as data. 
US: 
Patients randomized to Toujeo will be prescribed the appropriate number of disposable Toujeo 
SoloSTAR disposable pens to be dispensed at their pharmacy. Patients randomized to Lantus or 
Levemir will be prescribed the appropriate number of pens to be dispensed at their pharmacy. 
Canada: 
The appropriate number of disposable pens for Toujeo or the control drugs Lantus and Levemir 
will be dispensed at the site. Insulin will be obtained from a commercial source and will be 
labeled according to local regulation for use in the study.  Insulin will be dispensed by the site at 
investigator discretion and is not related to a visit. Specifically, there are no dispensing visits and 
no schedule for dispensing. 
8.1.5 Timing of investigational medicinal product 
Toujeo is self-administered by deep subcutaneous injection once daily in the morning or evening, 
not related to food intake, consistent with the label.  Lantus is self-administered once daily in the 
morning or evening, also not related to food intake.  Levemir is self-administered either once or 
twice daily, in the morning or evening. 
8.1.6 Starting dose of investigational medicinal product 
The starting dose for the insulin either tested or control will be consistent with the label and 
recorded in the source document. 
The recommended target range for fasting, pre-prandial plasma glucose is 80 to 130 mg/dL (4.4 to 
7.2 mmol/L), consistent with ADA guidelines. The dose of basal insulin will be adjusted to 
achieve this target.  However, glycemic targets may be adapted for individual patients, if deemed 
necessary, eg, due to age, comorbid conditions, and individual patient considerations.  The 
individual target range for glucose will be recorded in source documents. Insulin doses may be 
reduced or modified at any time for hypoglycemia. 
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Patients are to take their basal insulin once daily and with SMPG done per “usual habit” per 
provider instruction to assist in titration 
8.1.7 Evaluation of patients not meeting glycemic goals 
There are no central laboratory alerts on fasting plasma glucose or HbA1c to ensure that glycemic 
parameters remain below predefined threshold values. Patient SMPG monitoring is decided upon 
by site and patient diaries are reviewed at the time of visits to assist in titration. In addition, sites 
have access electronically to the information collected in the web based portal regarding 
hypoglycemia.  In case SMPG are not improving as expected in spite of successive Investigational 
Medicinal Product (IMP) dose titration, the investigator should ensure that no reasonable 
explanation exists for insufficient glucose control and in particular that: 
•
Compliance to treatment is appropriate
•
There is no inter-current disease which may jeopardize glycemic control
•
Compliance to diet and lifestyle is appropriate and per the usual custom for the site
•
Regular blood glucose monitoring is being done since it is important to achieve blood
glucose targets
Patients who are unable to achieve their target may have other medications “rescue medications” 
added to their existing regimen which might include the use of bolus or rapid acting insulin.  
When a medication is added or changed, the reason is captured in the e-CRF as well as the 
medication. 
Patients who change their background medication for reason other than being unable to achieve 
their target are not considered using “rescue medication”. 
8.1.8 Reasons for treatment discontinuation  
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time. List of criteria for discontinuation are found in Section 10.3.3 Handling of patients after 
discontinuation is described in Section 10.3.4. Sites are to follow their local SOP for stopping 
treatment if there is a potential adverse event (AE) related to use of the IMP and according to 
investigator discretion.  
8.2 
NONINVESTIGATIONAL MEDICINAL PRODUCTS (NIMP) 
Non-investigational products (NIMP) such as oral anti-diabetic agents and GLP-1 agonists for 
daily use and which can be used with insulin may be used throughout the trial. These agents may 
be changed or have their dose modified as part of the overall treatment plan during the trial. After 
randomization, any change in antidiabetic regimen including insulin dose and type will be done 
according to the local SOC. 
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8.3 
BLINDING PROCEDURES 
Toujeo SoloSTAR pen and the control drugs, Lantus SoloSTAR and Levemir FlexTouch are 
distinguishable and so this study is an open-label design. Despite the open label administration of 
the study insulin, the assessments of outcome, the HbA1c and FPG are determined in central 
laboratories blinded to the treatment received. The study team will review the data for the primary 
efficacy parameters and adverse events without treatment assignments. 
8.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUP 
At the screening visit the investigator or designee calls the interactive voice response 
system/interactive web response system (IVRS/IWRS) for allocation of the patient number. The 
patient identification (patient number) is composed of 9-digit number containing the 3-digit 
country code, the 3-digit center code and the 3-digit patient chronological number (which is 001 
for the first patient screened in a center, 002 for the second patient screened in the same center 
etc). 
On V2 (Day 1,), the investigator or designee contacts the IVRS/IWRS and provides the patient 
number provided by IVRS/IWRS at screening visit, date of birth, HbA1c, etc.  Afterwards the 
IVRS/IWRS is called again each time for each new visit and but does not include “standard of 
care” visits, which are not considered trial visits (please see Section 1.2). 
Treatment kits are not dispensed in US or Canada. In the US, the drugs are provided through 
pharmacy. The investigator provides the patient with a prescription for the insulin and a card to 
provide to the pharmacy to obtain the insulin, a “smart card” as a method of reimbursement. In 
Canada, IMP will be bought on local market and distributed through the sites not related to a visit 
and not recorded in IWRX. 
Randomization will be performed centrally by IVRS/IWRS, and will be stratified by 
individualized HbA1c target (<8% / <7%), GLP-1 RA use ever (y/n), SU use ever (y/n) and 
HbA1c (<9% ≥9%).  A patient cannot be randomized more than once in the study. Patients who 
need to be moved to another site will have a new randomization number assigned at the new site. 
Patient may be rescreened if there is reason to believe there laboratory data will differ at the time 
of rescreening or if the patient misses the window for randomization. These patients are reviewed 
by Sponsor and approved on case by case basis. 
8.5 
PACKAGING AND LABELING 
In the US, Toujeo and the comparator insulins are being dispensed via a standard dispensing 
pharmacy. The content of the labeling is in accordance with the local regulatory specifications and 
requirements.  Toujeo will be provided as commercially available disposable Toujeo SoloSTAR 
pens.  Lantus will be supplied as commercially available disposable Lantus SoloSTAR pens and 
Levemir as commercially available Levemir FlexTouch.  There will be no special labeling or 
re-packaging for the trial and there will be no study specific label or study specific box. In 
Canada, Toujeo and the comparator insulins will be bought on local market and distributed 
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through the sites. The content of the labeling will be in accordance with the local regulatory 
specifications and requirements. 
8.6 
STORAGE CONDITIONS AND SHELF LIFE 
Patients in the US are responsible for the correct storage of “not in in use” and “in-use” pens of 
investigational medicinal products Toujeo, Lantus, or Levemir. In Canada, sites are responsible 
for “not in use” pens and patients are responsible for “in use” pens. 
Information on in-use stability and instructions for handling will be reinforced to the patient by 
the dispensing pharmacy and the site staff. 
8.7 
RESPONSIBILITIES 
US: 
The Investigator, the hospital pharmacist, or other clinic staff personnel are not allowed to store 
and dispense the IMP and are not be responsible for ensuring that the IMP used in the clinical trial 
is securely maintained. This is the responsibility of the patient. 
All IMP will be prescribed by the Investigators to be dispensed at a pharmacy. 
Patients are responsible for returning unused pens to site. 
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 
prescribing pharmacy by the patient. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the dispensing pharmacy and smart card vendor will be responsible for 
promptly addressing any request made by the Sponsor, in order to recall IMP and eliminate 
potential hazards. 
Canada: 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP and NIMP will be responsible for ensuring that the IMP used in the clinical trial is securely 
maintained as specified by the Sponsor and in accordance with applicable regulatory 
requirements. 
All IMP will be dispensed in accordance with the Investigator’s prescription and it is the 
Investigator’s responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
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Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) should be promptly notified to the 
Sponsor. Some deficiencies may be recorded through a complaint procedure. 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party and allow the IMP or 
NIMP to be used other than as directed by this clinical trial protocol or dispose of IMP or NIMP 
in any other manner. 
IMP is not dispensed using the IVRS/IWRS system; the correct allocation of IMP at each 
dispensation is collected in source data. 
At each visit to dispense IMP after baseline as well as at the end of the treatment period, 
participants will take used and unused pens with them to the site. 
8.8 
TREATMENT ACCOUNTABILITY AND COMPLIANCE 
US: 
Medication use will be assessed by means of MPR and persistence measures based on data 
collected by the Smart card vendor (date of fill or refill and quantity of medication dispensed for 
30 day supply).  The site does not complete a treatment log form and no compliance information 
is entered into the e-CRF. 
Canada: 
An adequate supply of pre-packaged and labeled commercial insulin labeled for the study 
according to local regulations (IMP) with shelf life adequate to at least reach the next in-person 
visit will be provided  starting with V2 (Day1, baseline).  
The Investigator or delegate fills the Center IMP tracking log and inventory form per patient 
based on the used/unused IMP (study drug disposable pens) each time the patient receives the 
study drug. 
8.9 
CONCOMITANT MEDICATION  
A concomitant medication is any treatment received by the patient at the same time as the IMP 
treatment.  
•
Therapy with short acting insulin either such as may occur during an acute illness or
surgery or as a rescue medication is allowed.
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8.9.1 Prohibited medications 
Prohibited concomitant medication is limited to drugs contraindicated with use of basal insulin as 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT  
All biological efficacy (HbA1c and FPG) and safety analysis will be performed by a Central 
Laboratory. Detailed information on samples drawing, management, and analysis will be provided 
in a specific manual. 
9.1 
PRIMARY ENDPOINT 
•
Proportion of patients with individualized HbA1c target attainment per HEDIS criteria
<8% if age ≥65 years or with defined co-morbidities as listed in Appendix G or otherwise
<7%) at 6 months without documented symptomatic (BG ≤70 mg/dl) or severe
hypoglycemia at any time of day from baseline to 6 months.
•
The individual components of individualized HbA1c target attainment and absence of any
documented symptomatic (BG ≤70 mg/dl) or severe hypoglycemia will also be evaluated
as supportive analyses to evaluate consistency.
9.2 
SECONDARY ENDPOINTS 
9.2.1 Secondary efficacy endpoints 
•
Change in HbA1c from baseline (obtained at screening visit within one week of study
initiation) to 6 months.
•
Proportion of patients who remain on assigned basal insulin therapy (persistent with
assigned therapy) at 6 and 12 months.
•
Proportion of patients with individualized HbA1c target attainment per HEDIS criteria at
6 months without documented symptomatic (BG <54 mg/dl) or severe hypoglycemia at
any time of day from baseline to 6 months.
•
Proportion of patients with individualized HbA1c target attainment per HEDIS criteria at
12 months without documented symptomatic (BG <54 mg/dl) or severe hypoglycemia at
any time of day from baseline to 12 months.
•
Proportion of patients with individualized HbA1c target attainment (per HEDIS criteria) at
12 months without documented symptomatic (BG ≤70 mg/dl) or severe hypoglycemia at
any time of day from baseline to 12 months.
All secondary endpoints will be exploratory and descriptive and therefore no adjustments for 
multiplicity are specified. 
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9.2.2 Other endpoint(s) 
•
Change in HbA1c from baseline to 12 months,
•
Change in fasting plasma glucose from baseline to 6 months and 12 months,
•
Change in body weight from baseline to 6 months and 12 months,
•
Basal insulin dose at 6 and 12 months.
9.2.2.1 Observation period of efficacy variables 
•
The efficacy whole study period is defined as the time from randomization up to Day 360
(Visit 4) and the extension to allow for collection of additional endpoint data such as
health care utilization
•
The efficacy 6-month period is defined as the time from randomization up to Day 180
(Visit 3)
9.2.2.2 Efficacy assessment methods 
9.2.2.2.1 HbA1c measurement 
For the eligibility and efficacy assessments of the study, HbA1c is measured by a certified Level I 
“National Glycohemoglobin Standardization Program” central laboratory at time points 
referenced according to the Flow Chart in Section 1.2. 
9.2.2.2.2 Fasting plasma glucose 
Blood samples for FPG measurement are taken and measured at central laboratory at time points 
referenced according to the Flow Chart in Section 1.2. 
9.2.2.2.3 Self-measured plasma glucose during symptomatic hypoglycemia 
At V2, the randomization visit, the Investigator or a member of the clinical staff will provide 
patients with a Bluetooth enabled blood glucometer including the corresponding supplies (lancets, 
control solutions, test strips etc) and training. Blood glucose values will be measured by the 
patient using the sponsor-provided blood glucometer throughout the trial after randomization. The 
patients will be instructed to bring the blood glucometers provided by the sponsor with them to 
each scheduled trial office visit and encouraged to also bring the meter to any SOC visits so the 
site can document proper meter function and facilitate hypoglycemia reporting. The blood 
glucometers should be calibrated according to instructions given in the package leaflet and the 
investigational site should also check regularly the glucometers using the provided control 
solutions for data validity.  
At V2, the randomization visit, the Investigator or a member of the clinical staff will also provide 
the patient with an electronic diary and instruction on its use. Patients will be instructed to 
complete a hypoglycemia page in the e-diary for each hypoglycemic event. The site reviews 
hypoglycemia values and related clinical information before entering into the hypoglycemia pages 
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of the e-CRF at the visits. 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. Patients are instructed on use of the 
paper back up form for hypoglycemia reporting for events recorded on non-sponsor meter or 
when the LBGE was not completed in the e-diary. In addition to review of hypoglycemia at the 
on-site visits, the sites will review hypoglycemia events electronically at approximately Day 45 
and approximately Day 90 using information in the web based portal obtained from the electronic 
diary. 
9.2.2.2.4 SMPG done per usual habit 
SMPG done according to usual daily habit is not considered an efficacy endpoint but is reviewed 
by the clinical site to assist in titration oversight. This is done according to local, usual standard of 
care for the site and at the discretion of the Investigator who evaluates the individual patient’s 
needs. This may be recorded in a paper diary provided by the site or patient according to usual 
practice or in the e-diary. 
9.2.3 Safety endpoints 
The following safety parameters will be analyzed in the clinical study report: 
•
Hypoglycemia (according to ADA Workgroup on Hypoglycemia),
•
Adverse events, serious adverse events,
•
Injection site reactions,
•
Hypersensitivity reactions,
•
Vital signs.
Hypoglycemia endpoints will be classified in categories (Section 9.2.3.1) after events have been 
characterized using ADA Working group. 
•
Incidence of documented symptomatic (BG ≤ 70 mg/dl) nocturnal (0000-0559)
hypoglycemia from baseline to 6 and 12 months, and 24-hour hypoglycemia from baseline
to 12 months
•
Rate of documented symptomatic (BG ≤ 70 mg/dl) hypoglycemia (24 hour and nocturnal )
from baseline to 6 and 12 months
•
Incidence and rate of documented symptomatic (BG <54) hypoglycemia (24 hour and
nocturnal) from baseline to 6 and 12 months
•
Incidence and rate of severe hypoglycemia (24 hour, per ADA definition) from baseline to
6 and 12 months
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The observation period of safety data is divided into 3 main categories: 
•
The pre-treatment period is defined as the time from informed consent up to the time of
the first injection of IMP
•
The on-treatment period of the whole study is defined as the time from the first injection
of IMP up to 1 day after the last injection of IMP
•
The 6-month on-treatment period is defined as the time from first injection of IMP up to
Week 26 (Visit 8) or up to 1 day after the last injection of IMP whichever comes earlier
•
The post-treatment period is defined as the time starting 1 day after last injection of IMP
(after the on-treatment period)
9.2.3.1 Hypoglycemia classification 
Hypoglycemia events will be categorized as follows: 
•
Severe hypoglycemia: Severe hypoglycemia is an event requiring 3rd party assistance of
another person to actively administer carbohydrate, glucagon, or other resuscitative
actions. These episodes may be associated with sufficient neuroglycopenia to induce
seizure, unconsciousness or coma.  Plasma glucose measurements may not be available
during such an event, but neurological recovery attributable to the restoration of plasma
glucose to normal is considered sufficient evidence that the event was induced by a low
plasma glucose concentration.  The definition of severe symptomatic hypoglycemia
includes all episodes in which neurological impairment was severe enough to prevent
self-treatment and which were thus thought to place patients at risk for injury to
themselves or others.  Note that “requires 3rd party assistance” means that the patient
could not help himself or herself.  Assisting a patient out of kindness, when assistance is
not required, should not be considered a “requires assistance” incident.
•
Severe hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria.  All
events of seizure, unconsciousness or coma must be reported as SAEs.
•
Documented symptomatic hypoglycemia: Documented symptomatic hypoglycemia is an
event during which typical symptoms of hypoglycemia 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 are, eg, increased sweating,
nervousness, asthenia/weakness, tremor, dizziness, increased appetite, palpitations,
headache, sleep disorder, confusion, seizures, unconsciousness, or coma.
•
Asymptomatic hypoglycemia: Asymptomatic hypoglycemia is an event not accompanied
by typical symptoms of hypoglycemia but with a measured plasma glucose concentration
less than 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
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•
Relative hypoglycemia: (recently termed “pseudo-hypoglycemia”) is an event during
which the person with diabetes reports any of the typical symptoms of hypoglycemia, and
interprets the symptoms as indicative of hypoglycemia, but with a measured plasma
glucose concentration greater than 70 mg/dL (3.9 mmol/L).
Hypoglycemia events will be evaluated regardless the time of onset and in addition in the 
following time periods defined by time of the day: 
•
Nocturnal hypoglycemia defined by time of the day: any hypoglycemia of the above
categories that occurs between 00:00 and 05:59 AM hours, regardless whether patient was
awake or woke up because of the event.
•
Nocturnal hypoglycemia defined by sleep status: any hypoglycemia of the above
categories that occurs while the patient was asleep between bedtime and before getting up
in the morning, ie, before the morning determination of fasting pre-breakfast SMPG and
before any morning insulin injection and patient woke-up due to the hypoglycemia.
•
Daytime hypoglycemia: any hypoglycemia of the above categories that occurs between
6:00 AM to 23:59.
Documented hypoglycemia will be analyzed in addition to the threshold of plasma glucose of less 
than or equal to 70 mg/dL (3.9 mmol/L), by using a threshold of plasma glucose of <54 mg/dL 
(3.0 mmol/L). 
Hypoglycemic events will be transferred from the glucometer to a web based portal that serves as 
an electronic source document. 
9.2.3.2 Adverse events, serious adverse events 
All AEs and SAEs will be coded to a “Lower Level Term (LLT)”, “Preferred Term (PT)”, “High 
Level term (HLT)”, “High Level Group Term (HLGT)” and associated primary “System Organ 
Class (SOC)” using the version of MedDRA (Medical Dictionary for Regulatory Activities) 
currently in effect at the sponsor at the time of database lock. MedDRA terms for hypersensitivity 
and injection site reactions will be included. The occurrence of AEs and SAEs is recorded from 
the time of signed informed consent until the end of the study. 
9.2.3.3 Adverse event observation period 
All reported AEs and SAEs are collected from the time of signed informed consent until the end 
of the study (defined as patient´s last visit planned per protocol or the resolution/stabilization of 
all SAE and adverse events of special interest (AESIs). All events will be managed and reported 
in compliance with all applicable regulations, and included in the final clinical study report. 
If an AE/SAE is ongoing and not resolved by the end of the study observation period and leads to 
subsequent death of the patient, it will be reported. 
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The AE observations will be classified per the observation periods of safety data as defined above 
into: 
•
Pre-treatment AEs are AEs that developed or worsened or became serious during the
pretreatment period.
•
Treatment-emergent AEs (TEAEs) are AEs that developed or worsened or became
serious during the on-treatment period.
•
Post-treatment AEs are AEs that developed or worsened or became serious during the
post-treatment period.
9.2.3.4 Death observation periods 
The death observations are per the observation periods defined above. In addition, after the 
post-treatment period, death related to IMP as well as death resulting from TEAE must be 
reported to the Sponsor. 
•
Death on-study: deaths occurring during the on-study observation period (defined as the
time from the signed informed consent date up to the end of the study, ie, last protocol
planned visit or the resolution/stabilization of all SAE),
•
Death on-treatment: deaths occurring during the on-treatment period.
9.2.3.5 Laboratory safety variables 
The clinical laboratory data consist of blood analysis done at Central Laboratory at screening only 
(including LFTs and creatinine) Clinical laboratory values will be analyzed after conversion into 
standard international units.  International units will be used in all listings and tables. No listings 
will be provided during the study and laboratory data from local laboratory related to AEs will not 
be entered into data base. 
9.2.3.6 Vital Signs 
Vital signs include heart rate and systolic and diastolic blood pressure in sitting position. 
9.2.3.7 Electrocardiogram variables 
ECG is not done routinely in the protocol. It may be done at the discretion of the investigator 
when clinically indicated.  This data is not routinely recorded in the e-CRF and if abnormal, 
should be recorded as an AE. 
9.2.3.8 Injection site reactions, hypersensitivity reactions and immunogenicity 
No immunogenicity assessment is planned as part of the protocol. Injection site and local 
reactions are recorded on a standard AE page with its complementary page. 
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9.3 
OTHER ENDPOINTS 
9.3.1 Patient reported outcomes 
Patients will complete self-reported questionnaires at designated time points in the study:  
The Diabetes Treatment Satisfaction Questionnaire Status Version (DTSQs) will be used to 
evaluate patient satisfaction with treatment and patient perception of blood glucose control over a 
several week period.  The DTSQs is comprised of 8 questions which are answered on a Likert 
scale from 0 to 6.  Responses to these questions would be summarized into the three domain 
scores of Total Treatment Satisfaction, Hyperglycemia Perception and Hypoglycemia Perception 
such that a higher score would be indicative of better satisfaction.  Mean differences in scores 
between groups would be evaluated to understand the impact of treatment on patient satisfaction. 
The Diabetes Treatment Satisfaction Questionnaire Change Version (DTSQc) will be used to 
measure change in treatment satisfaction at 12 months. Scores for DTSQc treatment satisfaction 
items range from −3 to +3, and the sum of the treatment satisfaction scores range from −18 to 
+18. Positive scores are indicative of increases in treatment satisfaction relative to baseline 
measures.  Perceived hyperglycemia and hypoglycemia items have scores that range from −3 to 
+3 in the DTSQc, with higher scores indicating more frequent perceived hyperglycemia or 
hypoglycemia by the end of the study.  To control for baseline scores, DTSQs will be used as a 
measure of treatment satisfaction at baseline. 
Patients will also complete the Hypoglycemia Patient Questionnaire which will require them to 
report frequency of hypoglycemia experienced during the course of the study. Responses to 
questions 5 & 6 on the Hypoglycemia Patient Questionnaire will be used to assess the endpoint.  
A patient report of 1 or more episodes of either moderate or severe hypoglycemia since the last 
visit will be indicative of patient experience of hypoglycemia. The proportion of patients reporting 
1 or more episodes of either moderate or severe hypoglycemia will be compared between 
treatment groups.  
Patient and Physician reported Global Effectiveness Scale (GES): This measure, originally 
developed to assess the impact of treatment on asthma control, will be adapted for diabetes (GES). 
The GES assesses impact of treatment on a 5-point scale (excellent, good, moderate, poor, or 
worsening of condition).  These assessments will be completed twice by patients at 6 and 
12 months.  Physicians will complete the GES twice for each patient they manage at 6 and 
12 months.  Proportion of patients reporting “excellent” or “good” on the GES will be compared 
between the two treatment groups at each of the time points. 
9.3.2 Health utilization endpoints 
•
Mean number and proportion of patients with hospitalizations over a 6 month and 12
month period,
•
Mean number and proportion of patients with emergency room visits over a 6 month and
12 month period,
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•
Mean number of provider office visits and proportion of patients with specialty visits over
a 6 month and 12 month period
•
Mean overall and diabetes-related costs at 6 months and 12 months.
9.4 
FUTURE USE OF SAMPLES 
Not applicable. 
9.5 
APPROPRIATENESS OF MEASUREMENTS 
The primary efficacy analysis will test superiority of Toujeo compared to other commercially 
available insulin in achieving individualized HEDIS HbA1c targets at 6 months without 
documented symptomatic or severe hypoglycemia as the primary endpoint.  The 180 day duration 
of study treatment is considered to be sufficient for achieving steady state conditions with the 
commercially available basal insulins after randomization since there is no switching of basal, 
enabling an adequate assessment of time-dependent changes in HbA1c and the concomitant risk 
of hypoglycemia. 
HbA1c is accepted by regulatory agencies as primary endpoint to support a claim based on 
glycemic control. 
HbA1c is assayed using a central laboratory at screening V1 (Week -1), V3 (Day 180), and V4 
(Day 360) (see Section 1.2). 
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10 
STUDY PROCEDURES 
10.1 
VISIT SCHEDULE 
The visit schedule and procedures/assessments listed in the “Study Flow Chart” (Section 1.2) are 
not repeated in this section.  The aim of this section is to provide details on how some of the 
procedures/assessments have to be performed. 
This is an outpatient study and consists of a minimum of a screening visit followed by 3 on-site 
visits and without routinely scheduled other visits or phone-call visits.  In this “real world trial” 
additional, optional on site visits and phone call visits for “standard of care” should be scheduled 
whenever considered necessary by the investigator and consistent with usual practice and local 
standards of care.  These additional “standard of care visits” are for the routine care of the patient 
and are not part of the trial visit schedule. Some of these visits may be to monitor and support the 
progress of insulin titration according to Investigator discretion or may be related to other aspects 
of diabetes management or general medical care. 
Retesting of HbA1c in central laboratory is allowed where the HbA1c measured in Central 
Laboratory is unexpectedly lower than 8% and not consistent with local laboratory done prior to 
screening.  
If the patient has HbA1c outside of inclusion range, they may be rescreened if the HbA1c is 
greater than 11% since they would be expected to improve under their physicians care. HbA1c 
rescreening is not allowed where there is the potential for patients to allow their control to 
deteriorate. 
Patients may be screen failed if they miss the window for randomization and can then be 
rescreened. 
Patients to be rescreened are reviewed by Sponsor and approved on a case by case basis. 
All on-site visits should take place in the morning.  The patient needs to be in fasting conditions at 
on site visit, V1, screening visit, (Week-1) and also for V3 (Day 180, baseline), and V4 
(Day 360), or at early discontinuation from IMP.  Patient is required to come to the visit after a 
fasting period of at least 8 hours: during this time, only water or tea without sugar or sweetener 
and without milk is allowed.  No coffee, no other beverages are allowed.  
Visit window: from the screening visit, (V1, Week -1), V2 (Day 1) until the primary efficacy 
endpoint visit (Day 180), visits should occur within ± 30 days.  End of treatment (Day 360) may 
occur within ± 30 days.  If one visit date is changed, the next visit should occur according to the 
original schedule. 
Patients in the US do not need to bring their used or unused pens to visits other than EOT visit as 
a log of insulin pens will not be used to assess compliance.  Patients in Canada need to bring their 
used and unused pens to the site when IMP will be dispensed by the site and to the EOT visit.  
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For a complete list of procedures scheduled for each study visit please refer to the Study flowchart 
(Section 1.2).  The aim of the sections of the “Visit Schedule” as well as “Assessment Methods” 
in (Section 9, Section 10.1) is to detail procedures to be performed. 
Patients who stop treatment early should be seen as soon as possible for an early end of treatment 
visit when 180 day  assessment is completed and an EOT page in the CRF. 
All data in the trial visits are reviewed by the clinician at the site who is qualified in the 
management of type 2 diabetes and initiation of insulin treatment. 
10.1.1 Screening Period 
The duration of the screening period is up to 1 week from Visit 1 (Week –1) to V2 (Week 0) such 
that patients must be randomized within 1 week of screening.  
Patients will be screened at Visit 1 after signature of the informed consent form.  All laboratory 
tests measured at central laboratory needed for checking the exclusion criteria of the patients will 
be performed at V1. Patients who meet the inclusion criteria and who have no exclusion criteria as 
noted in, Section 7.1, will be randomized at V2 (Day 1). 
The IVRS/IWRS will be contacted at V1 for notification of screening and for patient number 
allocation.  
10.1.1.1 On-site Visit 1 (Week -1) Screening visit 
The following procedures/assessments will be performed at the visit 1 (Week-1): 
•
Obtaining the informed consent:
- 
The patient will receive verbal information concerning the aims and methods of the
study, its constraints and risks and the study duration. Written information will be 
provided to the patient. Written informed consent must be signed by the patient and 
investigator prior to any investigations.  
•
IVRS/IWRS notified (allocation of patient number, registration of screening, collection of
demographic information).
- 
The patient number is composed of a 9-digit number containing the 3-digit country
code, the 3-digit center code and the 3-digit patient chronological number (which is 
001 for the first patient screened in a center, 002 for the second patient screened in the 
same center etc). 
•
Assessment of inclusion/exclusion criteria.
•
Demographics (age, gender, and ethnic origin).
•
Patient’s medical (including detailed cardiovascular) and surgical history.
•
History of type 2 diabetes treatment including documentation of insulin treatment regimen,
and microvascular complications (eye, kidney) and their treatments.
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•
Concomitant medication history.
•
Prior medication history, particularly as it relates to diabetes medications.
•
Physical examination including vital signs (SBP and DBP including in sitting position,
heart rate).
•
Body height and weight.
•
Laboratory testing by central laboratory:
•
HbA1c and FPG,
•
Serum pregnancy test in women of child bearing potential,
•
Safety laboratory; serum creatinine and LFT (please refer to Section 9.2.3.6).
•
Instruction on recording information related to hypoglycemia in e-diary or on paper back
up form, instruction on recording routine SMPG recommended by site either in e-diary or
a paper diary per usual site practice, and AE reporting, (report any events that may occur
after signing informed consent).
•
DTSQs (Appendix D), Hypoglycemia Patient Questionnaire (Appendix H), and PAM
(Appendix F) are administered at the screening visit completed and collected at the site.
10.1.1.2 Baseline Visit 2 (Week 0, Day1) +/-7 days 
Patients meeting all inclusion criteria and with no exclusion criteria at the end of the screening 
period (based on data collected at the screening visit V1 (Week -1) are eligible to be randomized 
and can participate in the study. 
For the complete list of procedures scheduled for this visit, please refer to the study flowchart 
Section 1.2) and for detailed description of assessments. 
At this visit, the patient does not need to be fasting.  
During the visit; 
•
Concomitant medications are reviewed.
•
Patient diaries, both paper and electronic, are reviewed for hypoglycemia and AE/SAE by
the Investigator or Sub-Investigator who are qualified and familiar with the study and then
entered into the e-CRF.
•
Dispensation of Bluetooth enabled glucometer, e-diary,  training materials and supplies
•
Training is provided for use of glucometer and e-diary. IVRS is called to randomize the
patient.
•
Diet and lifestyle counseling is provided according to the routine custom of the practice.
•
DTSQs and the Hypoglycemia patient questionnaire will be completed
•
In the US, patients will be provided with a prescription for Toujeo or the control insulin
and a “smart card” for obtaining the insulin at a commercial pharmacy.
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•
Training is provided by the site investigator or site staff regarding insulin pen use.
•
A patient card, including emergency contact details and treatment arm will be provided to
every patient who participates in the study.
•
Patient will be invited to be enrolled into the Toujeo PSP for those patients randomized to
Toujeo. Patients may also choose to participate in other PSP available to them. Data on
enrollment in a PSP will be collected at this visit.
•
Patients are provided glycemic targets and guidance on dose adjustment at the discretion
of the Investigator and consistent with local practice guidelines and recorded in the clinical
source documents. This information is not recorded in the e-CRF.
•
IVRS/IWRS notified
•
At Canadian sites, process of dispensing insulin is discussed and first insulin may be
provided by site.
10.1.1.3 Visit 3 (Day 180) +/- 30 days 
•
Vital signs (SBP and DBP, heart rate) and weight.
•
Physical examination.
•
Laboratory testing done by central laboratory:
- 
HbA1c and FPG.
•
Concomitant medications are reviewed.
•
Patient diaries, both paper and electronic, are reviewed for hypoglycemia and AE/SAE by
the Investigator or Sub Investigator who are qualified and familiar with the study and then
entered into the e-CRF.
•
Insulin dose the day of the visit is recorded in the source and e-CRF.
•
DTSQs, Hypoglycemia Patient Questionnaire, Patient and Provider Global Effectiveness
Scales (Appendix C) are completed.
•
Health Care Utilization Forms are completed
•
Urine pregnancy test at site in WOCBP.
•
IVRS/IWRS notified
10.1.1.4 Visit 4 (Day 360) +/- 30 days 
•
Vital signs (SBP and DBP, heart rate) and weight.
•
Physical examination.
•
Laboratory testing done by central laboratory:
- 
HbA1c and FPG.
•
Concomitant medications are reviewed.
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•
Patient diaries, both paper and electronic, are reviewed for hypoglycemia and AE/SAE by
the Investigator or Sub Investigator who are qualified and familiar with the study and then
entered into the e-CRF.
•
Insulin dose the day of the visit is recorded in the source and e-CRF.
•
DTSQs, DTSQc Hypoglycemia Patient Questionnaire, Patient and Provider Global
Effectiveness Scales are completed.
•
Health Care Utilization Forms are completed
•
Urine pregnancy test at site in WOCBP.
•
IVRS/IWRS notified
10.1.1.5 Unscheduled phone visits 
Under certain circumstances, sites will be requested to contact patient to obtain additional safety 
information which may not have been collected due to the infrequent schedule of trial visits 
•
To review hypoglycemic events to obtain clinical information necessary for ADA
classification
•
To review severe or serious hypoglycemic events
•
To collect missing information regarding SAE
10.1.1.6 Glucose review at Day 45 and Day 90 
Sites are encouraged to review hypoglycemic events in the web based portal (Trial Manager) at 
approximately Day 45 and Day 90. 
10.1.1.7 “Standard of Care” visits 
•
Laboratory testing done at discretion of investigator by local labs, and are not recorded in
CRF
•
Patient diaries, both paper and electronic (Trial Manager), are reviewed for hypoglycemia
and AE/SAE by the Investigator or Sub Investigator who are qualified and familiar with
the study and then entered into the e-CRF.
During these routine, “standard of care” visits” the physician records the reason for the visit and 
any trial actions taken in the medical record. Visit are not recorded in IVRS; visit is entered as an 
office visit in e-CRF form for capturing utilization data and any hypoglycemia and AE/SAE noted 
at the time of these visits are entered into the dedicated e-CRF pages for these events. No 
additional clinical information is entered into the data base and these visits are not considered part 
of the trial visit schedule. Visits should be documented as per usual for the practice site in their 
clinical record. The reason for the visit may be recorded as an AE if appropriate. 
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10.2 
DEFINITION OF SOURCE DATA 
10.2.1 Source data to be found in patient’s file 
Evaluations recorded in the e-CRF must be supported by appropriately signed source 
documentation related but not limited to the following: 
•
Agreement and signature of informed consent form with the study identification and any
privacy forms.
•
Study identification (name).
•
Patient number, confirmation of randomization.
•
Medical, surgical, diabetes history, including information on:
- 
Demography, inclusion and exclusion criteria,
- 
Comorbidities,
- 
Calculation of HEDIS assignment worksheet, if available,
- 
Last participation in a clinical trial,
- 
Contraception method for WOCP,
- 
Previous and concomitant medication.
•
Dates and times of visits and assessments including examination results.
•
Vital signs, height, body weight, laboratory reports.
•
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. 
•
Date of premature study discontinuation (if any) and reason.
•
Office notes related to the ongoing routine clinical care of this patient to include:
- 
Nursing and other clinical staff notes,
- 
Dietician’s and diabetes educators notes,
- 
Physician’s notes.
10.2.1.1 Source data verification requirements for screen failures 
For screen failure patients, the following source data must be verified: patient’s identification 
details, the informed consent signed by the patient, the study identification (name), dates of study 
visits and the main reasons for screen failure. In addition, target HbA1c assigned is also recorded. 
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10.3 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. Any IMP discontinuation should be fully 
documented in the e-CRF. 
10.3.1 Temporary treatment discontinuation with investigational medicinal product(s) 
It is in the interest of the patient to monitor plasma glucose during the temporary discontinuation 
period, therefore SMPG or other regular determination of plasma glucose is to be performed and 
documented. 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the appropriate pages when considered as confirmed. 
Temporary treatment discontinuation decided by the Investigator corresponds to more than 1 dose 
not administered to the patient. Use of a different insulin during the time of temporary treatment 
discontinuation is recorded (such as during a hospitalization) with the name and doses recorded in 
the CRF. 
10.3.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP at 
any time.  This is done consistent standards for withdrawing a drug and according to the 
experience of the investigator. 
10.3.3 List of criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
determine the reasons for treatment discontinuation and this should be documented in the e-CRF. 
The following reasons lead to permanent discontinuation: 
•
At the patient’s own request.
•
If, in the investigator’s opinion, continuation with the administration of the study treatment
would be detrimental to the patient’s well-being.
•
Inter-current condition that requires permanent discontinuation of the study treatment
(eg, laboratory abnormalities according to the decision tree in Appendix B as long as the
abnormality persists and if the casual relationship of the concerned event and the IMP is
possible according to the Investigator’s best medical judgment).
•
Pregnancy.
•
Specific request of the sponsor.
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Any abnormal laboratory value or ECG will be immediately rechecked for confirmation before 
making a decision of permanent discontinuation of the IMP for the concerned patient.  
For patients who prematurely discontinue the IMP, the end-of-treatment visit assessments for 
Day 360 will be done (Section 10.3.2) as soon as possible after stopping the IMP.  However, the 
patients will be informed that they should continue to report hypoglycemia events in their e-Diary, 
and come back to the Day 180 visit for HbA1c assessment and hypoglycemia review with 
investigator and encouraged to continue to Day 360, end of the extension period). 
10.3.4 Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, to a minimum of Day 180 or up to recovery or 
stabilization of any AE to be followed-up as specified in this protocol, whichever comes last. If 
possible, and after the permanent discontinuation of treatment, the patients will be assessed using 
the procedure normally planned for the last dosing day with the IMP. 
All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
10.3.5 Procedure and consequence for patient withdrawal from study 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. If possible, the patients are assessed using the procedure 
normally planned for the end-of-study visit.  
For patients who fail to return to the site, the Investigator should make the best effort to re-contact 
the patient to determine his/her health status according to local standards of care.  Patients may 
continue to have their care provided by the site physician without participating in the trial. 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be re-randomized (treated) in the study.  
Their inclusion and treatment numbers must not be reused. 
The treatment period is over when the last dose of IMP is received. An EOT visit is completed 
including recording reason for EOT. Patients are not allowed to “switch” to insulin in the other 
treatment arm and insulin will not be reimbursed by Sponsor after EOT. Patients are encouraged 
to continue in trial off treatment and in this case the insulin is recorded on the Conmed CRF page. 
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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 (silures, epilepsy, epileptic fit, absence, etc), 
- 
Development of drug dependence or drug abuse, 
- 
ALT >3 x ULN + 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 (only if judged 
unusual/significant by the Investigators in oncology studies), 
- 
Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically 
the effect of a study drug on these diseases). 
10.4.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required.  Such events may require 
further investigation in order to characterize and understand them.  Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
The AESI for this study: 
•
Increase in alanine transaminase (ALT) (see the “Increase in ALT” flow diagram in
Appendix B of the protocol) which would only be identified by local laboratory as there is
no lab testing by Central Laboratory during the trial
•
Pregnancy of a female subject entered in a study as well as pregnancy occurring in a
female partner of a male subject entered in a study with IMP/NIMP.
- 
Pregnancy occurring in a female patient entered in the clinical trial or in a female
partner of a male patient entered in the clinical trial. It will be qualified as an SAE only 
if it fulfills one of the seriousness criteria (see Section 10.4.1.2). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued, 
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined. 
•
Symptomatic overdose (serious or non-serious) 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 and resulting in 
clinical symptoms and/or signs and considered a “significant overdose” by the 
Investigator.  It will be recorded in the e-CRF as an AESI with immediate notification 
“Symptomatic OVERDOSE (accidental or intentional)” in all cases and will be 
qualified as an SAE only if it fulfills the SAE criteria. 
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Asymptomatic overdose (accidental or intentional) with the IMP/NIMP is defined as any 
“significant” overdose, without clinical symptoms and/or signs, either suspected by the 
investigator or spontaneously notified by the patient.  It will be recorded as an AE “Asymptomatic 
OVERDOSE (accidental or intentional)”.  The event must be clinically relevant and be more of an 
event than just using a titration dose increase compared to what had been previously prescribed. 
Asymptomatic overdose does not require immediate notification. 
10.4.2 Serious adverse events waived from expedited regulatory reporting to regulatory 
authorities 
There are no waivers from expedited reporting of serious health events to health authorities in this 
trial. 
10.4.3 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 CRF.
•
AEs may also be identified by pharmacists, and providers other than the provider primarily
responsible for the diabetes management such as specialists, nurse educators.  It is the
responsibility of the patient to keep a record of their AEs and the site investigator will
enter these AEs from these multiple providers.
•
Whenever possible, diagnosis or single syndrome should be reported instead of symptoms.
The Investigator should specify the date of onset, intensity, action taken with respect to
IMP, corrective treatment/therapy given, additional investigations performed, outcome,
and his/her opinion as to whether there is a reasonable possibility that the AE was caused
by the IMP or by the study procedure(s).  For events reported through the PSP vendor,
global safety officer (GSO) is responsible for identifying potential SAE that are not
included in the data base and whether the SAE was caused by the IMP.
•
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.
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10.4.4 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator 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
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 CRF process) is available and should be used when the
e-CRF system does not work.
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to the monitoring team. 
10.4.5 Guidelines for reporting adverse events of special interest 
For AESIs, the Sponsor must be informed immediately (ie, within 24 hours), as per SAE 
notification guidelines described in Section 10.4.4, even if not fulfilling a seriousness criterion, 
using the corresponding pages of the CRF (to be sent) or screens in the e-CRF. 
Instructions for AE reporting are summarized in Table 1. 
10.4.6 Guidelines for management of specific laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities by Sanofi are provided in 
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The following laboratory abnormalities are not routinely monitored. When abnormal labs are 
identified by local laboratory during the reporting of an AE, they are monitored, documented, and 
managed according to the related flow chart in protocol appendices.  
•
Neutropenia,
•
Thrombocytopenia,
•
Increase in ALT,
•
Acute renal insufficiency,
•
Suspicion of rhabdomyolysis.
Table 1 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
AE 
form 
Safety 
Complementary 
Form 
Other 
specific 
forms 
Adverse Event (non-
SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse 
Event (non-AESI or 
AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness criterion 
per Section 10.4.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest 
Expedited (within 
24 hours) 
No 
Pregnancy 
Yes 
Yes 
Yes 
Symptomatic overdose 
Yes 
Yes 
No 
ALT≥3 ULN (if baseline ALT<ULN) and 
ALT≥2 x baseline (if baseline ALT≥ULN) 
Yes 
Yes 
Yes 
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, IECs/IRBs as appropriate and to the Investigators.
•
All SAEs that are expected and at least reasonably related to the IMPs to the regulatory
authorities, according to local regulations.
•
There are no specified AESIs.
In this study, some AEs are considered related to the underlying condition and thus will not be 
considered unexpected [please refer to the package]. 
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Any other AE not listed as an expected event in the Package Insert or in this protocol will be 
considered unexpected. 
As this is an open label study, no un-blinding of SUSARs is necessary.  
The Sponsor will report all safety observations made during the conduct of the trial in the clinical 
study report. 
Sponsor will review potential SAEs identified through the COACH Patient Support Program.  
Review of claims data for SAE is not planned for the study as it will be included as a separate 
analysis; as the analysis will be done after the 12 month whole treatment period and will be 
contained in a report separate from the main study report. 
10.6 
SAFETY INSTRUCTIONS 
10.6.1  Hypoglycemia 
Severe symptomatic hypoglycemia 
Severe symptomatic hypoglycemia is an event requiring assistance of another person to actively 
administer carbohydrate, glucagon, or other resuscitative actions.  These episodes may be 
associated with sufficient neuroglycopenia to induce seizure, unconsciousness or coma.  Plasma 
glucose measurements may not be available during such an event, but neurological recovery 
attributable to the restoration of plasma glucose to normal is considered sufficient evidence that 
the event was induced by a low plasma glucose concentration.  
The definition of severe symptomatic hypoglycemia includes all episodes in which neurological 
impairment was severe enough to prevent self-treatment and which were thus thought to place 
patients at risk for injury to themselves or others.  
Note that “requires assistance” means that the patient could not help himself or herself.  Assisting 
a patient out of kindness, when assistance is not required, should not be considered a “requires 
assistance” incident.  
Severe symptomatic hypoglycemia will be qualified as an SAE only if it fulfills SAE criteria.  All 
events of seizure, unconsciousness or coma must be reported as SAEs.  
Documented symptomatic hypoglycemia 
Documented symptomatic hypoglycemia is an event during which typical symptoms of 
hypoglycemia are accompanied by a measured plasma glucose concentration of ≤70 mg/dL 
(3.9 mmol/L).  In addition, hypoglycemia episodes with a plasma glucose of <54 mg/dL 
(3.0 mmol/L) will be analyzed. 
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Clinical symptoms that are considered to result from a hypoglycemic episode are, eg, increased 
sweating, nervousness, asthenia, tremor, dizziness, increased appetite, palpitations, headache, 
sleep disorder, confusion, seizures, unconsciousness, and coma. 
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. 
Patients will be instructed to measure finger stick plasma glucose levels prior to the administration 
of carbohydrates whenever symptomatic hypoglycemia is suspected, unless safety considerations 
necessitate immediate glucose rescue prior to confirmation, and then a glucose measurement 
should be performed as soon as safe, with appropriate diary documentation.  Details on 
hypoglycemia episodes will be captured in the patient e-diaries and then available in the vendor 
web based portal.  Patients will contact the sites as soon as possible following severe events to 
review the details and decide on any necessary measures to be taken. 
Symptomatic hypoglycemia episodes will be documented on the Low Blood Glucose Event 
(LBGE) page in the clinical data base.  Symptomatic hypoglycemia events fulfilling the criteria of 
a SAE will also be documented on AE and SAE forms form in the e-CRF.  
For discussion of endpoints related to hypoglycemia, see Section 9.2.3.1  
10.6.2 Local safety  
In case the investigator or the patient recognizes any sign related to local safety at the injection 
site this should be recorded on the standard AE page in the e-CRF. 
In case a patient experiences an allergic reaction or an allergic-like reaction this has to be reported 
as an adverse event and recorded in the e-CRF on the standard AE form.  
Sometimes transient injection site reactions, irritant in nature may occur requiring no intervention 
and are of dubious significance.  These reactions would not be considered to be allergic reactions. 
A Product Technical Complaint should be completed if a problem with the device is noted. 
10.6.3 Follow-up of laboratory abnormalities 
Decision trees for the management of certain laboratory abnormalities are provided in  
Appendix B. This is applicable to abnormal laboratories at screening done in Central Laboratory 
or local laboratories obtained related to a reported AE. 
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10.6.4 SMPG 
Routine SMPG is done by the patient according to guidelines set by the investigator to support 
titration.  No specific safety instructions are provided and SMPG is monitored by the site and not 
recorded in the clinical data base. 
10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
The sample size (1662 patients per treatment group) calculations take into account one Interim 
Analysis performed after 1800 randomized patients having completed their 6 months visit. They 
are based on superiority testing of the primary efficacy variable of the proportion of patients 
reaching individualized HbA1c target at Month 6 without a documented symptomatic  
(BG ≤ 70 mg/dl) or severe hypoglycemic event at any time of day from baseline to Month 6, with 
the following assumptions: 
•
Individualized HbA1c target attainment per HEDIS criteria of <8% if older or presence of
medical comorbidities, or otherwise <7%,
•
An absolute difference of 5.5% in favor of Toujeo in patients assigned a target
HbA1c < 7%, assuming a 30.1% rate in the Toujeo arm, based on data from the
EDITION 3 study,
•
An absolute difference of 5.4% in favor of Toujeo in patients assigned a target
HbA1c < 8%, assuming a 55.8% rate in the Toujeo arm, based on data from the
EDITION 3 study,
•
An absolute overall (weighted average) difference of 5.5% in favor of Toujeo for all
patients combined, assuming that 70% of the study patients would have a target
HbA1c < 7%, and 30% would have a target HbA1c < 8%, based on data from a
commercially available database,
•
A maximum overall response rate of 33% in the comparator basal insulins arm,
•
A 2-sided chi-squared test at the 5% significance level, with 90% power,
•
All patients will be eligible for the primary endpoint analysis.
As a logistic model will be used for the primary analysis, it is anticipated that the power will be 
higher due to reduced estimate variability compared with the chi-square test.  Calculations were 
made using nQuery Advisor 6.01. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
All randomized patients will be included in the Intent-to-Treat Population.  
Patients will not be randomized more than once. 
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11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
11.3.1.1 Intent–to-treat population 
• ITT population: all randomized population analyzed according to the treatment group 
allocated by randomization. 
11.3.2 Safety population 
• As treated: defined as all randomized patients who actually received at least 1 dose or part 
of a dose of IMP, analyzed according to the treatment actually received.  In addition:  
- 
Nonrandomized but treated patients will not be part of the safety population.  This is a 
post marketing real world trial with commercially available insulin so that 
nonrandomized but treated patients are not considered part of the trial and safety data 
is neither collected nor presented.  
- 
Randomized patients for whom it is unclear whether they took the study medication 
will be included in the safety population as randomized. 
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, accounting for 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. 
11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
A superiority test will be performed at interim analysis (2-sided, alpha=0.010) and at final 
6-month analysis (2-sided, alpha=0.046) to compare the proportion of patients reaching 
individualized HbA1c target at 6 months without documented symptomatic (BG ≤ 70 mg/dl) or 
severe hypoglycemia between treatment groups using a logistic model with log link, adjusting for 
HbA1c target and other stratification factors used at randomization: SU use ever (y/n), GLP-1 RA 
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use ever (y/n), and baseline HbA1c (as continuous).  In a sensitivity analysis a multivariate 
analysis will be performed, adding the following baseline characteristics such as BMI, Patient 
Activation Measure (PAM) as an assessment of patient engagement, duration of diabetes and age. 
Patients with missing HbA1c data at 6 months will be regarded as not having reached HbA1c 
target. 
In order to examine the consistency of this analysis, the individual components of HbA1c target 
attainment and absence of any documented symptomatic (BG ≤70 mg/dl) or severe hypoglycemia 
will also be evaluated.  Each individual component will be compared between treatment groups 
using logistic regression, adjusting for randomization strata and other baseline characteristics as 
clinically appropriate. 
Further, a predictive subgroup identification method will be employed to identify subgroups of 
potential responders. 
Analyses of secondary efficacy endpoints (Section 9.2.1). 
Persistence: 
• Treatment persistence will be determined based on vendor database that would be 
responsible for managing and administration of the study drugs (Toujeo, Lantus, Levemir) 
from the vendor database administering the study drugs, information on prescription fill 
date, quantity dispensed, days of supply, number of units dispensed, prescription refill 
dates will be obtained in estimation of treatment persistence and discontinuation. 
• In addition, for US patients, a medication possession ratio will be assessed for patients 
based on number of days that patients had possession of study drug based on prescription 
date and days of supply.  A MPR of 80% would be indicative of patients being persistent 
on study medication.  Those not persistent will be considered discontinued on their study 
medication. 
• Treatment persistence will be summarized descriptively (N, Mean, SD, Median, Min, and 
Max). 
Efficacy Endpoints: 
The change in HbA1c from baseline to 6 months will be analyzed using a mixed-effect model 
with repeated measures (MMRM) approach under the missing at random framework, using an 
adequate contrast at Month 6.  The model will include fixed categorical effects of treatment arm, 
visit, treatment-by-visit interaction, HbA1c target and other randomization strata; SU use ever 
(y/n), GLP-1 RA use ever (y/n), and baseline A1c (as continuous),as well as baseline 
HbA1c-by-visit interaction. 
The change in fasting plasma glucose and bodyweight from baseline to 6 and 12 months will be 
analyzed in a similar fashion to the change in HbA1c. 
The proportion of patients with individualized HbA1c target attainment without hypoglycemia 
will be analyzed as described for the primary endpoint.  
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11.4.3 Analyses of safety data 
The summary of safety and tolerance results will be presented by treatment group (Section 9.2.3). 
All safety analyses will be performed on the Safety population using the following common rules: 
• The baseline value is defined as the last available value prior to the first injection of IMP, 
• There are no pre-defined Potentially Clinically Significant Abnormality (PCSA) values for 
this study, 
• There are no safety endpoints which are adjudicated. 
The baseline values for all safety analyses are defined as the last available value prior to the first 
dose of randomized treatment. There are no quantitative safety parameters based on central 
laboratory measurements.  The last on-treatment value is defined as the value collected at the 
same day/time of the last dose of randomized product.  If this value is missing, this on-treatment 
value is the closest one prior to the last dose intake.  Given the short half-life for duration of 
action of insulin, the TEAE reporting period is one day after last administration of IMP. 
The analysis of the safety variables is essentially descriptive and no systematic testing is planned. 
Relative risk for the Toujeo arm of the study versus the comparator basal insulins group, and their 
95% CI may be provided, if relevant. 
Hypoglycemia 
The incidence of hypoglycemia will be analyzed using logistic regression, adjusting for 
randomization strata and other baseline characteristics as clinically appropriate and if the model 
permits.  The rate per patient-year of hypoglycemic events will be analyzed using an over-
dispersed Poisson regression model, adjusting for randomization strata and other baseline 
characteristics as clinically appropriate and if the model permits. 
11.4.4 Analyses of Patient Reported Outcomes 
Self-reported patient satisfaction and hypoglycemia: Satisfaction scores at 6 and 12 months will 
be compared between treatment groups using a MMRM approach as described for the continuous 
efficacy variables.  To adjust for the baseline differences between treatment groups, logistic 
regression will be conducted, adjusting for randomization strata of HbA1c target, SU use ever 
(y/n), GLP-1 RA use ever (y/n) and baseline A1c (as continuous). 
Global Effectiveness Scale (GES): At each study endpoint, the proportion of patients and 
providers who reported “Excellent” or “Good” at 6 and 12 months will be analyzed using CMH 
tests adjusting for randomization strata. 
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11.4.5 Health-related Quality of Life/health economics variables 
Health resource utilization for each treatment group will be analyzed by descriptive analysis. 
Multivariate analysis will be used to evaluate the difference in health resource utilization and cost 
between treatment groups with t adjustments for patient level data from CRF to include baseline 
characteristics and comorbidities as covariates. 
11.5 
INTERIM ANALYSIS 
One interim analysis is planned for the purpose of efficacy to provide an early evaluation of 
Toujeo effectiveness, when approximately 1800 patients (54.2% information fraction of targeted 
sample size) have completed their 6-month (Day 180) visit.  
Using a group sequential approach with a Gamma(-3) alpha-spending function and an overall 
two-sided alpha-level of 0.05, the two-sided nominal significance level is 0.010  at interim 
analysis, and 0.046 at final analysis. 
If the targeted sample size (1800) cannot be reached, it could be considered to include a lower 
number of patients, however not below 1700. In this case, the nominal significance level to be 
spent at interim and at final 6-month analyses would be recalculated accordingly before the 
database lock for IA. 
Overwhelming efficacy will be shown at interim analysis if the efficacy boundary is met, ie, if the 
two-sided p-value for comparison of primary composite endpoint incidence is below 0.010, with a 
difference in favor of Toujeo between percentages of patients reaching the primary composite 
endpoint. The corresponding power to show overwhelming efficacy at interim analysis under the 
alternative hypothesis is of 45%. 
Scenario 1: If overwhelming efficacy is shown:  
• The recruitment would be stopped (total sample size at that time estimated to be between 
2600-3000 patients, 
• The patients already enrolled would continue the study as planned, 
• The results will be disclosed to the Sponsor and a communication plan to protect clinical 
data integrity is detailed in the DMC charter. 
Scenario 2: If overwhelming efficacy is not shown: 
• The study would continue as planned 
• The Sponsor would not have access to any unblinded data,  
• No results would be communicated.  
For the interim analysis, analyses will be performed by an independent statistician external to the 
Sponsor. Results will be delivered directly to the independent Data Monitoring Committee for 
review. 
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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 ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sanofi public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator’s responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (IRB/IEC).  All participants should be informed to the fullest 
extent possible about the study, in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form and/or 
privacy form should be signed, name filled in and personally dated by the patient or by the 
patient’s legally acceptable representative, and by the person who conducted the informed consent 
discussion.  A copy of the signed and dated written informed consent form will be provided to the 
patient. 
This informed consent contains a section allowing for release of claims data from the payer to the 
sponsor that may be signed anytime up until end of trial visit. The informed consent describes the 
use of this information in the study analysis and that the claims data is linked to the clinical data 
base for purpose of analysis. 
The informed consent form used by the Investigator for obtaining the patient’s informed consent 
must be reviewed and approved by the Sponsor prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
A separate privacy form request may be necessary and if required by local law, the form will be 
completed and signed by the patient. 
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12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or the Sponsor must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party a 
copy of the written and dated approval/favorable opinion signed by the Chairman with IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be prescribed 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 and privacy board at least annually and a summary of the 
clinical trial’s outcome will be sent at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by the Sponsor (including security rules).  The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient’s data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as 
Sub-investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol.  All Sub-investigators shall be appointed and listed in a timely manner.  The 
Sub-investigators will be supervised by and work under the responsibility of the Investigator.  The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
The Sponsor of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs.  Thus, the main duty of 
the monitoring team is to help the Investigator and the Sponsor maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems.  These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, concomitant 
therapy use and quality of data. In addition, the monitoring team may as a safety and a compliance 
issue, review the hypoglycemia data obtained by the patient with the sponsor provided glucometer 
and with results stored in a web based portal as an electronic source document. 
In Canada, monitoring will also include patient compliance with the IMP regimen and IMP 
accountability. 
 
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13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents, except for the pre-identified source data directly recorded in the CRF.  The informed 
consent form will include a statement by which the patient allows the Sponsor’s duly authorized 
personnel, the Ethics Committee (IRB/IEC), and the regulatory authorities to have direct access to 
original medical records which support the data on the CRFs (eg, patient’s medical file, 
appointment books, original laboratory records, etc).  These personnel, bound by professional 
secrecy, must maintain the confidentiality of all personal identity or personal medical information 
(according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner.  All CRFs 
should be completed in their entirety in a neat, legible manner to ensure accurate interpretation of 
data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned.  The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the curriculum vitae describing the experience, qualification and training of 
each Investigator and Sub-investigator will be signed, dated and provided to the Sponsor prior to 
the beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator’s personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator’s Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results.  The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub-investigators shall be bound by the same obligation as the Investigator.  The Investigator 
shall inform the Sub-investigators of the confidential nature of the clinical trial. 
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The Investigator and the Sub-investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party’s account. 
14.4 
PROPERTY RIGHTS 
All information, and documents 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. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy.  An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
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14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, Good Clinical Practice and 
applicable regulatory requirements, the Investigator should permit auditing by or on the behalf of 
the Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and inspections, 
giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio 
• Patient enrollment is unsatisfactory 
• The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon 
• 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. 
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14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days’ prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought.  However, if no multicenter publication is submitted, underway 
or planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders.  The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor.  The 
Sponsor shall not use the name(s) of the Investigator and/or the collaborators in advertising or 
promotional material or publication without having received his/her and/or their prior written 
consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC 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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16 
BIBLIOGRAPHIC REFERENCES 
1. UK Prospective Diabetes Study Group. UK prospective diabetes study 16. Overview of 6 
years’ therapy of type II diabetes: a progressive disease.  Diabetes. 1995;44(11):1249-58. 
2. Turner RC, Cull CA, Frighi V, Holman RR, UK Prospective Diabetes Study Group. Glycemic 
control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: 
progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study 
(UKPDS) Group. JJAMA. 1999;281(21):2005-12. 
3. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al.; American 
Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). 
Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position 
statement of the American Diabetes Association (ADA) and the European Association for the 
Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-79. 
4. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas 
or insulin compared with conventional treatment and risk of complications in patients with 
type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 
1998;352(9131):837-53. 
5. UK Prospective Diabetes Study Group.  Effect of intensive blood-glucose control with 
metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK 
Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-65. 
6. Tillner J, Bergmann K, Teichert L, Dahmen R, Heise T, Becker R, et al.   Euglycemic clamp 
profile of new insulin glargine U300 formulation in patients with type 1 diabetes (T1DM) is 
different from glargine U100.  Diabetes. 2013;62(Suppl 1):A234.  Poster 920 P. Available 
from URL:  http://www.abstractsonline.com/plan. [Accessed February 2015]. 
7. Dahmen R, Bergmann K, Lehmann A, Tillner J, Jax T, Heise T, et al.  New insulin glargine 
U300 formulation evens and prolongs steady state PK and PD profiles during euglycemic 
clamp in patients with type 1 diabetes (T1DM).  Diabetes. 2013;62(Suppl 1):A29.  Poster 113 
OR. Available from URL: http://www.abstractsonline.com/plan.  [Accessed February 2015]. 
8. Riddle MC, Bolli GB, Ziemen M, Muehlen-Bartmer I, Bizet F, Home PD, et al. New insulin 
glargine 300 units/mL versus glargine 100 units/mL in people with type 2 diabetes using basal 
and mealtime insulin: glucose control and hypoglycemia in a 6-month randomized controlled 
trial (EDITION 1). Diabetes Care. 2014;37(10):2755-62. 
9. Yki-Järvinen H, Bergenstal R, Ziemen M, Wardecki M, Muehlen-Bartmer I, Boelle E, et al.  
New insulin glargine 300 units/mL versus glargine 100 units/mL in people with type 2 
diabetes using oral agents and basal insulin: glucose control and hypoglycemia in a 6-month 
randomized controlled trial (EDITION 2).  Diabetes Care. 2014;37(12):3235-43. 
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10. Bolli GB, Riddle MC, Bergenstal RM, Ziemen M, Sestakauskas K, Goyeau H, et al.  New 
insulin glargine 300 U/ml compared with glargine 100 U/ml in insulin-naïve people with type 
2 diabetes on oral glucose-lowering drugs: a randomized controlled trial (EDITION 3).  
Diabetes Obes Metab. 2015;Jan 14. [Epub ahead of print]. 
11. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff 
(Millwood). 2008;27(3):759-69. 
12. Lantus [package insert].  Bridgewater, NJ. sanofi-aventis US LLC; 2013. Available upon 
request. 
13. Levemir [package insert]. Copenhagen, Denmark.  Novo Nordisk A/S; 2013. Available upon 
request. 
14. National Committee for Quality Assurance. NCQA HEDIS Measures 2014 [online].  
Available from URL: 
http://www.ncqa.org/HEDISQualityMeasurement/HEDISMeasures/HEDIS2014.aspx 
15. Data on file. IMPACT® database analysis (2012).  Available upon request. 
16. Karve S, Cleves MA, Helm M, Hudson TJ, West DS, Martin BC, et al. Good and poor 
adherence: optimal cut-point for adherence measures using administrative claims data. Curr 
Med Res Opin. 2009;25(9):2303-10. 
17. Bradley C. Diabetes Treatment Satisfaction Questionnaire (DTSQ). In: Bradley C, ed. 
Handbook of psychology and diabetes. Chur (Switzerland): Harwood Academic Publishers; 
1994:111-132. 
18. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, et al. Hypoglycemia and 
diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine 
Society. Diabetes Care. 2013;36(5):1384-95.  
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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 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-002643 VERSION 6.0 (06-JUL-2016) 
Page 1
STATISTICAL ANALYSIS PLAN 
A randomized, open-label, parallel group real world pragmatic trial to assess the 
clinical and health outcomes of Toujeo® compared to commercially available basal 
insulins for initiation of therapy in insulin naïve patients with uncontrolled 
type 2 diabetes mellitus 
HOE901-LPS14347 
STATISTICIAN: 
/
Statistical Project Leader: 
/
DATE OF ISSUE: 11-Nov-2016 
Total number of pages: 
66 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ...................................................................................................................1 
TABLE OF CONTENTS..................................................................................................................................2 
LIST OF TABLES ...........................................................................................................................................5 
LIST OF FIGURES..........................................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................................................................7 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................9 
1.1 
STUDY DESIGN AND RANDOMIZATION ......................................................................................9 
1.2 
OBJECTIVES.................................................................................................................................10 
1.2.1 
Primary objectives..........................................................................................................................10 
1.2.2 
Secondary objectives.....................................................................................................................10 
1.3 
DETERMINATION OF SAMPLE SIZE...........................................................................................11 
1.3.1 
Original sample size.......................................................................................................................11 
1.3.2 
Sample size for Interim Analysis....................................................................................................12 
1.4 
STUDY PLAN.................................................................................................................................12 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL................................16 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN .....................16 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ....................................................................17 
2.1 
ANALYSIS ENDPOINTS ...............................................................................................................17 
2.1.1 
Demographic and baseline characteristics ....................................................................................17 
2.1.2 
Prior and Concomitant medications...............................................................................................19 
2.1.3 
Efficacy endpoints..........................................................................................................................19 
2.1.3.1 
Primary efficacy endpoint(s) ..........................................................................................................20 
2.1.3.2 
Secondary efficacy endpoint(s)......................................................................................................20 
2.1.3.3 
Other efficacy endpoint(s)..............................................................................................................20 
2.1.4 
Safety endpoints ............................................................................................................................21 
2.1.4.1 
Hypoglycemia variables .................................................................................................................22 
2.1.4.2 
Adverse events variables...............................................................................................................23 
2.1.4.3 
Injection site reactions, hypersensitivity reactions and immunogenicity........................................23 
2.1.4.4 
Deaths............................................................................................................................................24 
2.1.4.5 
Laboratory safety variables............................................................................................................24 
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2.1.4.6 
Vital signs variables .......................................................................................................................24 
2.1.4.7 
Electrocardiogram variables ..........................................................................................................24 
2.1.5 
Pharmacokinetic variables .............................................................................................................24 
2.1.6 
Pharmacodynamic/genomics endpoints ........................................................................................24 
2.1.7 
Quality-of-life endpoints and patient reported outcomes ...............................................................25 
2.1.7.1 
Diabetes Treatment Satisfaction Questionnaire Status Version....................................................25 
2.1.7.2 
Diabetes Treatment Satisfaction Questionnaire Change Version .................................................26 
2.1.7.3 
Hypoglycemia Patient Questionnaire.............................................................................................27 
2.1.7.4 
Global Effectiveness Scale ............................................................................................................27 
2.1.8 
Health economic endpoints............................................................................................................27 
2.2 
DISPOSITION OF PATIENTS .......................................................................................................28 
2.2.1 
Randomization and drug dispensing irregularities.........................................................................29 
2.3 
ANALYSIS POPULATIONS...........................................................................................................30 
2.3.1 
Efficacy populations .......................................................................................................................30 
2.3.2 
Safety population ...........................................................................................................................31 
2.4 
STATISTICAL METHODS .............................................................................................................31 
2.4.1 
Demographics and baseline characteristics ..................................................................................31 
2.4.2 
Prior and Concomitant medications...............................................................................................32 
2.4.2.1 
Non anti-diabetic medication..........................................................................................................32 
2.4.2.2 
Anti-diabetic medication.................................................................................................................32 
2.4.2.3 
Prohibited medication.....................................................................................................................33 
2.4.3 
Extent of study treatment exposure ...............................................................................................33 
2.4.3.1 
Exposure and extent of investigational medicinal product exposure.............................................33 
2.4.3.2 
Persistence on study medication ...................................................................................................34 
2.4.3.3 
Basal insulin dose ..........................................................................................................................35 
2.4.4 
Analyses of efficacy endpoints.......................................................................................................35 
2.4.4.1 
Analysis of primary efficacy endpoint.............................................................................................35 
2.4.4.2 
Analyses of secondary efficacy endpoints.....................................................................................40 
2.4.4.3 
Multiplicity issues ...........................................................................................................................42 
2.4.5 
Analyses of safety endpoints .........................................................................................................42 
2.4.5.1 
Analyses of hypoglycemia .............................................................................................................42 
2.4.5.2 
Analyses of adverse events ...........................................................................................................44 
2.4.5.3 
Deaths............................................................................................................................................48 
2.4.5.4 
Analyses of laboratory safety variables .........................................................................................48 
2.4.5.5 
Analyses of vital sign variables ......................................................................................................48 
2.4.5.6 
Analyses of electrocardiogram variables .......................................................................................48 
2.4.5.7 
Analyses of Patient-Support Program (PSP).................................................................................48 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................49 
2.4.7 
Analyses of patient reported outcome variables............................................................................49 
2.4.8 
Analyses of Health economic endpoints........................................................................................49 
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2.5 
DATA HANDLING CONVENTIONS ..............................................................................................50 
2.5.1 
General conventions ......................................................................................................................50 
2.5.2 
Data handling conventions for secondary efficacy variables.........................................................53 
2.5.3 
Missing data...................................................................................................................................54 
2.5.4 
Windows for time points.................................................................................................................58 
2.5.5 
Unscheduled visits .........................................................................................................................58 
2.5.6 
Pooling of centers for statistical analyses......................................................................................58 
2.5.7 
Statistical technical issues .............................................................................................................58 
3 
INTERIM ANALYSIS .....................................................................................................................59 
4 
DATABASE LOCK........................................................................................................................60 
5 
SOFTWARE DOCUMENTATION .................................................................................................61 
6 
REFERENCES...............................................................................................................................62 
7 
LIST OF APPENDICES.................................................................................................................63 
APPENDIX A 
HYPOGLYCEMIA CLASSIFICATION (ADA/FDA) ..............................................................64 
APPENDIX B 
ANTI-DIABETIC CLASSIFICATION....................................................................................66 
 
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LIST OF TABLES 
Table 1 - Visit schedule ...................................................................................................................................9 
Table 2 - Study flow chart..............................................................................................................................14 
Table 3 - Randomization and drug allocation irregularities...........................................................................30 
Table 4 - Stratification factors discrepancies.................................................................................................36 
Table 5 - Unexpected Scoring.......................................................................................................................52 
Table 6 - PRO missing data handling............................................................................................................52 
Table 7 - Re-allocation time windows definition ............................................................................................58 
 
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LIST OF FIGURES 
Figure 1 - Graphical study design .................................................................................................................13 
Figure 2 - Flow chart for hypoglycemia event classification in case of missing items ..................................57 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ADA: 
American Diabetes Association 
AE: 
adverse event 
ALP: 
alkaline phosphatase 
ALT: 
alanine transaminase 
ANCOVA: 
analysis of covariance 
AST: 
aspartate aminotransferase  
ATC: 
anatomic or therapeutic category 
BG: 
blood glucose 
BMI: 
body mass index 
CI: 
confidence interval 
CLcr: 
creatinine clearance 
CRF: 
case report form 
DMC: 
data monitoring committee 
DTSQc: 
diabetes treatment satisfaction questionnaire change version 
DTSQs: 
diabetes treatment satisfaction questionnaire status version 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EOT: 
end of treatment 
ES: 
effect size 
FPG: 
fasting plasma glucose 
GES: 
global effectiveness scale 
GLP-1: 
glucagon like peptide-1  
HbA1c: 
hemoglobin A1c 
HEDIS: 
healthcare effectiveness data and information set  
HLGT: 
high level group term 
HLT: 
high level term 
IA: 
interim analysis 
IFCC: 
international federation of clinical chemistry 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IVRS: 
interactive voice response system 
IWRS: 
interactive web response system 
KM: 
Kaplan-Meier 
LBGE: 
low blood glucose event 
LFT: 
liver function test 
LLT: 
lower level term  
LS means: 
least square means 
MAR: 
missing at random 
MCID: 
minimal clinically important difference 
MCMC: 
Markov Chain Monte Carlo 
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MedDRA: 
medical dictionary for regulatory activities 
MMRM: 
mixed-effect model with repeated measure 
MPR: 
medication possession ratio 
NIMP: 
non-investigational medical product 
OAD: 
oral anti-diabetic agent 
PAM: 
patient activation measure 
PRO: 
patient reported outcome 
PSP: 
patient support program 
PT: 
preferred term 
RA: 
receptor agonist 
SAE: 
serious adverse event 
SD: 
standard deviation 
SE: 
standard error 
SIDES: 
subgroup identification based on difference effect search 
SMPG: 
self-measured plasma glucose 
SMQ: 
standardized MedDRA query 
SOC: 
system organ class 
SU: 
sulfonylurea 
T2DM: 
type 2 diabetes mellitus 
TEAE: 
treatment-emergent adverse event 
ULN: 
upper limit of normal 
WHO-DD: 
World Health Organization-Drug Dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
1.1 
STUDY DESIGN AND RANDOMIZATION 
This is a multi-center open label randomized active controlled 2 arm parallel group comparative 
“real world” or “pragmatic” trial in patients with type 2 diabetes (T2DM) who are insulin naïve 
and uncontrolled on two or more oral anti-diabetic agents (OADs) and/or glucagon like peptide-1 
(GLP-1) receptor agonist (RA). The goal of the study is to demonstrate that 
Toujeo HOE901 U300 insulin glargine in combination with its patient support program (PSP) are 
superior to other commercially available basal insulin, specifically insulin glargine (Lantus) and 
insulin detemir (Levemir), in attainment of individualized Healthcare Effectiveness Data and 
Information Set (HEDIS) glycosylated hemoglobin (HbA1c) targets at 6 months without 
documented symptomatic (blood glucose [BG] ≤70 mg/dL) or severe hypoglycemia at any time of 
day from baseline to 6 months. The protocol (1) allows for nearly all OADs and GLP-1 RA as 
background medication as allowed for use with insulin in the label. 
The trial will consist of: 
• 
One week screening period at site by clinician to screen the identified potential subjects, 
• 
Twenty-six week treatment period for primary efficacy endpoint, 
• 
Twenty-six week extension period for collecting persistence data and additional efficacy 
and safety data.  
Table 1 - Visit schedule 
Visit 
Comment 
Time 
Timeframe 
V1 
Screening visit 
Week -1 
 
V2 
Baseline Visit 
Week 0, Day 1 
±7 days 
V3 
Primary efficacy endpoint visit 
Day 180 
Should occur within ±30 days 
V4 
End of treatment visit (EOT) 
Day 360 
May occur within ±30 days 
ABBREVIATION: EOT = end of treatment.  
Randomization will be performed centrally on V2 (Day 1) by interactive voice response 
system/interactive web response system (IVRS/IWRS), and will be stratified by individualized 
HbA1c target (<8%/<7%), GLP-1 RA use (y/n), sulfonylurea (SU) use (y/n) and 
HbA1c (<9%/≥9%). Patients receive either Sanofi’s Toujeo as the test drug or Lantus or Levemir 
as the comparator/control drugs with or without a PSP. 
The maximum study duration is 53 weeks per patient. For patients who prematurely discontinue 
the trial, the EOT visit assessments are performed at the time of discontinuation. In addition, an 
early end of trial case report form (CRF) page will be completed which includes the reason for 
stopping the treatment. 
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Toujeo SoloSTAR pen and the control drugs, Lantus SoloSTAR and Levemir FlexTouch are 
distinguishable and so this study is an open-label design. Despite the open label administration of 
the study insulin, the assessments of outcome, the HbA1c and fasting plasma glucose (FPG) are 
determined in central laboratories blinded to the treatment received. The study team will review 
the data for the efficacy parameters, adverse events (AE) and hypoglycemia without treatment 
assignments. 
1.2 
OBJECTIVES 
1.2.1 Primary objectives 
The primary objective of this study is to demonstrate clinical benefit of Toujeo in achieving 
individualized HEDIS HbA1c targets as defined below at 6 months without documented 
symptomatic (BG ≤70 mg/dL) or severe hypoglycemia at any time of day from baseline to 
6 months in uncontrolled insulin naive patients with type 2 diabetes initiating basal insulin therapy 
in a real world setting. 
The individualized HEDIS HbA1c targets for this study are: 
• 
HbA1c <8% if the patient is ≥65 years, 
• 
HbA1c <8% if the patient is <65 years, and with evidence of any of these 
diseases/conditions: 
- 
Coronary artery bypass surgery or Percutaneous coronary intervention, 
- 
Ischemic vascular disease, 
- 
Thoracic aortic aneurysm, 
- 
Chronic heart failure, 
- 
Prior myocardial infarction, 
- 
Chronic renal failure/End stage renal disease, 
- 
Dementia, 
- 
Blindness, 
- 
Lower extremity amputation, 
• 
HbA1c <7% if the patient is <65 years, and without evidence of any of these 
diseases/conditions listed above. 
1.2.2 Secondary objectives 
Secondary objectives are to compare Toujeo to other commercially available basal insulins at 
6 and 12 months after initiating basal insulin therapy in a real world setting in terms of: 
• 
Patient persistence with assigned basal insulin therapy, 
• 
Risk of hypoglycemia including the incidence and rate of documented symptomatic and 
severe hypoglycemia, 
• 
Changes in HbA1c, FPG, body weight, 
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• 
Differences in patient and provider reported outcomes (including Diabetes Treatment 
Satisfaction Questionnaire Status and Change Versions [DTSQs and DTSQc], 
Hypoglycemia Patient Questionnaire, and patient and provider reported Global 
Effectiveness Scales [GES]), 
• 
Healthcare resource utilization including hospitalizations and emergency department or 
other provider visits and healthcare costs. 
1.3 
DETERMINATION OF SAMPLE SIZE 
1.3.1 Original sample size 
At time of initial protocol, calculations to determine the sample size of 1635 patients per treatment 
group are based on superiority testing of the primary efficacy variable of the proportion of 
patients reaching individualized HbA1c target at Month 6 without a documented symptomatic 
(BG ≤70 mg/dL) or severe hypoglycemic event at any time of day from baseline to Month 6, with 
the following assumptions: 
• 
Individualized HbA1c target attainment per HEDIS criteria of <8% if older or presence of 
medical comorbidities, or otherwise <7%, 
• 
An absolute difference of 5.5% in favor of Toujeo in patients assigned a target 
HbA1c <7%, assuming a 30.1% rate in the Toujeo arm, based on data from the 
EDITION 3 study, 
• 
An absolute difference of 5.4% in favor of Toujeo in patients assigned a target 
HbA1c <8%, assuming a 55.8% rate in the Toujeo arm, based on data from the 
EDITION 3 study, 
• 
An absolute overall (weighted average) difference of 5.5% in favor of Toujeo for all 
patients combined, assuming that 70% of the study patients would have a target 
HbA1c <7%, and 30% would have a target HbA1c <8%, based on data from 
a commercially available database, 
• 
A maximum overall response rate of 33% in the comparator basal insulins arm, 
• 
A 2-sided chi-squared test at the 5% significance level, with 90% power, 
• 
All patients will be eligible for the primary endpoint analysis. 
The assumptions are based on data from the EDITION program. 
As a logistic regression model will be used for the primary analysis of the composite endpoint of 
individualized HbA1c target attainment without hypoglycemia, it is anticipated that the power 
will be higher due to reduced estimate variability compared with the chi-square test. Calculations 
were made using nQuery Advisor 6.01. 
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1.3.2 Sample size for Interim Analysis 
One interim analysis (IA) was added per Clinical Trial Protocol Amendment No. 01, for the 
purpose of efficacy to provide an early evaluation of Toujeo effectiveness, when 
1800 randomized patients (54.2% information fraction of targeted sample size) have completed 
their 6-month (Day 180) visit. 
Due to the addition of the IA the sample size will be increased to 1662 patients per treatment 
group (total of 3324 patients). The calculation takes into account one IA using a group sequential 
approach with an efficacy boundary based on a gamma (-3) alpha spending function, and 
an overall two-sided alpha-level of 0.05, the two-sided nominal significance level is 0.010 at IA, 
and 0.046 at final analysis. 
The total sample size calculation of 3324 is based on the assumption of a maximum of 
a 33% overall (weighted average) response rate with Lantus, and at least a 5.5% increase in 
response rate with Toujeo, and assumes an overall 2-sided test with alpha-level 0.05 with an IA 
performed on 1800 patients followed 6 months. 
Overwhelming efficacy will be shown at IA if the efficacy boundary is met, ie, if the two-sided 
p-value for comparison of primary composite endpoint incidence is below 0.010, with a difference 
in favor of Toujeo between percentages of patients reaching the primary composite endpoint. The 
corresponding power to show overwhelming efficacy at IA under the alternative hypothesis is of 
45%.  
1.4 
STUDY PLAN 
The study will be a randomized, controlled, open label parallel group real world trial. 
It will include a 6 month treatment period ending in assessment of the primary and secondary 
endpoints followed by a 6 month extension period for assessment of certain additional endpoints. 
There will be three database locks:  
• 
One at interim 6-month analysis, 
• 
One at 6 months, once the last randomized patient has had an opportunity to complete 
6 months of treatment, 
• 
And one at 12 months.  
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Figure 1 - Graphical study design 
 
 
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Table 2 - Study flow chart 
 
 
Screening 
Treatment Period 
 
VISIT 
1 
2 
 
 
3 
4 
 
WEEK 
-1 
0 
 
 
26 ±4 
52 ±4 
 
DAY 
-7 
1 ±7
45
90
180 ±30
360 ±30 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
Patient Demography 
X 
 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
 
 
 
 
Prior Medication History 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
X 
 
Vital Signs (including body weight) 
X 
 
 
 
X 
X 
 
DTSQs 
X 
X 
 
 
X 
X 
 
DTSQc 
 
 
 
 
 
X 
 
Hypoglycemia Patient Questionnaire 
X 
X 
 
 
X 
X 
 
Patient activation measure (PAM) 
X 
 
 
 
 
 
 
Patient: GES 
 
 
 
 
X 
X 
 
Provider: GES 
 
 
 
 
X 
X 
 
Randomization 
 
X 
 
 
 
 
 
IVRS call 
X 
X 
 
 
X 
X 
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Screening 
Treatment Period 
 
VISIT 
1 
2 
 
 
3 
4 
 
WEEK 
-1 
0 
 
 
26 ±4 
52 ±4 
 
DAY 
-7 
1 ±7
45
90
180 ±30
360 ±30 
Treatment: 
Dispensation of investigational medicinal product (IMP) 
 
X 
 
 
 
 
 
Concomitant Medication 
X 
X 
 
 
X 
X 
 
Compliance 
 
 
 
 
X 
X 
 
Insulin Pen Instruction 
 
X 
 
 
 
 
 
BG meter dispensing and training 
 
X 
 
 
 
 
 
E-diary dispensing and training 
 
X 
 
 
 
 
 
Offer to Enroll in PSP 
 
X 
 
 
 
 
 
Insulin dose 
 
 
 
 
X 
X 
Safety: 
AE/serious adverse event (SAE) recording 
X 
X 
 
 
X 
X 
 
Diary Reviews at visits 
 
X 
 
 
X 
X 
 
Hypoglycemia review of electronic source a 
 
 
X 
X 
 
 
Laboratory Testing: 
HbA1c 
X 
 
 
 
X 
X 
 
FPG 
X 
 
 
 
X 
X 
 
Serum creatinine 
X 
 
 
 
 
 
 
Serum liver function tests (LFT) (aspartate aminotransferase [AST], alanine 
aminotransferase [ALT], total bilirubin, alkaline phosphatase [ALP]) 
X 
 
 
 
 
 
 
Pregnancy test (for women of childbearing potential) b 
X 
 
 
 
X 
X 
a Approximately Day 45 and approximately Day 90, review of electronic source without on site or telephone visit, 
b Pregnancy status should be checked by serum pregnancy testing prior to exposure to the investigational product, urine pregnancy tests may be done at subsequent visits. 
ABBREVIATION: DTSQs = diabetes treatment satisfaction questionnaire status version; DTSQc = diabetes treatment satisfaction questionnaire change version; PAM = patient activation measure; GES = global 
effectiveness scale; IVRS = interactive voice response system; IMP = investigational medicinal product; BG = blood glucose; PSP = patient support program; SAE = serious adverse event; FPG = fasting plasma 
glucose; LFT = liver function test; AST = aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; HbA1c = hemoglobin A1c
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
In the protocol (1) Section 11.4.2, Analyses of efficacy endpoints, defines the analysis of 
HbA1c endpoints (change from baseline to 6 months) and self-reported satisfaction score using 
a mixed-effect model with repeated measures (MMRM) approach under the missing at random 
(MAR) framework, using an adequate contrast at Month 6. Since at the time of the 6 month 
database lock, only baseline and 6 month HbA1c data are available, an analysis of covariance 
(ANCOVA) will be performed at time of 6 month database lock and a MMRM at time of 
12 month database lock. 
In the protocol (1) Section 11.4.2, Analysis of primary efficacy endpoint(s), exploratory analysis 
for primary endpoint was modified. The Predictive Enrichment method is replaced by Subgroup 
Identification Based on Difference Effect Search (SIDES). The rationale is that the predictive 
enrichment procedure does not adjust for multiplicity. Additionally, the definition of subgroups is 
based on a score, defined as a function of multiple covariates, which makes difficult the clinical 
interpretation. On the other side, SIDES method uses fewer covariates (ie, 2 or 3 covariates), that 
is easier to interpret from a clinical point of view. Additionally, SIDES corrects for multiplicity. 
As mentioned in Clinical Trial Protocol Amendment No. 01, an IA is planned when 1800 patients 
have completed their 6 month visit. The calculation takes into account one IA using a group 
sequential approach with an efficacy boundary based on a gamma (-3) alpha spending function. 
The cut-off date for the IA is the date when 1800 patients have completed their 6 month visit. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN 
Not applicable. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES 
2.1 
ANALYSIS ENDPOINTS 
2.1.1 Demographic and baseline characteristics 
The efficacy baseline value is defined as the last available value obtained before and up to the date 
of randomization.  
Baseline HbA1c will be obtained at screening visit within one week of study initiation. For all 
safety measures, the baseline value is defined as the last available value prior to the first injection 
of IMP. 
Demographic characteristics 
Demographic variables are, 
• 
Age in years,  
• 
Age groups (<65, ≥65 and <75, and ≥75 years),  
• 
Gender (Male, Female),  
• 
Race (Caucasian/white, Black, Asian/Oriental, American Indian or Alaska Native, Native 
Hawaiian or other Pacific Island, other), and, 
• 
Ethnicity (Hispanic, non-Hispanic). 
Medical or surgical history 
Medical or surgical history include medical history or surgical history related to diabetes and 
other medical or surgical history collected at Screening.  
Medical history or surgical history related to diabetes are pre-specified medical or surgical history 
related to diabetes.  
Other medical or surgical history will be coded to “Lower Level Term (LLT)”, “Preferred Term 
(PT)”, “High Level term (HLT)”, “High Level Group Term (HLGT)” and associated primary 
“System Organ Class (SOC)” by the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at the sponsor at the time of database lock. 
Disease characteristics at baseline  
Specific disease history includes history of diabetes collected at Screening and HEDIS 
components.  
Diabetes history includes, 
• 
Duration of type 2 diabetes (date of diagnosis ),  
• 
Age at diagnosis of diabetes,  
• 
Diabetes duration (years),  
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• 
Diabetic complications, (diabetic retinopathy, diabetic sensory or motor neuropathy, 
diabetic autonomic neuropathy, and diabetic nephropathy), 
• 
Anti-diabetic non-insulinic drugs,  
• 
Previous participation to a PSP, and,  
• 
PAM. 
Note: PAM as an assessment of patient engagement. PAM score is detailed in Appendix F of 
Achieve Control protocol (1). 
Vital signs  
Vital signs at baseline are, 
• 
Weight in kilograms,  
• 
Weight group (<50, ≥50 and <100, and ≥100 kg),  
• 
Height in centimeter,  
• 
Body mass index (BMI) in kg/m2, 
• 
Category of BMI (<25, [25-30], [30-40] and ≥40 kg/m²),  
• 
Blood pressures, and, 
• 
Heart rate. 
Other baseline characteristics 
Other baseline characteristics include,  
• 
Randomization strata Individualized HbA1c target (<8%/<7%) from IVRS and electronic 
CRF (e-CRF) data,  
• 
Randomization strata SU use (yes/no) from IVRS and e-CRF data,  
• 
Randomization strata GLP-1 RA use (yes/no) from IVRS and e-CRF data, 
• 
Payer or non-payer patients, defined as patients who have (or not) provided consent to 
release of insurance data,  
• 
Geographical region of the sites, and, 
• 
Physician type (endocrinologist, internal medicine or primary care physician). 
Baseline efficacy data 
• 
HbA1c (% and mmol/mol), 
• 
Baseline HbA1c category (<9%/≥9%), and, 
• 
FPG (mmol/L and mg/dL). 
Baseline safety laboratory data 
Clinical chemistry data for centralized clinical laboratories will be described after conversion into 
standard international units.  
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Renal function 
• 
Baseline Creatinine (µmol/L), 
• 
Baseline Creatinine Clearance : CLcr (mL/min),  
• 
CLcr category (mL/min): ≥90, [60–90], [30–60], <30. 
Pancreatic function 
• 
Lipase (U/L and ULN ratio), 
• 
Amylase (U/L and ULN ratio). 
Alcohol and smoking habit 
• 
Tobacco habit (never smoke, quit smoking, currently smokes) including the average 
number of cigarettes per day for currently smokers, 
• 
Alcohol habit (never, occasionally, at least monthly, at least weekly, at least daily) 
including the number of daily standard drink (1 or 2, >2). 
2.1.2 Prior and Concomitant medications  
Prior medications are those the patient used prior to the first IMP intake. Prior medications can be 
discontinued before first administration or can be ongoing during treatment phase.  
Concomitant medication is any treatment received by the patient at the same time as the IMP 
treatment, from 1st IMP injection up to last IMP injection + 1 day (0 day for anti-diabetic therapy) 
whichever comes earlier. 
All medications will be coded using the most current version of World Health Organization-Drug 
Dictionary (WHO-DD) at the time of each database lock.  
Prohibited concomitant medication is limited to drugs contraindicated with use of basal insulin as 
per drug labels. 
2.1.3 Efficacy endpoints 
HbA1c and FPG will be measured by central laboratory. Blood sample taken used for analyses are 
those collected at baseline, Month 6, Month 12 or premature EOT. Analysis time point will be 
either the nominal visit or the reallocated visit (reallocation process is described in Section 2.5.4). 
For patients randomized and not treated, the baseline value is defined as the last available value 
obtained up to the date and time of randomization.  
Observation period of efficacy variables 
• 
The 12-month randomized period is defined as the time from randomization up to 
Day 360 (Visit 4). It includes the extension period (after Day 180 [Visit 3] to Day 360 
[Visit 4]) to allow for collection of additional endpoint data such as health care 
utilization2.  
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• 
The 6-month randomized period is defined as the time from randomization up to 
Day 180 (Visit 3) or date of end of study whichever come earlier1. 
• 
The 6-month on-treatment period is defined as the time from 1st IMP intake up to 
Day 180 (Visit 3) or date of last IMP + 1 day (7 days for HbA1c), whichever comes 
earlier1. 
• 
The 6 to 12-month randomized period named “from start of Month 7 to Month 12” is 
defined as the time from the day following the 6-month randomized treatment period up to 
the end of the 12-month randomized period2. 
1. 
Used at time of 6 month database lock, 
2. 
Used at time of 12 month database lock.  
2.1.3.1 Primary efficacy endpoint(s) 
The primary efficacy endpoint is the proportion of patients with individualized HbA1c target 
attainment per HEDIS criteria assessed at randomization without documented symptomatic 
(BG ≤70 mg/dL) or severe hypoglycemia at any time of day from baseline to 6 months. 
The individual components of individualized HbA1c target attainment and absence of any 
documented symptomatic (BG ≤70 mg/dL) or severe hypoglycemia will also be evaluated as 
supportive analyses to evaluate consistency: 
• 
Proportion of patients with individualized HbA1c target attainment at 6 months, and, 
• 
Proportion of patients without documented symptomatic (BG ≤70 mg/dL) or severe 
hypoglycemia. 
2.1.3.2 Secondary efficacy endpoint(s) 
• 
Change in HbA1c from baseline (obtained at screening visit within one week of study 
initiation) to 6 months, 
• 
Proportion of patients who remain on assigned basal insulin therapy (persistent with 
assigned therapy) at 6 and 12 months, 
• 
Proportion of patients with individualized HbA1c target attainment per HEDIS criteria at 
6 months without documented symptomatic (BG <54 mg/dL) or severe hypoglycemia at 
any time of day from baseline to 6 months, 
• 
Proportion of patients with individualized HbA1c target attainment per HEDIS criteria at 
12 months without documented symptomatic (BG <54 mg/dL) or severe hypoglycemia at 
any time of day from baseline to 12 months, and, 
• 
Proportion of patients with individualized HbA1c target attainment (per HEDIS criteria) at 
12 months without documented symptomatic (BG ≤70 mg/dL) or severe hypoglycemia at 
any time of day from baseline to 12 months. 
2.1.3.3 Other efficacy endpoint(s) 
• 
Change in HbA1c from baseline to 12 months, 
• 
Change in FPG from baseline to 6 months and 12 months, 
• 
Change in body weight from baseline to 6 months and 12 months, 
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• 
Basal insulin dose collected at the study visit on the e-CRF at 6 and 12 months, 
• 
Proportion of patients with HbA1c <8% at 6 months without documented symptomatic 
(BG ≤70 mg/dL) or severe hypoglycemia, 
• 
Proportion of patients with HbA1c <7% at 6 months without documented symptomatic 
(BG ≤70 mg/dL) or severe hypoglycemia, 
• 
Proportion of patients with HbA1c <8% at 6 months, and, 
• 
Proportion of patients with HbA1c <7% at 6 months. 
2.1.4 Safety endpoints 
The following safety parameters will be analyzed in the clinical study report: 
• 
Hypoglycemia (according to American Diabetes Association [ADA] Workgroup on 
Hypoglycemia) (2), 
• 
AEs, SAEs, 
• 
Injection site reactions, 
• 
Hypersensitivity reactions, 
• 
Vital signs, and, 
• 
Healthcare resource utilization including hospitalizations and emergency department or 
other provider visits and healthcare costs. 
Observation period for safety endpoints 
• 
The pre-treatment period is defined as the time from informed consent up to the time of 
the first injection of IMP. 
• 
The 12-month on-treatment period is defined as the time from the 1st IMP intake up to 
1 day after the trial is completed2. 
• 
The 6-month on-treatment period named “Month 1 to Month 6” is defined as the time 
from 1st IMP intake up to Day 180 (Visit 3) or 1 day after date of last insulin (either IMP 
or commercial basal insulin prescribed following a switch) or 6-month visit, whichever 
comes earlier3. 
• 
The 6 to 12-month on-treatment period named “from start of Month 7 to Month 12” is 
defined as the time from the day following the 6-month on-treatment period up to the end 
of the 12-month on-treatment period2. 
• 
The post-treatment period is defined as the time starting 2 days after last injection of 
IMP (after the on-treatment period). 
• 
The on-study observation period is defined as the time from randomization until the end 
of the study (defined as last protocol planned visit or the resolution/stabilization of all 
SAEs and AE with pre-specified monitoring).  
2. 
Used at time of 12 month database lock,  
3. 
Used for 6 month and 12 month database lock. 
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2.1.4.1 Hypoglycemia variables 
Hypoglycemia observation periods  
• 
Pre-treatment hypoglycemia events are events that occur during the pre-treatment period, 
• 
Treatment-emergent hypoglycemia events are events that occur during the 12-month 
on-treatment period, 
- 
The 6-month treatment-emergent hypoglycemia events are events that occur during the 
6-month on-treatment period, 
• 
Post-treatment hypoglycemia events are events that occur during the post-treatment period. 
Hypoglycemia endpoints will be classified in categories after events have been characterized 
using ADA Working group (2). More specifically, the following variables will be analyzed: 
• 
Incidence and rate of documented symptomatic (BG ≤70 mg/dL) or severe hypoglycemia 
(24 hour and nocturnal ) from baseline to 6 and 12 months, 
• 
Incidence and rate of documented symptomatic (BG <54 mg/dL) or severe hypoglycemia 
(24 hour and nocturnal) from baseline to 6 and 12 months, and, 
• 
Incidence and rate of severe hypoglycemia (24 hour, per ADA definition) from baseline to 
6 and 12 months. 
Nocturnal hypoglycemia is defined as any hypoglycemia of the above categories that occurs 
between 00:00AM and 05:59 AM hours, regardless whether patient was awake or woke up because 
of the event. Daytime hypoglycemia is defined as any hypoglycemia of the above categories that 
occurs between 6:00 AM to 23:59. 
For each class of hypoglycemia as defined in Appendix A, documented hypoglycemia will be 
analyzed in addition to the threshold of plasma glucose of less than or equal to 70 mg/dL 
(3.9 mmol/L), by using a threshold of plasma glucose of <54 mg/dL (3.0 mmol/L).  
Patients are dispensed: 
• 
A Bluetooth enabled study glucometer,  
• 
E-diary,  
• 
And Low Blood Glucose Event (LBGE) paper back-up page. 
For all self-measured plasma glucose (SMPG) equal to or less than 70 mg/dL (or equivalent) 
LBGE symptoms, patients are instructed to complete:  
• 
A hypoglycemia page in the e-diary,  
• 
Or paper back-up page. 
Hypoglycemic events will be transferred from the glucometer to a web based portal that serves as 
an electronic source document. Some hypoglycemic events may be recovered from paper source 
such as the hypoglycemia back up report or the patient paper diary. In all cases, the source will be 
reviewed by the site and manually entered into the CRF.  
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2.1.4.2 Adverse events variables 
All reported AEs and SAEs is collected from the time of signed informed consent until the end of 
the study (defined as patient´s last visit planned per protocol or the resolution/stabilization of all 
SAE and AEs with pre-specified monitoring). All events will be managed and reported in 
compliance with all applicable regulations, and included in the final clinical study report. 
All AEs and SAEs will be coded to a “LLT”, “PT”, “HLT”, “HLGT” and associated primary 
“SOC” using MedDRA. MedDRA terms for hypersensitivity and injection site reactions will be 
included. The occurrence of AEs and SAEs is recorded from the time of signed informed consent 
until the end of the study. 
If an AE/SAE is ongoing and not resolved by the end of the study observation period and leads to 
subsequent death of the patient, it will have to be reported. 
The AE observations will be classified per the observation periods of safety data as defined above 
into: 
• 
Pre-treatment AEs are AEs that developed or worsened or became serious during the 
pre-treatment period. 
• 
Treatment-emergent AEs (TEAE) are AEs that developed or worsened or became 
serious during the 12-month on-treatment period. 
- 
The 6-month TEAEs are AEs that developed or worsened or became serious during 
the 6 month on-treatment period. 
to be used at time of 6-month database lock only. 
• 
Post-treatment AEs are AEs that developed or worsened or became serious during the 
post-treatment period. 
Symptomatic overdose 
Symptomatic overdose with IMP/anti-hyperglycemic non-investigational medicinal 
product (NIMP) will be identified through a specific question on the AE page in the e-CRF. 
Pregnancy 
Pregnancy occurring, either in female subject or in a female partner of a male subject, entered in a 
study will be identified through a dedicated AE page in the e-CRF. 
2.1.4.3 Injection site reactions, hypersensitivity reactions and immunogenicity 
No immunogenicity assessment is planned as part of the protocol (1).  
Injection site and hypersensitivity reactions are AEs recorded on AE page and identified for the 
statistical analysis using the following MedDRA codes: 
• 
Injection site reactions will be identified using the following MedDRA searches: HLGT 
“Administration site reactions” and HLTs “Administration site reactions NEC”, “Infusion 
site reactions”, “Injection site reactions” and “Application and instillation site reactions” 
and excluding HLTs “Implant and catheter site reactions” and “Vaccination site 
reactions”. 
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• 
Hypersensitivity reactions will be identified using the following MedDRA 
searches: Angioedema standardized MedDRA query (SMQ) (Narrow), Severe cutaneous 
adverse reactions SMQ (Broad), Hypersensitivity SMQ (Broad and Narrow) and 
excluding PTs related to administration, application, injection and infusion sites. High 
level term “Anaphylactic Responses” are included in those SMQs. 
2.1.4.4 Deaths 
The death observations are per the observation periods defined above. In addition, after the 
post-treatment period, death related to IMP as well as death resulting from TEAE must be 
reported to the Sponsor. 
• 
Death on-study: deaths occurring during the on-study observation period (defined as the 
time from the signed informed consent date up to the end of the study, ie, last protocol 
planned visit or the resolution/stabilization of all SAE), 
• 
Death pre-treatment: deaths occurring before the on-study observation period, 
• 
Death on-treatment: deaths occurring during the on-treatment period, 
• 
Death post study: death occurring after the end of study. 
2.1.4.5 Laboratory safety variables 
The clinical laboratory data consist of blood analysis (including, LFTs namely AST, ALT, ALP, 
total bilirubin, ALP, and creatinine) at Screening. They are not considered as part of safety 
endpoints to evaluate the study objectives during the treatment period. 
2.1.4.6 Vital signs variables 
Vital signs include: observed and change from baseline of heart rate (bpm), systolic and diastolic 
blood pressures (mmHg), and weight (kg) at baseline, 6 months and 12 months. 
2.1.4.7 Electrocardiogram variables 
Electrocardiogram (ECG) is not done routinely in the protocol (1). It may be done at the 
discretion of the investigator when clinically indicated. This data is not routinely recorded in the 
e-CRF and if abnormal, should be recorded as an AE. 
2.1.5 Pharmacokinetic variables  
Not applicable. 
2.1.6 Pharmacodynamic/genomics endpoints  
Not applicable. 
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2.1.7 Quality-of-life endpoints and patient reported outcomes 
Patients will complete self-reported questionnaires at designated time points in the study. 
2.1.7.1 Diabetes Treatment Satisfaction Questionnaire Status Version 
The DTSQs is a validated questionnaire to assess patient satisfaction with treatment and patient 
perception of BG control (3). The DTSQs will be used to evaluate patient satisfaction with 
treatment and patient perception of BG control over a several week period. The DTSQs is 
comprised of 8 questions which are answered on a Likert scale from 0 to 6. Responses to these 
questions would be summarized into the three domain scores of Total Treatment Satisfaction 
(Questions 1, 4-8), Hyperglycemia Perception (Question 2) and Hypoglycemia Perception 
(Questions 3) such that a higher score would be indicative of better satisfaction. Mean differences 
in scores between groups would be evaluated to understand the impact of treatment on patient 
satisfaction. DTSQs will be evaluated at Screening, Day 1, 6 months and 12 months in this study. 
The total treatment satisfaction score and the 2 other scores are determined by computing the 
mean of item responses: 
• 
Total treatment satisfaction score: sum of Items 1, 4, 5, 6, 7 and 8, ranging from 0 (no 
satisfaction) to 36 (high satisfaction), 
• 
Perceived frequency of hyperglycemia score: Item 2, ranging from 0 (none of the time) to 
6 (most of time), 
• 
Perceived frequency of hypoglycemia score: Item 3, ranging from 0 (none of the time) to 6 
(most of time). 
The DTSQs endpoints are: 
• 
Average scores on total treatment satisfaction from DTSQs at 6 months and 12 months, 
• 
Average scores on hyperglycemia perception from DTSQs at 6 months and 12 months; 
and, 
• 
Average scores on hypoglycemia perception from DTSQs at 6 months and 12 months. 
Additionally, on these 3 scores (total treatment satisfaction, hyperglycemia perception and 
hypoglycemia perception), evaluation will be performed on: 
• 
Change from baseline to 6 months,  
• 
Change from baseline to 12 months,  
• 
Change between 6 and 12 months. 
Additional endpoints are: 
• 
Percentage of patient responders on total treatment satisfaction score, defined as patients 
presenting a change from baseline to respectively Month 6 and Month 12 of at least the 
distribution-based minimal clinically important difference (MCID) value (Section 2.5.1).  
• 
Percentage of patient responders on perceived frequency of hyperglycemia score, defined 
as patients presenting a change from baseline to respectively Month 6 and Month 12 of at 
least the standard MCID value (Section 2.5.1). 
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• 
Percentage of patient responders on perceived frequency of hypoglycemia score, 
presenting a change from baseline to respectively Month 6 and Month 12 of at least the 
standard MCID (Section 2.5.1). 
2.1.7.2 Diabetes Treatment Satisfaction Questionnaire Change Version 
The DTSQc was developed from the original DTSQ to evaluate the change in treatment 
satisfaction at a specific time point (4).  
The DTSQc will be used to produce a measure of relative change in satisfaction rather than 
measure of absolute satisfaction, which is subject to ceiling and floor effects. 
A score for DTSQc treatment satisfaction items (Questions 1, 4-8) range from −3 to +3, and the 
sum of the treatment satisfaction scores range from −18 to +18.  
Positive scores are indicative of increases in treatment satisfaction relative to one year ago (start 
of the study). 
Perceived hyperglycemia (Question 2) and hypoglycemia (Question 3) items have scores that 
range from −3 to +3 in the DTSQc, with higher scores indicating more frequent perceived 
hyperglycemia or hypoglycemia by the end of the study.  
To control for baseline scores, DTSQs will be used as a measure of treatment satisfaction at 
baseline. DTSQc will be evaluated at 12 months in this study. 
The total treatment satisfaction score and the 2 other scores are determined by computing the 
mean of item responses: 
• 
Total treatment satisfaction score: sum of Items 1, 4, 5, 6, 7 and 8, ranging from -18 
(deterioration in treatment satisfaction) to +18 (improvement in treatment satisfaction), 
• 
Perceived frequency of hyperglycemia score: Item 2, ranging from -3 (fewer problems 
than before with hyperglycemia) to + 3 (more problems), 
• 
Perceived frequency of hypoglycemia score : Item 3, ranging from -3 (fewer problems 
than before with hypoglycemia) to +3 (more problems). 
The DTSQc endpoints are: 
• 
Average scores on change in total treatment satisfaction from DTSQc at 12 months, 
• 
Average scores on change in hyperglycemia perception from DTSQc at 12 months,  
• 
Average scores on change in hypoglycemia perception from DTSQc at 12 months. 
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2.1.7.3 Hypoglycemia Patient Questionnaire 
Patients will also complete the Hypoglycemia Patient Questionnaire, detailed in Appendix H of 
Achieve Control protocol (1). 
This questionnaire will require them to report frequency of hypoglycemia experienced during the 
course of the study. Responses to Questions 4 and 5 on the Hypoglycemia Patient Questionnaire 
will be used to assess the endpoints. a patient report of one or more episodes of either moderate or 
severe hypoglycemia since the last visit will be indicative of patient experience of hypoglycemia.  
The Hypoglycemia Patient Questionnaire endpoints are: 
• 
Proportion of patients who report moderate or severe hypoglycemia since last visit on the 
Hypoglycemia Patient Questionnaire (Questions 4 and 5) at baseline, at 6 months and at 
12 months.  
2.1.7.4 Global Effectiveness Scale 
Patient and Physician reported GES: This measure, originally developed to assess the impact of 
treatment on asthma control, will be adapted for diabetes (GES). The GES assesses impact of 
treatment on a 5-point scale: 
• 
Complete control of diabetes, 
• 
Marked improvement of diabetes, 
• 
Discernible, but limited improvement in diabetes, 
• 
No appreciable change in diabetes, 
• 
Worsening of diabetes. 
These assessments will be completed twice by patients at 6 and 12 months. Physicians will 
complete the GES twice for each patient they manage at 6 and 12 months.  
The GES endpoints are: 
• 
Proportions of patient and provider reported “Complete control of diabetes” or “Marked 
improvement of diabetes” responses to GES question at 6 months and 12 months.  
2.1.8 Health economic endpoints  
The healthcare utilization endpoints are: 
• 
Mean number and proportion of patients with hospitalizations over a 6 month and 
12 month period, 
• 
Mean number and proportion of patients with emergency room visits over a 6 month and 
12 month period, 
• 
Mean number of provider office visits and proportion of patients with specialty visits over 
a 6 month and 12 month period, 
• 
Mean overall and diabetes-related costs at 6 months and 12 months. 
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2.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the inclusion criteria and signed the 
informed consent.  
All randomized patients will be included in the Intent-to-Treat (ITT) Population.  
Patients will not be randomized more than once.  
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
• 
Screened: all patients who originally met inclusion criteria and signed the informed 
consent3,  
• 
Screen failure patients and reason for screen failure3,  
• 
Non-randomized but treated patients3,  
• 
Randomized: all screened patients with a treatment arm allocated and recorded in the IRT 
database, regardless of whether IMP was used or not and regardless of use of a PSP 
program3, 
• 
Randomized but not treated patients3,  
• 
Randomized and treated patients3,  
• 
The 12-month treatment completer population (presented as randomized): patients who 
complete the 12-month treatment period (have performed Visit 4 [D360]) without 
permanently discontinue treatment2,  
• 
The 6-month-treatment completer population (presented as randomized): patients who 
patients who complete the 6-month treatment period (have performed Visit 3 [D180]) 
without permanently discontinuing treatment1, 
• 
Patients who permanently discontinued treatment during the 12-month study period and 
reason for permanent treatment discontinuation presented as randomized2,  
• 
Patients who permanently discontinued treatment during the 6-month treatment period 
(before Month 6) and reason for permanent treatment discontinuation presented as 
randomized1, 
• 
Patients who permanently discontinued treatment at or after the 6-month treatment period 
and reason for permanent treatment discontinuation presented as randomized2,  
1. 
Used at time of 6 month database lock, 
2. 
Used at time of 12 month database lock,  
3. 
Used for 6 month and 12 month database lock. 
For all categories of patients (except for the screened and non-randomized categories) percentages 
will be calculated using the number of randomized patients as the denominator. Reasons for 
treatment discontinuation will be supplied in tables giving numbers and percentages by treatment 
group. This summary will be provided by treatment group within each center and will also be 
further sub-grouped by geographic region.  
Kaplan-Meier (KM) plots and estimates of the cumulative incidence of IMP discontinuation based 
on CRF collected data will be performed. 
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All critical or major deviations potentially impacting efficacy analyses, randomization, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages of deviations by treatment group. 
Additionally, the analysis populations for safety and efficacy will be summarized in a table by 
number of patients on the randomized population (Section 2.3).  
2.2.1 Randomization and drug dispensing irregularities 
On V2 (Day 1), the investigator or designee contacts the IVRS/IWRS and provides the patient 
number provided by IVRS/IWRS at screening visit, date of birth, HbA1c, individualized 
HbA1c target (<8%/<7%), GLP-1 RA use (y/n), SU use (y/n) and HbA1c (<9%/≥9%). Afterwards 
the IVRS/IWRS is called again each time for each new visit but does not include “standard of 
care” visits, which are not considered trial visits. 
Treatment kits are not dispensed since the drugs are provided through a pharmacy. The 
investigator provides the patient with a prescription for the insulin and a card to provide to the 
pharmacy to obtain the insulin, a “smart card” as a method of reimbursement. 
Randomization will be performed centrally by IVRS/IWRS, and will be stratified by 
individualized HbA1c target (<8%/<7%), GLP-1 RA use (y/n), SU use (y/n) and 
HbA1c (<9%/≥9%). a patient cannot be randomized more than once in the study. Patients who 
need to be moved to another site will have a new randomization number assigned at the new site. 
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, 
2. A patient is dispensed/prescribed an IMP not allocated by the protocol-defined 
randomization, such as,  
a) A patient at any time in the study is dispensed/prescribed different IMP than as 
randomized (which may or may not contain the correct-as-randomized IMP), or, 
b) A non-randomized 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/prescription 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). Non-randomized, treated patients will be described separately. 
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Patients with the following deviations will be identified and described in separate listings: 
• 
Treated but not randomized, 
• 
Randomized but not treated, 
• 
Randomized but not following the treatment arm as randomized. 
Randomization and drug-dispensing irregularities to be prospectively identified include but are 
not limited to: 
Table 3 - Randomization and drug allocation irregularities 
Randomization and drug allocation irregularities 
Treatment dispensation without IRT transaction 
Erroneous treatment delivery 
Treatment not available 
Randomization by error 
Patient randomized twice 
Forced randomization 
Stratification error 
Patient switched to another site 
2.3 
ANALYSIS POPULATIONS 
Patients treated without being randomized will not be considered randomized and will not be 
included in any safety or efficacy population. 
Patients who are dispensed/prescribed study drug without calling the IRT or before calling the 
IRT are considered non-randomized patients. They are excluded from any population for analysis, 
including efficacy and 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 signed her/his informed consent and has 
been allocated to a randomized treatment arm regardless of whether the treatment was delivered 
or used. 
The safety and efficacy populations will be defined at time of 6-month data base-lock based on 
data collected during the 6 month-randomized period. 
2.3.1 Efficacy populations 
The efficacy population is the ITT population, defined as all randomized population, irrespective 
of the treatment actually received, analyzed according to the treatment group allocated by 
randomization.  
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2.3.2 Safety population 
The safety population is defined as: all randomized patients who actually received at least 
one dose or part of a dose of IMP, analyzed according to the treatment actually received.  
In addition:  
• 
Non-randomized but treated patients will not be part of the safety population. This is 
a post marketing real world trial with commercially available insulin so that 
non-randomized but treated patients are not considered part of the trial and safety data are 
listed separately.  
• 
Randomized patients for whom it is unclear whether they took the study medication will 
be included in the safety population as randomized.  
• 
For any patient receiving more than one study treatment (Toujeo or “standard of care” 
basal insulin) during the trial, the patient will be analyzed in the treatment arm in which 
he/she was treated longer by either IMP (allocated by IRT or prescribed/dispensed) or 
Commercial basal insulin prescribed following a switch during the 6-month on-treatment 
period. This actual treatment arm, defined at time of 6-month database lock on the 
6-month on-treatment period, will be applied at time of 12-month database lock (ie, to the 
12-month on-treatment period). 
If a patient is randomized more than once, only the data associated with the first randomization 
are used in the analysis population. The subject will be analyzed according to the first 
randomization treatment arm. All data collected after the second randomization will be excluded 
from the primary efficacy analysis. The safety experience associated with any later randomization 
is described separately. 
2.4 
STATISTICAL METHODS 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, and maximum for each treatment group. Categorical and 
ordinal data will be summarized using the number and percentage of patients in each treatment 
group. 
2.4.1 Demographics and baseline characteristics 
Parameters will be summarized on the ITT population analyzed in the treatment group to which 
they were randomized. Analyses for the safety population will be included in the appendices if the 
size of the safety population is different (>10%) from the size of that in the primary analysis 
population for any treatment group. 
Parameters described in Section 2.1.1 will be summarized by treatment group and overall using 
descriptive statistics.  
Other medical or surgical history not related to diabetes will be summarized by SOC and HLT for 
each treatment group. Table will be sorted in descending order of the Toujeo treatment arm. 
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P-values on demographic and baseline characteristic data will not be calculated.  
2.4.2 Prior and Concomitant medications 
The prior and concomitant medications will be presented for the ITT population, separately for 
anti-diabetic and non-anti-diabetic medication.  
Prior medication will be presented by treatment arm and overall, whereas concomitant and 
post-treatment medication will be presented by treatment arm. 
2.4.2.1 Non anti-diabetic medication 
Non anti-diabetic medications will be summarized by treatment arm according to the WHO-DD 
dictionary, considering the first digit of the anatomic category (ATC) class 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.  
The tables for non-anti-diabetic prior medications will be sorted by decreasing frequency of 
anatomic class followed by therapeutic class based on the overall incidence across treatment arms. 
In case of equal frequency regarding ATCs, alphabetical order will be used. 
The tables for non-anti-diabetic concomitant and post-treatment medications will be sorted by 
decreasing frequency of anatomic class followed by therapeutic classes based on the incidence in 
Toujeo treatment arm. In case of equal frequency regarding ATCs, alphabetical order will be used.  
An individual listing sorted by treatment arm and subject number will be populated instead of 
summary table only if few non-anti-diabetic either prior or post-treatment medications are 
observed.  
2.4.2.2 Anti-diabetic medication 
Anti-diabetic medications will be summarized by treatment arm according to the WHO-DD 
dictionary considering the pharmacological class (ATC3), chemical class (ATC4) and 
standardized medication name. 
The table for anti-diabetic prior medications will be sorted by decreasing frequency of 
pharmacological class followed by chemical class and standardized medication name based on the 
overall incidence across treatment arm. In case of equal frequency, alphabetical order will be 
used. 
The tables for anti-diabetic concomitant and post-treatment medications will be sorted by 
decreasing frequency of pharmacological class followed by chemical class and standardized 
medication name based on the incidence in Toujeo treatment arm. In case of equal frequency, 
alphabetical order will be used. 
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Furthermore,  
•
Prior and post-treatment anti-diabetic insulin therapy will also be summarized by
predefined classification (basal insulin, short-acting insulin, pre-mixed insulin) and 
standardized medication name.  
•
Prior, concomitant and post-treatment anti-diabetic non-insulin therapy will also be
summarized by predefined classification: 
- 
Biguanides,  
- 
SU,  
- 
Glinides,  
- 
Thiazolidinedione,  
- 
DPP-4 inhibitors, 
- 
SGLT-2 inhibitors, 
- 
GLP1-RA,  
- 
Alpha-glucosidase inhibitors, 
- 
Other. 
and standardized medication name. 
•
Medication will be summarized by pre-defined classification (insulin and non-insulin
therapy) then insulin therapy will be split by pre-defined classification (basal insulin, short 
acting insulin, premixed insulin) and standardized medication name whereas non-insulin 
therapy will be split by predefined classification (as described just above) and standardized 
medication name. 
2.4.2.3 Prohibited medication 
Previous and concomitant prohibited medications will be presented separately by prohibited 
medication category as defined in deviation and standardized medication name. 
2.4.3 Extent of study treatment exposure  
2.4.3.1 Exposure and extent of investigational medicinal product exposure 
Extent of exposure 
The extent (or duration) of exposure during the study will be the total number of days of 
administration of IMP, ignoring temporary drug discontinuation, as follows: 
Extent (or 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, maximum, Q1 and Q3). 
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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: 
Categories 
At time of 6 month database lock, 
•
Up to 4 weeks,
•
>4 to 13 weeks,
•
>13 to 25 weeks,
•
>25 to 26 weeks,
•
>26 to 30 weeks,
•
>30 weeks.
At time of 12 month database lock, 
•
Up to 4 weeks,
•
>4 to 13 weeks,
•
>13 to 26 weeks,
•
>26 to 39 weeks,
•
>39 to 50 weeks,
•
>50 to 52 weeks,
•
>52 to 60 weeks,
•
>60 weeks.
2.4.3.2 Persistence on study medication  
Treatment persistence will be determined based on vendor claims database that would be 
responsible for managing and administration of the study drugs (Toujeo, Lantus, Levemir) from 
the vendor database administering the study drugs, information on prescription fill date, quantity 
dispensed, days of supply, number of units dispensed, prescription refill dates will be obtained in 
estimation of treatment persistence and discontinuation.  
A medication possession ratio (MPR) will be assessed based on number of days that patients had 
possession of study drug based on prescription date and days of supply. a MPR of 80% would be 
indicative of patients being persistent on study medication (5). Those not persistent will be 
considered discontinued on their study medication. Patients identified by the provider and where 
there is not data available for calculation of MPR will be summarized by observance of the actual 
treatment received from the e-CRF.  
Treatment persistence will be summarized descriptively (N, Mean, SD, Median, Minimum, and 
Maximum): 
•
Mean proportion of patients who have MPR, and,
•
The proportion of MPR <80%,
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• 
The incidence of patients completing the 6 month and the 12 month periods based on 
study visits will be described by treatment arm, 
• 
The proportion of patients who withdraw from study treatment before Month 6 and before 
Month 12 will be analyzed by treatment group using a logistic regression methodology 
with the same covariates used in the primary efficacy analysis (Section 2.4.4.1), 
• 
Cumulative incidence of treatment discontinuation based on the e-CRF collected treatment 
discontinuation dates will be plotted/estimated by treatment arm using a KM by treatment 
arm. 
Patients are not responsible for returning insulin pens or dosing records to their clinic visits to 
assess compliance. Medication use will be assessed by MPR and persistence measures based on 
data collected by the Smart card vendor (date of fill or refill and quantity of medication dispensed 
for 30 day supply). The site does not complete a treatment log form and no compliance 
information is entered into the e-CRF. 
2.4.3.3 Basal insulin dose 
The baseline for basal insulin dose is the total IMP dose taken the 1st day of administration 
(ie, 1st IMP dose for subject following a once daily regimen and the two 1st IMP dose for patients 
following a twice daily injection regimen). 
Observed and change and relative change from baseline value of total daily basal insulin dose 
(U and U/kg) will be described by visit (at baseline, 6 months and 12 months) per treatment arm. 
Mean (±√2 SE) insulin dose per group at baseline, 6-month and 12-month will be plotted. 
2.4.4 Analyses of efficacy endpoints 
The baseline value for laboratory efficacy endpoints (HbA1c and FPG), is the last available value 
prior and up to randomization. 
Unless otherwise specified the efficacy analyses will be performed on the ITT population based 
on the 6-month randomized period at time of 6 month database lock and based on the 12-month 
randomized period at time of 12-month database lock. 
2.4.4.1 Analysis of primary efficacy endpoint 
The primary efficacy analysis will be performed on the ITT population, using all post-baseline 
HbA1c data available and hypoglycemia events collected on the 6-month randomized period, 
regardless of IMP discontinuation. 
The primary efficacy endpoint: proportion of patients reaching individualized HbA1c target at 
6 months without documented symptomatic (BG ≤70 mg/dL) hypoglycemia will be analyzed 
using a logistic regression model, adjusting for HbA1c target and other stratification factors used 
at randomization: SU use (y/n), GLP-1 RA use (y/n) and baseline HbA1c (as continuous). 
a superiority test will be performed to compare this proportion between treatment groups at IA 
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(2-sided, alpha = 0.010) and at final 6-month analysis (2-sided, alpha = 0.046). Treatment 
difference will be assessed by odds ratios and CIs. For the primary efficacy analysis, the 
randomization strata from IVRS will be used. 
Patients with missing HbA1c data at 6 months will be regarded as not having reached HbA1c 
target. In order to examine the consistency of this analysis, the individual components of HbA1c 
target attainment and absence of any documented symptomatic (BG ≤70 mg/dL) or severe 
hypoglycemia will also be evaluated. Each individual component (HbA1c target attainment at 
6 month, or absence of any documented symptomatic [BG ≤70 mg/dL] or severe hypoglycemia), 
will be compared between treatment groups, respectively, using same logistic regression model as 
the primary efficacy analysis. 
Sensitivity analyses 
The sensitivity analyses of primary efficacy endpoint will be performed at time of 6-month 
database lock. 
• 
On-treatment sensitivity analysis. 
A sensitivity analysis for the primary efficacy endpoint will be performed on the 6-month 
on-treatment period, as defined in Section 2.1.3. 
• 
Multivariate analysis. 
As a sensitivity analysis, a multivariate analysis will be performed, adding the following 
baseline covariates in the model: BMI, duration of diabetes, baseline PAM score, 
hypoglycemic history and age. a backward selection procedure at 0.10 level will be used 
get the final model with these exploratory factors. Treatment effect will be re-evaluated 
based on the final model.  
Country (USA/Canada) and US region effect systematic group difference will be explored.  
• 
Sensitivity analysis of primary efficacy endpoint with randomization strata from 
e-CRF. 
The information collected in the e-CRF on SU use, GLP-1 RA use and comorbidity at 
baseline slightly differs from the definition of randomization stratification factors as per 
IVRS, as detailed below in Table 4. 
Table 4 - Stratification factors discrepancies 
 
SU use 
GLP-1 RA use 
Comorbidity (used for HEDIS HbA1c target 
definition) 
IVRS 
"Used previously"  
(anytime in patient history) 
"Used previously"  
(anytime in patient history) 
Did the patient exhibit comorbid conditions as outlined 
per the IVRS worksheets? Refer to Protocol (1) 
Appendix G (anytime in patient history) 
e-CRF 
Currently being treated  
(at study entry) 
Within past 6 months 
Within past 12 months 
IVRS = interactive voice response system; e-CRF = electronic case report form; GLP-1 = glucagon like peptide-1; HEDIS = healthcare 
effectiveness data and information set; RA = receptor agonist; HbA1c = glycosylated hemoglobin. 
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To assess the impact of these differences between IVRS randomization strata and the 
strata which can be derived based on e-CRF data, two sensitivity analyses will be 
performed. 
1. SU use (y/n), GLP-1 RA use (y/n) as per e-CRF and the HEDIS target from IVRS will
be used in the logistic regression model.
2. SU use (y/n), GLP-1 RA use (y/n) from IVRS included in the logistic regression model
and HEDIS target strata will be dropped from the logistic model.
•
Sensitivity analysis of primary efficacy endpoint with MAR multiple imputation.
As a sensitivity analysis to assess the impact of missing data, missing HbA1c data and
documented (BG ≤70 mg/dL) or severe hypoglycemia will be handled using the multiple
imputation method.
Months 6 and 12 data will be imputed separately. For 6-months data, randomization strata,
and treatment will be included in the imputation model. For 12-month data, 6-month data,
randomization strata, and treatment will be included in the imputation model.
Documented hypoglycemia (yes/no/missing) and HbA1c values by visit will be presented
by for each treatment group, using descriptive statistics.
For documented hypoglycemia, if a patient drops out from the study prior to 6 months and
no documented hypoglycemia is entered into the CRF during the first 6-month treatment
period, the patient status with regard to documented hypoglycemia (presence or absence of
hypoglycemia) will be considered as missing. Similarly, if a patient drops out from the
study prior to 12 months and no documented hypoglycemia is entered during the
12-month treatment period, the patient’s documented hypoglycemia status will be
considered missing. If a patient has a documented hypoglycemia event within the time
frame, then this subject will be considered as a subject with documented hypoglycemia, no
matter it is a completer or early withdrawal.
Missing data will be imputed 100 times to generate 100 complete data sets with the MI 
with Markov Chain Monte Carlo (MCMC) method in SAS procedure in two steps.  
- 
Step 1: Six-month HbA1c value will be imputed using the regression method with 
stratification factors and treatment. For each simulation leading to imputed HbA1c 
values outside of 3.5% to 16%, another value will be redrawn for imputation. 
- 
Step 2: If the 6-month documented (BG ≤70 mg/dL) hypoglycemia status is missing, 
after Step 1, HbA1c is imputed, 6-month documented (BG ≤70 mg/dL) hypoglycemia 
status will be subsequently imputed using a logistic regression method with 6-month 
HbA1c, stratification factors, and treatment.  
For each of the 100 imputed datasets, the composite endpoint will be constructed and 
compared between treatment groups using the same logistic regression model as specified 
above in the primary efficacy endpoint analysis. The estimates from the 100 fitted models 
will be combined to provide an overall estimate with corresponding confidence intervals 
(CI). The difference between treatments and the corresponding CI will be presented. The 
imputed values of HbA1c will also be used in the analysis of HbA1c change as continuous 
variable (secondary efficacy endpoint). 
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x 
Sensitivity analysis of primary efficacy endpoint with tipping point analysis. 
Robustness of the primary analysis results to departure from the MAR assumption will be 
explored in the ITT population using tipping-point analysis based on the pattern mixture 
model approach. 
Estimations will be performed using the same multiple imputation approach as described 
previously. In each treatment arm, a penalty į will be added to the imputed values  
(į = 0 corresponds to the MAR assumption) in the HbA1c multiple imputation step.  
The documented hypoglycemia status will be imputed as described previously following 
the HbA1c imputation with various į.  
To investigate how the conclusions for the composite endpoint depend on the adopted 
values į, the testing will be repeated over a range of plausible values for the pairs  
(į_Toujeo, į_std_care_basal_insulin). The į values range from -1 to 1 by 0.1, in each treatment 
group. Results will then be summarized using graphs. 
The smallest value of į_Toujeo for a value of į_std_care_basal_insulin equal to 0 which will 
statistically reverse the conclusion for the composite primary endpoint will be assessed 
and interpreted from its clinical plausibility.  
x 
Sensitivity analysis excluding patient data from sites at which research activities were 
terminated due to non-compliance.  
A sensitivity analysis using the same method as for the primary efficacy analysis will be 
performed excluding patient data from sites at which research activities were terminated 
due to ongoing non-compliance with the clinical protocol and violations of GCP.  
Sites 
 and site 
 are the two 
concerned. They will be excluded for a sensitivity analysis at 6 months. 
Subgroup Identification based on Differential Effect Search  
If superiority of Toujeo with respect to standard-of-care basal insulin is not shown in the primary 
efficacy analysis, an exploratory analysis will be conducted to identify potential subgroups of 
patients with enhanced treatment effect of Toujeo versus standard of care (Lantus or Levemir) 
basal insulin.  
A procedure based on Subgroup Identification based on Differential Effect Search (6) will be 
employed to identify such subgroups of potential responders. 
The outcome variable used in the SIDES method is the primary endpoint of the study which is the 
proportion of patients with individualized HbA1c target at 6 months, without any documented 
symptomatic or severe hypoglycemia.  
Patient characteristics on which potential subgroups will be defined, include randomization strata 
which are used in the primary efficacy analysis and other variables collected at 
baseline: randomization strata; SU use (y/n), GLP-1 RA use (y/n), baseline HbA1c 
(as continuous), baseline age, race/ethnicity, gender, baseline fasting glucose level, baseline BMI, 
duration of diabetes, diabetic disease history (diabetic retinopathy, diabetic sensory or motor 
HOHFWURQLF




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neuropathy, diabetic autonomic neuropathy, diabetic nephropathy), comorbidity (coronary artery 
bypass graft, percutaneous coronary intervention, ischemic vascular disease, thoracic aortic 
aneurysm, chronic heart failure, prior myocardial infarction, chronic renal failure or end stage of 
renal disease, dementia, blindness, and leg amputation). Since HbA1 target as per HEDIS depends 
on age and comorbidity, both already included, it will not be added to the list of covariates for 
subgroup search. 
The global procedure includes the following steps: 
• 
Balanced allocation procedure: 
The data is split into one training data set on which the subgroup identification procedure 
will be applied, and one or several validation data set. This allocation procedure is based 
on an imbalanced score so that the distribution of patients' treatment and covariates is 
balanced between sets. 
• 
SIDES recursive partitioning algorithm: 
Subgroups are constructed from the training data set by recursively partitioning from 
covariates the data set into two subgroups at each parent group so that the treatment effect 
in one group is maximized compared to the other. 
• 
Validation of identified candidates subgroups: 
One validation set is used to confirm or reject candidate subgroups identified in the 
previous step based on-treatment effect p-value estimated on the validation set. 
Note: 
As specified in the article (6), the identification of candidate subgroups step can be applied 
to the entire data set, and confirmation performed in a subsequent independent study. 
This will be the preferred option: the dataset will not be divided in training and test 
datasets, and only Step 2 (SIDES recursive partitioning algorithm) will be applied. 
The SIDES recursive partitioning algorithm can be described as follows: 
Consider the current parent subgroup. At the beginning, no covariate is used to define 
subgroup and the parent subgroup is the entire training set.  
- 
Among covariates not already used to define parent subgroup, 
- 
For each covariate, consider all possible splits of the covariate into two child 
subgroups (the number of possible splits depends on the type of the covariate), 
- 
If the subgroup with the larger treatment effect of one split has a sample size lower 
than a pre-defined threshold, then the split is excluded, 
- 
For each split among all splits of the previous step, calculate the splitting criterion that 
aims at maximizing the differential effect between the two child subgroups, 
- 
⎥⎦
⎤
⎢⎣
⎡
⎟
⎠
⎞
⎜
⎝
⎛
Ζ
−
Ζ
−
=
2
1
2
2
1
φ
ρ
, 
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- 
Where 
1
Ζ  and 
2
Ζ  denote the Z-statistics for efficacy of the subgroups pair composing 
one split, and φ  represents the standard normal distribution function, 
- 
Apply multiplicity adjustment to splitting criterion, based on modified Sidak 
correction, for covariates with more than two levels. 
- 
Order all splits in terms of adjusted splitting criterion, and select the best M splits, 
where M is a pre-defined value. 
- 
From each pair composing one split, select the subgroup with the larger treatment 
effect. These subgroups are called “promising child subgroups”. 
- 
If a promising child subgroup meets the continuation criterion, that is if 
p
c
ρ
ρ ≤
where 
c
ρ , respectively 
p
ρ , are the p-values of treatment effect for child, respectively 
parent, subgroups; then it is added to the set of parent groups. 
- 
In addition of meeting the continuation criterion, if a promising child subgroup meets 
the selection criterion, it is added to the set of candidate subgroups return at the end of 
the recursive search algorithm. Treatment effect p-values of promising child subgroups 
are adjusted using a standard resampling-based method to have a weak control of type 
I error at a level α. Then, the selection criterion is met if the adjusted p-value in the 
subgroup is significant at a pre-defined level α. 
- 
Call recursively the algorithm on each updated parent subgroups. The algorithm stops 
when a maximum number of L covariates are used to define parents, where L is 
pre-defined, or when no promising child subgroup meets the continuation criterion. 
2.4.4.2 Analyses of secondary efficacy endpoints 
Change in HbA1c 
The change in HbA1c from baseline to 6 months will be analyzed using an analysis covariance 
(ANCOVA) model. The model will include a fixed categorical effect of treatment arm, 
HbA1c target and other randomization strata; SU use (y/n), GLP-1 RA use (y/n), as well as 
baseline BMI (as continuous) and baseline HbA1c (as continuous).  
The change in HbA1c from baseline to 12 months will be analyzed a MMRM approach under the 
MAR framework, using an adequate contrast at Month 12. The model will include fixed 
categorical effects of treatment arm, visit, treatment-by-visit interaction, HbA1c target and other 
randomization strata; SU use (y/n), GLP-1 RA use (y/n), and baseline A1c (as continuous), as 
well as baseline HbA1c-by-visit interaction. Both 6 months and 12 months HbA1c data will be 
included in the MMRM model.  
The analysis of HbA1c is based on patients in the ITT population. For those with missing HbA1c 
value at 6 months, the change in HbA1c will be missing. Therefore, those patients will not be 
included in the analysis.  
As sensitivity analysis, the imputed HbA1c values at 6 months and 12 months described 
in Section 2.4.4.1 will be used to repeat the change in HbA1c from baseline to 6 months and to 
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12 months analysis models. The estimates from the 100 fitted models will be combined to provide 
an overall estimate with corresponding CIs for the treatment differences in change from baseline 
in HbA1c to 6 months and 12 months. 
Change in FPG and body weight 
The change in FPG and body weight from baseline to 6 and 12 months will be analyzed in 
a similar fashion to the change in HbA1c.  
Other binary endpoints 
The proportion of patients with HbA1c <8% and <7% without documented symptomatic 
(BG ≤70 mg/dL) or severe hypoglycemia at 6 months and of patients with HbA1c <8% and 
<7% at 6 months will also be analyzed by the same logistic regression model as for the primary 
efficacy analysis. 
The proportion of patients with individualized HbA1c target attainment without documented 
symptomatic (BG ≤70 mg/dL) or severe hypoglycemia at 12 months, and the proportion of 
patients with individualized HbA1c target attainment without documented symptomatic 
(BG <54 mg/dL) or severe hypoglycemia at 6 and 12 months be analyzed as described for the 
primary endpoint.  
Health resource utilization 
Detailed analysis methods for health resource utilization will be described in a separate analysis 
plan. 
Subgroup factors 
For subpopulations of sufficient size, additional subgroup analyses may also be performed. 
The following treatment effects across different subgroups (baseline or screening factors), where 
appropriate according to subgroup size, will be explored on primary efficacy endpoint: 
• 
Gender (male, female), 
• 
Randomization strata of individualized HbA1c target (<8%/<7%), 
• 
Randomization strata of GLP-1 RA use (y/n),  
• 
Randomization strata of SU use (y/n),  
• 
Baseline HbA1c category (<9%/≥9%), 
• 
Age group (<65, [65–75] and ≥75 years of age), 
• 
Baseline BMI categories (<25, [25-30], [30-40] and ≥40 kg/m²), 
• 
Category of duration of diabetes (<10, ≥10 years). 
For each subgroup, the primary efficacy variable will be analyzed in the ITT population using 
post-baseline HbA1c data available on the 6-month randomized treatment period. A similar 
logistic regression as described for primary analysis will be applied adding the corresponding 
subgroup factor, subgroup factor-by-treatment interaction and subgroup factor-by-visit-by 
treatment interaction (for 12-month analysis only). 
(electronic 
 
 
 
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When the subgroup considered is equal to one of randomization stratum or is part of one of the 
adjustment factor, this randomization stratum/adjustment factor is removed from the model. 
The significance level of the treatment-by-subgroup factor interaction term at Month 6 will also 
be determined for each factor for descriptive purpose. Forest plots will be provided. 
The individual components of the composite endpoint of the primary efficacy variable will also be 
assessed for each subgroup factor. 
2.4.4.3 Multiplicity issues 
All secondary endpoints will be exploratory and descriptive and therefore no adjustments for 
multiplicity are specified. 
2.4.5 Analyses of safety endpoints 
The summary of safety and tolerance results will be presented by treatment group. 
All safety analyses will be performed on the safety population using the following common rules: 
• 
The baseline value is defined as the last available value prior to the first injection of IMP, 
• 
There are no safety endpoints which are adjudicated. 
The baseline values for all safety analyses are defined as the last available value prior to the 
first dose of randomized treatment. Given the short half-life for duration of action of insulin, the 
TEAE reporting period is up to one day after last administration of IMP. 
The analysis of the safety variables is essentially descriptive and no systematic testing is planned.  
In addition, for hypoglycemia events, relative risks and odd-ratios with their associated 95% CI 
will be provided. 
2.4.5.1 Analyses of hypoglycemia 
All safety analyses of hypoglycemia events will be performed by actual treatment arm in the 
safety population, using events occurring during TEAE period. 
• 
At time of 6-month database lock during: 
- 
The 6-month on-treatment period.  
• 
At time of 12-month database lock during: 
- 
The 12-month on-treatment period but also,  
- 
The 6-month on-treatment period,  
- 
The 6 to 12 month on-treatment period. 
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The number and proportion of patients experiencing at least one hypoglycemia event and the 
number and rate (per patient-year of exposure) of hypoglycemic events will be presented by 
treatment arm and type of hypoglycemia event (Appendix A) according to time of occurrence:  
• 
Nocturnal (defined by clock time:00:00 AM-5:59 AM),  
• 
Daytime (defined by clock time: 6:00 AM-23:59),  
• 
And at any time of the day.  
during each on-treatment period (as defined above).  
Any hypoglycemia and un-classified ones (if any) will also be presented by treatment arm. 
The incidence of hypoglycemia will be analyzed using logistic regression, adjusting for 
randomization strata: HbA1c target, SU use (y/n) and GLP-1 RA use (y/n), as well as baseline 
HbA1c (as continuous). 
The rate per patient-year of hypoglycemic events will be analyzed using an over-dispersed 
Poisson regression model, adjusting for randomization strata. The model will include the 
logarithm of the duration of the considered on-treatment period (in years) as an offset variable and 
a log-link function. 
Cumulative mean number of severe and/or symptomatic documented (≤70 mg/dL and <54 mg/dL) 
hypoglycemia will be summarized over time using Nelson-Aalen estimates and plotted. 
Subgroup analyses 
The proportion of patients with at least one: 
• 
Severe and/or symptomatic documented (≤3.9 mmol/L [≤70 md/dL]) hypoglycemia, 
• 
Severe and/or symptomatic documented (<3.0 mmol/L [<54 md/dL]) hypoglycemia. 
during respectively the 6-month on-treatment period and the 12-month on-treatment period (any 
time of the day), will also be presented by the following subgroups: 
• 
Gender (male, female), 
• 
Randomization strata of individualized HbA1c target (<8%/<7%), 
• 
Randomization strata of GLP-1 use (yes/no), 
• 
Randomization strata of SU use (yes/no), 
• 
Baseline HbA1c category (<9%/≥9%), 
• 
Age group (<65, [65-75] and ≥75 years of age), 
• 
Baseline BMI categories (<25, [25-30], [30-40] and ≥40 kg/m²), 
• 
Category of duration of diabetes (<10, ≥10 years). 
and analyzed using a similar logistic regression model approach as presented previously, but 
adding the corresponding subgroup factor and treatment arm-by-subgroup interaction factor. Odds 
ratio estimates and 95% CI will be provided in each subgroup category. 
The interaction treatment arm-by-subgroup p-value will be provided for descriptive propose. 
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When the subgroup considered is equal to one of the randomization strata or is part of one of the 
adjustment factor, this randomization stratum/adjustment factor is removed from the model. 
If the logistic regression model does not converge (eg, due to sparse data) some of the 
randomization strata may be removed.  
Forest plots will be provided. 
Relative Risks 
For each hypoglycemic category of event (Appendix A) except relative and probable, the 
estimated proportions along with their corresponding 95% CI, as well as the relative risk of 
Toujeo arm versus SOC basal insulin arm and their corresponding 95% CI, will be estimated by 
the mean of a log-binomial regression model, using a log-link function and a binomial response 
distribution, and adjusting for: 
• 
Randomization strata HbA1c target, 
• 
Randomization strata of SU use (y/n),  
• 
Randomization strata of GLP-1 RA (y/n), 
• 
Baseline HbA1c (as continuous).  
Risk difference 
For each hypoglycemic category of event (Appendix A) except relative and probable, the adjusted 
risk differences of Toujeo arm versus SOC basal insulin arm and their corresponding 95% CI, will 
be estimated by the mean of a log binomial regression model, with an identity link function and 
a binomial response distribution, and adjusting for: 
• 
Randomization strata HbA1c target, 
• 
Randomization strata of SU use (y/n),  
• 
Randomization strata of GLP-1 RA (y/n), 
• 
Baseline HbA1c (as continuous).  
Scatter plots 
Scatter plots of Relative Risk versus Risk Difference presenting each type of analyzed 
hypoglycemia for patient experiencing at least one hypoglycemia event. 
• 
During respectively the 6-Month on-treatment period and the 12-Month on-treatment 
period, 
• 
According to time of occurrence (any time of the day, nocturnal [defined by clock 
time: 00:00 AM-5:59 AM]). 
2.4.5.2 Analyses of adverse events 
Generalities 
All safety analyses of hypoglycemia events will be performed by actual treatment arm in the 
safety population. The primary focus of AE reporting will be on TEAEs. Pre-treatment and 
post-treatment AEs will be described separately.  
(electronic 
 
 
 
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The primary focus of AE reporting will be: 
• 
At time of 6 month database lock: 6 month on-treatment AE, occurring during the 6 month 
on-treatment period. 
• 
At time of 12 month database lock: on treatment-emergent adverse events, occurring 
during the 12 month on-treatment period. 
Pre-treatment and post-treatment AEs will be described separately.  
Post-treatment AE will only be displayed at time of 12-month database lock but also at time of 
6 month database lock for patients who permanently discontinued treatment during the 6 month 
randomized period. 
If an AE date/time of onset (occurrence, worsening, or becoming serious) is incomplete, an 
imputation algorithm will be used to classify the AE as pre-treatment, treatment-emergent, or 
post-treatment. The algorithm for imputing date/time of onset will be conservative and will 
classify an AE as treatment-emergent unless there is definitive information to determine it is 
pre-treatment or post-treatment. Details on classification of AEs with missing or partial onset 
dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for each 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. 
Sorting within tables ensures 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 
treatment-emergent adverse events presented by SOC and PT sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs will define the presentation order for all 
other tables unless otherwise specified. Sorting will be based on results for the IMP.  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• 
Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any, 
- 
Treatment-emergent adverse event, 
- 
Serious treatment-emergent adverse event, 
- 
Treatment-emergent adverse event leading to death, 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation,  
- 
Treatment-emergent adverse event related to IMP, 
- 
Treatment-emergent adverse event related to anti-diabetic NIMP, 
- 
Treatment-emergent adverse event related to pen device. 
(electronic 
 
 
 
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•
All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the
SOC internationally agreed order. The other levels (HLGT, HLT, PT) will be presented in
alphabetical order.
•
Number (%) of patients experiencing TEAE(s) presented by PT, sorted by decreasing
incidence of PT in the Toujeo arm.
•
All treatment-emergent adverse events by primary SOC and PT, showing the number (%)
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally
agreed SOC order and by decreasing incidence of PTs in the Toujeo arm within each SOC.
This sorting order will be applied to all other tables, unless otherwise specified.
•
All common TEAEs (HLT incidence ≥2% in any treatment arm) by primary SOC, HLT
and PT, showing the number (%) of patients with at least 1 common TEAE, sorted by the
internationally agreed SOC order. The other levels (HLT, PT) will be presented in
alphabetical order.
•
All treatment-emergent adverse events regardless of relationship and related to IMP by
primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least
1 treatment-emergent adverse event, sorted by the internationally agreed SOC order. The
other levels (HLGT, HLT, PT) will be presented in alphabetical order.
•
All treatment-emergent adverse events regardless of relationship and related to
anti-diabetic NIMP by primary SOC, HLGT, HLT and PT, showing the number (%) of
patients with at least 1 treatment-emergent adverse event, sorted by the internationally
agreed SOC order. The other levels (HLGT, HLT, PT) will be presented in alphabetical
order.
•
All treatment-emergent adverse events regardless of relationship and related to pen device
by primary SOC, HLGT, HLT and PT, showing the number (%) of patients with at least
1 treatment-emergent adverse event, sorted by the internationally agreed SOC order. The
other levels (HLGT, HLT, PT) will be presented in alphabetical order.
•
All treatment-emergent adverse events by maximal severity, presented by primary SOC
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above,
•
Number (%) of patients experiencing treatment-emergent adverse event(s) presented by
primary and secondary SOC, HLGT, HLT, and PT sorted by the internationally agreed
SOC order. The other levels (HLGT, HLT, PT) will be presented in alphabetical order.
Analysis of all treatment-emergent serious adverse event(s) 
•
All treatment-emergent SAEs by primary SOC, HLGT, HLT, and PT, showing the number
(%) of patients with at least 1 serious treatment-emergent adverse event, sorted by the
internationally agreed SOC order. The other levels (HLGT, HLT, PT) will be presented in
alphabetical order.
•
All treatment-emergent SAEs regardless of relationship and related to IMP, by primary
SOC, HLGT, HLT, and PT, showing the number (%) of patients with at least
1 treatment-emergent SAE, sorted by the internationally agreed SOC order. The other
levels (HLGT, HLT, PT) will be presented in alphabetical order.
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Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• 
All treatment-emergent adverse events leading to treatment discontinuation, by primary 
SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order. 
Injection site reaction and hypersensitivity reaction 
• 
Number (%) of patients with events related to injection site reactions and hypersensitivity 
reactions will be provided separately. 
Adverse event of special interest 
Symptomatic overdose 
• 
A listing of patients with symptomatic overdose with IMP/NIMP will be provided. 
ALT increase 
• 
A listing of patients with increase of ALT (collected as an AE) will be provided. 
Pregnancy 
• 
A listing of patients with pregnancy (including event occurring to a partner) will be 
provided. 
Analysis of pre-treatment and post-treatment adverse events  
• 
All pre-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 pre-treatment AE, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC.  
• 
All pre-treatment SAEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment SAE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 
• 
All pre-treatment AEs leading to study discontinuation by primary SOC and PT, showing 
the number (%) of patients, sorted by the internationally agreed SOC order and decreasing 
incidence of PTs within each SOC. 
• 
All post-treatment AEs by primary SOC and PT, showing the number (%) of patients with 
at least 1 post-treatment AE, sorted by the internationally agreed SOC order and 
decreasing incidence of PTs within each SOC. 
• 
All post-treatment SAEs by primary SOC and PT, showing the number (%) of patients 
with at least 1 post-treatment serious AE, sorted by the internationally agreed SOC order 
and decreasing incidence of PTs within each SOC. 
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2.4.5.3 Deaths 
The following deaths summaries will be generated on the safety population: 
• 
Number (%) of patients who died by study period (pre-treatment, on-study, on-treatment, 
post-study) and reasons for death summarized by treatment arm, 
• 
Death in non-randomized patients or randomized and not treated patients, 
• 
TEAE leading to death (death as an outcome on the AE 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 presented in alphabetic order within SOC. 
• 
All pre-treatment AEs leading to death by primary SOC and PT, showing the number (%) 
of patients, sorted by the internationally agreed SOC order and decreasing incidence of 
PTs within each SOC (if more than 5 patient with the event), 
• 
All post -treatment AEs leading to death by primary SOC and PT, showing the number 
(%) of patients, sorted by the internationally agreed SOC order and decreasing incidence 
of PTs within each SOC (if more than 5 patient with the event). 
A listing of all deaths sorted by treatment arm will be performed. 
2.4.5.4 Analyses of laboratory safety variables  
Not applicable. 
2.4.5.5 Analyses of vital sign variables 
The summary statistics (including number, mean, median, SD, minimum and maximum) of blood 
pressure, heart rate and body weight (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 arm. 
2.4.5.6 Analyses of electrocardiogram variables 
Not applicable. 
2.4.5.7 Analyses of Patient-Support Program (PSP) 
Participation to a PSP will be described by visit and overall per randomized treatment arm on the 
safety population.  
Furthermore, the number and percentage of patients having or not initiated a Toujeo PSP at any 
time during respectively the 6-month randomized period at time of 6 month database lock and the 
12-month randomized period at time of 12 month database lock will be described in the Toujeo 
randomized treatment arm, according to demographic and baseline characteristics. 
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2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables 
Not applicable. 
2.4.7 Analyses of patient reported outcome variables 
The patient report outcomes (PRO) analyses will be performed on the ITT population.  
Self-reported treatment satisfaction  
DTSQs and DTSQc scores at 6 and 12 months will be compared between treatment groups using 
an ANCOVA approach as described for the continuous efficacy variables. The ANCOVA model 
with satisfaction score as the dependent variable includes HbA1c target and other stratification 
factors used at randomization: SU use (y/n), GLP-1 RA use (y/n) and baseline HbA1c 
(as continuous) in the model. 
The consistency between results of DTSQs change from baseline to 12 months and DTSQc scores 
at 12 months will be assessed.  
Cumulative distribution function of score changes from baseline at 6 and 12-months will be 
plotted by treatment arm for each of the 3 DTSQs scores. Cumulative distribution function of 
12-month DTSQc scores will be plotted by treatment arm.  
Hypoglycemia Patient Questionnaire 
Items of the Hypoglycemia Patient Questionnaire will be summarized by descriptive statistics. 
a graphical presentation will also be provided. 
The proportion of patients reporting one or more episodes of either moderate or severe 
hypoglycemia will be compared between treatment groups using the same logistic regression 
model as for GES detailed in following paragraph. 
Global Effectiveness Scale 
At each study endpoint, the proportion of patients and providers who reported “complete control 
of diabetes” or “marked improvement of diabetes” at 6 and 12 months will be analyzed using 
a logistic regression same as the primary efficacy analysis. The dependent variable is the 
“complete control/marked improvement” (y/n). The logistic model includes HbA1c target and 
other stratification factors used at randomization: SU use (y/n), GLP-1 RA use (y/n) and baseline 
HbA1c (as continuous) in the model. 
Additionally, at each time point (6 months and 12 months), all response choices for both patients 
and provider will be summarized by descriptive statistics. 
2.4.8 Analyses of Health economic endpoints 
Detailed analysis methods for health resource utilization will be described in a separate analysis 
plan. 
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2.5 
DATA HANDLING CONVENTIONS 
2.5.1 General conventions 
Reference day  
The reference day for the calculation of extent of exposure, time to onset and relative days is the 
day of the first IMP administration, denoted as Day 1. 
Demographic formulas 
Age (years) will be calculated as follows = Integer ([Date of informed consent – Date of 
birth + 1]/365.25) 
BMI (kg/m²) will be calculated as follows = (Weight in kg)/(Height in meters²)  
In case of partial dates, (Section 2.5.3).  
Disease history 
Diabetes duration of (years) will be calculated as follows = (Date of informed consent – Date of 
diagnosis of diabetes + 1)/365.25. 
Age at diagnosis of diabetes (years) will be calculated as follows = (Date [MM-YYYY] of 
diagnosis of diabetes – date [MM-YYYY] of birth + 1)/365.25.  
In case of unavailable date of birth, only the year of the date of diabetes diagnosis and the year of 
the date of birth (retrieve using the age recorded at screening) will be considered in the age at 
diagnosis of diabetes calculation. 
Duration of previous non-insulin anti-hyperglycemic treatment (years) will be calculated as 
follows = (Date of informed consent – date of first dose of previous non-insulin 
anti-hyperglycemic treatment + 1)/365.25 
IMP exposure 
IIMP (U/Kg) will be determined as: 
IMP dose (U)/Body weight (kg) obtained at a given visit. 
Laboratory efficacy data conversion 
HbA1c conversion: 
IFCC in mmol/mol = (10.93× NGSP in %) - 23.5. 
FPG and SMPG conversion: 
From mg/dL to mmol/L: x 0.0555, 
From mmol/L to mg/dL: x 18.0148. 
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Renal function formulas 
Conversion for serum creatinine:  
From mg/dL to µmol/L: x 88.402. 
Conversion for total bilirubin:  
From mg/dL to µmol/L: x 17.104. 
Creatinine clearance value will be derived using the equation of Cockroft and Gault, using weight 
assessed at the same visit: 
For Male: 
For Female: result above multiplied by 0.85. 
Hepatic function formulas 
Conversion for total bilirubin: 
From mg/dL to µmol/L: 17.10. 
Patient reported outcomes 
Minimal clinically important difference: 
•
Standard MCID threshold will be calculated as half- SD at baseline.
•
Distribution-based MCID threshold will be calculated as 
r
SDbaseline
−
× 1
 where r is the
Cronbach’s α reliability coefficient at baseline.
Effect sizes (ES) 
•
Within and between effect sizes (ES) interpretation is the following:
- 
An ES <0.2 is considered negligible,
- 
0.2 ≤ES <0.5 is considered small,
- 
0.5 ≤ES <0.8 is considered moderate,
- 
ES ≥0.8 is considered important.
•
Within ES, calculated at treatment arm level, indicates if a change from baseline to the
Month 6/Month 12 is clinically meaningful:
SD
baseline
Pooled
t
timepo
at
baseline
from
change
mean
LS
int
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• 
Between ES, calculated when comparing treatment arm, indicates if the mean changes 
from baseline to Month 6/Month 12 are clinically meaningful between treatment arm,  
SD
baseline
Pooled
t
timepo
at
groups
between
means
LS
in
Difference
int
 
• 
Both LS means will be determined using the MMRM/ANCOVA whereas pooled baseline 
SD will be determine from descriptive statistic at baseline.  
al_insulin
f_care_bas
standard_o
Toujeo
al_insulin
f_care_bas
standard_o
al_insulin
f_care_bas
standard_o
N
N
+
×
+
×
SD
N
SD
N
Toujeo
Toujeo
 
Table 5 - Unexpected Scoring 
Scoring issues 
DTSQs 
DTSQc 
In between score 
If patients answer in between choices, score should be coded as mean of both 
scores  
(ie, if between 2 and 3 coded 2.5) 
Item answered twice using 2 consecutive 
scores 
Midpoint score should be used  
(ie, if 1 and 2 are answered should be coded 1.5) 
Item answered twice but using non-
consecutive scores 
Score is set to missing 
Item is circled but accompanied by word 
Only score should be taken into account 
If respondent as circle word of the extremes of 
the scale instead of value 
Score should be the nearest value 
(ie, 0 or 6) 
Score should be the nearest value 
 (ie, -3 or 3) 
ABBREVIATION: DTSQs = diabetes treatment satisfaction questionnaire status version. 
Table 6 - PRO missing data handling 
PRO scales 
Score 
Number of items 
included in score 
derivation 
Minimum number of 
items required for 
score calculation 
DTSQs 
Total treatment satisfaction score 
6 
4 
 
Perceived frequency of hyperglycemia score 
1 
1 
 
Perceived frequency of hypoglycemia score 
1 
1 
DTSQc 
Total treatment satisfaction score 
6 
4 
 
Perceived frequency of hyperglycemia score 
1 
1 
 
Perceived frequency of hypoglycemia score 
1 
1 
ABBREVIATION: DTSQs = diabetes treatment satisfaction questionnaire status version; DTSQc = diabetes treatment satisfaction questionnaire 
change version. 
DTSQc and DTSQs total treatment satisfaction score 
If no more than 2 out of the 6 questions comprising the treatment satisfaction score are missing, 
the treatment satisfaction score is imputed by calculating the average of the scores from the 
answered questions, dividing this sum by the number of answered questions and multiplying the 
average by six.  
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2.5.2 Data handling conventions for secondary efficacy variables 
Fasting condition 
FPG measurement not collecting in fasting condition will not be used in the analyses. 
Invalid laboratory data 
HbA1c or FPG measurements flagged as invalid by the laboratory will not be used in the 
analyses.  
Treatment persistence/switch 
A switch is defined by: 
• 
A switch from Toujeo IMP to any commercial “standard of care” basal insulin or, 
• 
A switch from “Lantus or Levemir” IMP basal insulin to commercial Toujeo.  
Change in “standard of care” basal insulin to another basal insulin not being considered as 
a “switch”. 
Remain on assigned therapy is defined by, 
• 
Neither permanently withdraw,  
• 
Nor switch: 
- 
From IMP Toujeo to Lantus or Levemir insulin,  
- 
Or from “standard of care” basal insulin to commercial Toujeo, 
• 
Assigned therapy refers to the treatment allocated by IRT: Toujeo or Lantus/Levemir, 
• 
Commercial Toujeo not being allowed in both treatment arms. 
Persistence is defined by, 
• 
Remained on assigned therapy. 
HbA1c target and severe and or symptomatic hypoglycemia 
HbA1c target missing data handling, 
• 
Patients with missing HbA1c data at respectively Month 6 and Month 12 will be regarded 
as not having reached the HbA1c target (ie, as failure) at each given time-point. 
Symptomatic hypoglycemia target missing data handling 
In case of at least one symptomatic event with glycemic value missing it will be considered that 
the patients experiences at least: 
• 
One document symptomatic hypoglycemia (BG ≤70 mg/dL [≤3.9 mmol/L]) and, 
• 
One document symptomatic hypoglycemia (BG <54 mg/dL [<3.0 mmol/L]).  
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In case of at least one symptomatic event with timing missing it will be considered that the 
patients experiences at least: 
• 
One symptomatic hypoglycemia event occurring at any time of the day and, 
• 
One nocturnal symptomatic hypoglycemia event. 
Composite endpoints missing data handling 
• 
For each cases presented above regarding missing HbA1c values the patient will be 
considered as failure for each composite endpoint of the corresponding randomized period.  
• 
For each case presented above regarding missing hypoglycemia event information the 
patient will be regarded as failure for each related composite endpoint. 
• 
In case of premature end of study during the 6 month randomized period the patient will 
be considered as failure for each composite endpoint relative to the 6-month and the 
12 month period. 
• 
In case of premature end of study during the 12 month randomized period the patient will 
be considered as failure for each composite endpoint relative to the 12-month period. 
Change in HbA1c category 
Patients with missing: 
• 
Baseline HbA1c will be regarded as not having reached the HbA1c target at Month 6 and 
Month 12. 
• 
HbA1c data at respectively Month 6 and Month 12 will be regarded as not having reached 
the HbA1c target at each given time-point. 
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. Number of patients/events with imputed missing data should be identified and 
presented in table (if applicable). 
Handling missing first IMP date and reference start date 
For patient randomized and exposed with missing IMP start date the reference day will be set to 
randomization date. 
Handling of missing weight in the calculation of basal insulin dose in (u/kg) 
For calculation of basal insulin dose expressed in U/kg if the body weight measurement is missing 
at a given visit, the last available measurement from previous visit will be used. 
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Handling partial date of birth 
For calculation age, missing birth day is assumed as the 15 of the month. If day and month are 
missing, missing birth month and day are assumed as the 15 of June. If year is missing, age could 
not be calculated. If calculated age is less than 18 (but not less from 17) and corresponding 
exclusion criteria (E02) not met, 18 will be assumed. 
Handling of partial date of diagnosis of Type 2 diabetes 
Partial date of diagnosis of Type 2 diabetes will be imputed to calculate the duration of diabetes. 
In order to calculate: 
• 
Duration of diabetes (year), 
• 
Age at diagnosis of diabetes (year). 
If only day is missing, only month and year will be used.  
If month is missing, only year will be used in calculation. 
Handling of partial date of start date of treatment with OADs 
Partial start date of treatment with OADs will be imputed to calculate the OAD duration. 
• 
If the day is missing and month is present the 15 of the month will be used. 
• 
If year is present and equal to year of date of diagnosis of Type 2 diabetes and day and 
month are missing then the date of diagnosis of Type 2 diabetes will be used. 
• 
If year is present (and not equal to year of date of diagnosis of Type 2 diabetes) and day 
and month are missing then the 1st July will be used. 
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 CRF page. If this date is missing, the 
exposure duration should be left as missing (ie, in extent of exposure duration).  
The last dose intake should be clearly identified in the CRF 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. 
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Handling of adverse events/hypoglycemia with missing or partial date/time of onset 
Missing or partial AE/hypoglycemia event onset dates and times will be imputed so that if the 
partial AE/hypoglycemia event onset date/time information does not indicate that the event started 
prior to treatment or after the TEAE/12 month on-treatment period, the event will be classified as 
treatment-emergent.  
Furthermore, if the hypoglycemia event onset dates and times does not indicate that the event 
belongs:  
• 
At time of 6-month database lock to either the 3 month on-treatment period or to the 3 to 
6 month on-treatment period the hypoglycemia will be classified in both periods, 
• 
At time of 12-month database lock to either the 6-month on-treatment period or to the 6 to 
12 month on-treatment period the hypoglycemia will be classified in both periods. 
These data imputations are for categorization purpose only and will not be used in listings.  
No imputation is planned for date/time of AE resolution. 
Handling of adverse events/hypoglycemia when date and time of first/last investigational 
medicinal product administration is missing 
When the date and time of the first IMP administration is missing, all AEs: hypoglycemia that 
occurred on or after the day of randomization should be considered as treatment-emergent.  
The last dose intake should be clearly identified in the CRF and should not be approximated by 
the last returned package date. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the AE considered as such in the frequency tables of possibly related AEs, but no 
imputation should be done at the data level. 
Handling of missing severity of adverse events 
If a severity is missing, estimate the missing severity/by the maximal severity/observed in the 
treatment arms. 
Handling hypoglycemia with missing or partial time 
No imputation for missing or partial time of hypoglycemia will be done.  
However:  
• 
If the minutes are missing and the hours comprised between 00 and 05, the event will be 
considered as nocturnal, 
• 
If hours are missing and the patient was awaken during nocturnal, the event will be 
considered as nocturnal (defined by clock time). 
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Handling of hypoglycemia event classification when some classification items are missing 
In case of information missing on the item “Assistance required”, “Associated with clinical 
symptoms”, or “Plasma glucose”, the following algorithm was applied: 
Figure 2 - Flow chart for hypoglycemia event classification in case of missing items 
 
As a conclusion, for cases where hypoglycemia could not be fully classified, as described above, 
two categories will therefore be created: 
• 
Hypoglycemia classified as Non-classified Hypoglycemia (severity unknown)  
if the variable “assistance required” is equal to “missing”. 
• 
Hypoglycemia classified as Non-classified Hypoglycemia (non-severe)  
if the variable “assistance required” is equal to “No”. 
Handling of PRO missing data 
• 
Handling of missing data and multiple answers on DTSQ available in user 
guidelines: refer to Table 6.  
• 
For Hypoglycemia Patient Questionnaire, if items 4 and 5 missing, patients will be 
considered as non-responders. 
• 
For GES, if data are missing, patients will also be considered as non-responders.  
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2.5.4 Windows for time points 
The following process will be applied for Month 6, Month 12, premature EOT visits and 
unscheduled visits re-allocation. Re-allocated visits will be used in statistical analyses for the 
following endpoints: HbA1c, FPG, Body weight, dose and PROs (descriptive statistics, graphs, 
and statistical models).  
Assessments will be re-allocated to the closest visit using the time windows given in Table 7. 
Table 7 - Re-allocation time windows definition 
Re-allocated 
scheduled visit 
Targeted study 
day/month 
Re-allocation time windows in study days/month 
as 30-day period 
Visit 3 (Month 6) 
180 (Month 6) 
(120-240)/end of Month 4 to end of Month 8 
Visit 4 (Month 12) 
360 (Month 12) 
(300-420)/end of Month 10 to end of Month 14 
Study days are calculated from the randomization day, being Day 1. 
If more than one visits/measurements fall into a visit window, the one closest to the scheduled 
visit will be used. 
For efficacy labs, only central lab data will be used. 
2.5.5 Unscheduled visits 
The determination of baselines and values at Month 6 and Month 12 for efficacy variables 
(measurements from the central laboratory only) is based on all measurements from both 
scheduled and unscheduled visits. 
The determination of the last on-treatment value for safety parameters is also based on all 
assessments from both scheduled and unscheduled visits. 
Unscheduled visit measurements of laboratory data, vital signs, will not be included in the by-visit 
summaries. 
2.5.6 Pooling of centers for statistical analyses 
Centers will be pooled to geographic US region and explored as a sensitivity analysis. 
Note: this sensitivity analysis will concern US region only. It is not applicable to Canada due to 
low number of patients to be enrolled there, in comparison with US. 
2.5.7 Statistical technical issues 
Not applicable. 
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3 
INTERIM ANALYSIS 
One IA of primary composite endpoint is planned for the purpose of overwhelming efficacy to 
provide an early evaluation of Toujeo effectiveness, when approximately 1800 patients 
(54.2% information fraction of targeted sample size) have completed their 6-month (Day 180) 
visit. 
Using a group sequential approach with a Gamma (-3) alpha-spending function and an overall 
two-sided alpha-level of 0.05, the two-sided nominal significance level is 0.010 at IA, and 0.046 
at final analysis. 
If the targeted sample size (1800) cannot be reached, it could be considered to include a lower 
number of patients, however not below 1700. In this case, the nominal significance level to be 
spent at interim and at final 6-month analyses would be recalculated accordingly before the 
database lock for IA. 
Overwhelming efficacy will be shown at IA if the efficacy boundary is met, ie, if the two-sided 
p-value for comparison of primary composite endpoint incidence is below 0.010, corresponding to 
an estimated difference of 5.8% in favor of Toujeo between percentages of patients reaching the 
primary composite endpoint.  
The corresponding conditional power to show overwhelming efficacy at IA under the alternative 
hypothesis is of 45%. 
For the IA, analyses will be performed by an independent statistician, external to the Sponsor. 
Results will be delivered directly to an independent Data Monitoring Committee (DMC) for 
review. a DMC meeting will be organized for this IA.  
• 
Scenario 1: If overwhelming efficacy is shown: 
- 
The recruitment would be stopped (total sample size at that time estimated to be 
between 2600 and 3000 patients), 
- 
The patients already enrolled would continue the study as planned. 
- 
The results will be disclosed to the Sponsor and a communication plan to protect 
clinical data integrity is detailed in the DMC charter. 
• 
Scenario 2: If overwhelming efficacy is not shown (probability of 55% under the 
alternative hypothesis): 
- 
The study would continue as planned, up to the final 6-month and 12-month analyses. 
- 
The Sponsor would not have access to any unblinded data. 
- 
No results would be communicated. 
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4 
DATABASE LOCK 
The database is planned to be locked at approximately 2 months after last patient last visit.  
Prior to the final analysis of the 12 months, database will be locked: 
• 
For the need of IA, when the 1800 patients have completed their 6-month visit, and their 
data have been cleaned and reconciled,  
• 
At 6 months, when 6-month efficacy and safety data are available for all patients.  
For the 6-months analysis, efficacy and safety data will be summarized and analyzed. Those 
CRF forms, which are not related to any specific study visits, will not be locked until the end of 
12 months. 
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5 
SOFTWARE DOCUMENTATION 
All summaries and statistical analyses will be generated using R and SAS Version 9.3 or higher. 
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6 
REFERENCES 
1. Toujeo Real World US Insulin Naïve Trial. CLINICAL TRIAL PROTOCOL. A randomized,
open-label, parallel group real world pragmatic trial to assess the clinical and health outcomes
of Toujeo compared to commercially available basal insulins for initiation of therapy in
insulin naïve patients with uncontrolled type 2 diabetes mellitus.
2. American Diabetes Association Workgroup on Hypoglycemia. Defining and reporting
hypoglycemia in diabetes. Diabetes Care. 2005;28:1245-9.
3. Bradley C. The diabetes treatment satisfaction questionnaire: (DTSQ). In: Bradley C, ed.
Handbook of Psychology and Diabetes: a guide to psychological measurement in diabetes
research and practice. Chur, Switzerland: Harwood Academic Publishers. 1994;111-32.
4. Bradley C, Plowright R, Stewart J, Valentine J, Witthaus E. The Diabetes Treatment
Satisfaction Questionnaire change version (DTSQc) evaluated in insulin glargine trials shows
greater responsiveness to improvements than the original DTSQ. Health Qual Life Outcomes.
2007;5:57.
5. Karve S, Cleves MA, Helm M, Hudson TJ, West DS, Martin BC. Good and poor
adherence: optimal cut-point for adherence measures using administrative claims data. Curr
Med Res Opin. 2009;25(9):2303-10.
6. Lipkovich I, Dmitrienko A, Denne J, Enas G. Subgroup identification based on differential
effect search-a recursive partitioning method for establishing response to treatment in patient
subpopulations. Stat Med. 2011;30(21):2601-21.
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